The sensitivity and specificity of touch preparation for rapid diagnosis of invasive fungal sinusitis: A pilot study.

PubMed

Schuman, Theodore A; Nguyen, Josephine H; Yelverton, Joshua C; Almenara, Jorge A; Powers, Celeste N

2018-01-01

Invasive fungal sinusitis is a morbid pathology that typically affects immunocompromised patients and may quickly progress to fulminant disease. The purpose of this study was to measure the sensitivity and specificity of touch preparation of nasal debridement specimens as a rapid diagnostic tool for invasive fungal sinusitis. A retrospective chart review was performed of 22 patients undergoing nasal debridement due to suspicion for invasive fungal sinusitis over a 10-year period. Thirteen patients had touch preparation of nasal specimens followed by routine histologic processing; 2 of these patients underwent two and 1 patient had three separate debridements, for a total of 17 touch preparations performed. The sensitivity and specificity of touch preparation were calculated by correlating the initial results with the presence of fungal invasion on final pathologic analysis. The sensitivity of touch preparation was 56% (95% confidence interval [CI]: 0.23 to 0.85), specificity was 100% (95% CI: 0.60 to 1.00), positive predictive value was 100% (95% CI: 0.46 to 1.00), and negative predictive value was 67% (95% CI: 0.35 to 0.89). This procedure may be a useful adjunct in situations requiring rapid diagnosis of invasive fungal sinusitis but should not be used as the sole criterion for determining the need for surgical intervention.

How We Manage Invasive Fungal Disease in Acute Myeloid Leukemia Patients with Glucose 6 Dehydrogenase Deficiency

PubMed Central

Sanna, Marco; Caocci, Giovanni; La Nasa, Giorgio

2017-01-01

Glucose-6-phosphate dehydrogenase (G6PD) represents a common human enzyme defect, particularly prevalent in the Mediterranean, African e Asian area, where malaria was or is still endemic. Recently, we identified G6PD deficiency as a risk factor for developing invasive fungal disease (IFD) and particularly Candida Sepsis in patients undergoing intensive chemotherapy for acute myeloid leukemia (AML), suggesting that there is an urgent need for strategies to properly manage this kind of patients at high risk of invasive mycoses. Here we propose our algorithm for correct identification, prophylaxis, and treatment of IFD in patients with G6PD deficiency undergoing intensive chemotherapy for AML. PMID:28894556

How We Manage Invasive Fungal Disease in Acute Myeloid Leukemia Patients with Glucose 6 Dehydrogenase Deficiency.

PubMed

Sanna, Marco; Caocci, Giovanni; La Nasa, Giorgio

2017-01-01

Glucose-6-phosphate dehydrogenase (G6PD) represents a common human enzyme defect, particularly prevalent in the Mediterranean, African e Asian area, where malaria was or is still endemic. Recently, we identified G6PD deficiency as a risk factor for developing invasive fungal disease (IFD) and particularly Candida Sepsis in patients undergoing intensive chemotherapy for acute myeloid leukemia (AML), suggesting that there is an urgent need for strategies to properly manage this kind of patients at high risk of invasive mycoses. Here we propose our algorithm for correct identification, prophylaxis, and treatment of IFD in patients with G6PD deficiency undergoing intensive chemotherapy for AML.

Complications of hematopoietic stem transplantation: Fungal infections.

PubMed

Omrani, Ali S; Almaghrabi, Reem S

2017-12-01

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of invasive fungal infections, especially during the early neutropenic phase and severe graft-versus-host disease. Mold-active prophylaxis should be limited to the highest risk groups. Empiric antifungal therapy for HSCT with persistent febrile neutropenia is associated with unacceptable response rates, unnecessary antifungal therapy, increased risk of toxicity, and inflated costs. Empiric therapy should not be a substitute for detailed work up to identify the cause of fever in such patients. The improved diagnostic performance of serum biomarkers such as galactomannan and β-D-glucan, as well as polymerase chain reaction assays has allowed the development of diagnostic-driven antifungal therapy strategies for high risk patients. Diagnostic-driven approaches have resulted in reduced unnecessary antifungal exposure, improved diagnosis of invasive fungal disease, and reduced costs without increased risk of mortality. The appropriateness of diagnostic-driven antifungal strategy for individual HSCT centers depends on the availability and turnaround times for diagnostics, multidisciplinary expertise, and the local epidemiology of invasive fungal infections. Echinocandins are the treatment of choice for invasive candidiasis in most HSCT recipients. Fluconazole may be used for the treatment of invasive candidiasis in hemodynamically stable patients with no prior azole exposure. The primary treatment of choice for invasive aspergillosis is voriconazole. Alternatives include isavuconazole and lipid formulations of amphotericin. Currently available evidence does not support routine primary combination antifungal therapy for invasive aspergillosis. However, combination salvage antifungal therapy may be considered in selected patients. Therapeutic drug monitoring is recommended for the majority of HSCT recipients on itraconazole, posaconazole, or voriconazole. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Natural Killer Cells in Antifungal Immunity.

PubMed

Schmidt, Stanislaw; Tramsen, Lars; Lehrnbecher, Thomas

2017-01-01

Invasive fungal infections are still an important cause of morbidity and mortality in immunocompromised patients such as patients suffering from hematological malignancies or patients undergoing hematopoietic stem cell transplantion. In addition, other populations such as human immunodeficiency virus-patients are at higher risk for invasive fungal infection. Despite the availability of new antifungal compounds and better supportive care measures, the fatality rate of invasive fungal infection remained unacceptably high. It is therefore of major interest to improve our understanding of the host-pathogen interaction to develop new therapeutic approaches such as adoptive immunotherapy. As experimental methodologies have improved and we now better understand the complex network of the immune system, the insight in the interaction of the host with the fungus has significantly increased. It has become clear that host resistance to fungal infections is not only associated with strong innate immunity but that adaptive immunity (e.g., T cells) also plays an important role. The antifungal activity of natural killer (NK) cells has been underestimated for a long time. In vitro studies demonstrated that NK cells from murine and human origin are able to attack fungi of different genera and species. NK cells exhibit not only a direct antifungal activity via cytotoxic molecules but also an indirect antifungal activity via cytokines. However, it has been show that fungi exert immunosuppressive effects on NK cells. Whereas clinical data are scarce, animal models have clearly demonstrated that NK cells play an important role in the host response against invasive fungal infections. In this review, we summarize clinical data as well as results from in vitro and animal studies on the impact of NK cells on fungal pathogens.

Soil fungal abundance and diversity: another victim of the invasive plant Centaurea maculosa.

PubMed

Broz, Amanda K; Manter, Daniel K; Vivanco, Jorge M

2007-12-01

Interactions between plants and soil microbes are important determinants of both above- and belowground community composition, and ultimately ecosystem function. As exotic plants continue to invade and modify native plant communities, there has been increasing interest in determining the influence of exotic invasives on native soil microbial communities. Here, using highly sensitive molecular techniques, we examine fungal abundance and diversity in the soil surrounding a particularly aggressive invasive plant species in North America, Centaurea maculosa Lam. In mixed stands, we show that this invasive weed can alter the native fungal community composition within its own rhizosphere and that of neighboring native plants. At higher densities, the effect of C. maculosa on native soil fungal communities was even greater. Our results demonstrate that this invasive weed can have significant effects not only on visible aboveground biodiversity but also on the native soil microbial community that extends beyond its rhizosphere.

Pathogen dynamics during invasion and establishment of white-nose syndrome explain mechanisms of host persistence.

PubMed

Frick, Winifred F; Cheng, Tina L; Langwig, Kate E; Hoyt, Joseph R; Janicki, Amanda F; Parise, Katy L; Foster, Jeffrey T; Kilpatrick, A Marm

2017-03-01

Disease dynamics during pathogen invasion and establishment determine the impacts of disease on host populations and determine the mechanisms of host persistence. Temporal progression of prevalence and infection intensity illustrate whether tolerance, resistance, reduced transmission, or demographic compensation allow initially declining populations to persist. We measured infection dynamics of the fungal pathogen Pseudogymnoascus destructans that causes white-nose syndrome in bats by estimating pathogen prevalence and load in seven bat species at 167 hibernacula over a decade as the pathogen invaded, became established, and some host populations stabilized. Fungal loads increased rapidly and prevalence rose to nearly 100% at most sites within 2 yr of invasion in six of seven species. Prevalence and loads did not decline over time despite huge reductions in colony sizes, likely due to an extensive environmental reservoir. However, there was substantial variation in fungal load among sites with persisting colonies, suggesting that both tolerance and resistance developed at different sites in the same species. In contrast, one species disappeared from hibernacula within 3 yr of pathogen invasion. Variable host responses to pathogen invasion require different management strategies to prevent disease-induced extinction and to facilitate evolution of tolerance or resistance in persisting populations. © 2016 by the Ecological Society of America.

Mannose-binding lectin codon 54 gene polymorphism in relation to risk of nosocomial invasive fungal infection in preterm neonates in the neonatal intensive care unit.

PubMed

Aydemir, Cumhur; Onay, Huseyin; Oguz, Serife Suna; Ozdemir, Taha Resid; Erdeve, Omer; Ozkinay, Ferda; Dilmen, Ugur

2011-09-01

Preterm neonates are susceptible to infection due to a combination of sub-optimal immunity and increased exposure to invasive organisms. Invasive fungal infections are associated with significant morbidity and mortality among preterm infants cared for in the neonatal intensive care unit (NICU). Mannose-binding lectin (MBL) is a component of the innate immune system, which may be especially important in the neonatal setting. The objective of this study was to investigate the presence of any association between MBL gene polymorphism and nosocomial invasive fungal infection in preterm neonates. Codon 54 (B allele) polymorphism in exon 1 of the MBL gene was investigated in 31 patients diagnosed as nosocomial invasive fungal infection and 30 control preterm neonates. AB genotype was determined in 26% and 30% of patient and control groups, respectively, and the difference was not statistically significant. AA genotype was determined in 74% of the patient group and in 67% of the control group, and the difference was not statistically significant. B allele frequency was not different significantly in the patient group (13%) compared to the control group (18%). In our study, no relationship was found between MBL codon 54 gene polymorphism and the risk of nosocomial invasive fungal infection in preterm neonates in NICU.

Hyperbaric Oxygen Reduces Aspergillus fumigatus Proliferation In Vitro and Influences In Vivo Disease Outcomes.

PubMed

Dhingra, Sourabh; Buckey, Jay C; Cramer, Robert A

2018-03-01

Recent estimates suggest that more than 3 million people have chronic or invasive fungal infections, causing more than 600,000 deaths every year. Aspergillus fumigatus causes invasive pulmonary aspergillosis (IPA) in patients with compromised immune systems and is a primary contributor to increases in human fungal infections. Thus, the development of new clinical modalities as stand-alone or adjunctive therapy for improving IPA patient outcomes is critically needed. Here we tested the in vitro and in vivo impacts of hyperbaric oxygen (HBO) (100% oxygen, >1 atmosphere absolute [ATA]) on A. fumigatus proliferation and murine IPA outcomes. Our findings indicate that HBO reduces established fungal biofilm proliferation in vitro by over 50%. The effect of HBO under the treatment conditions was transient and fungistatic, with A. fumigatus metabolic activity rebounding within 6 h of HBO treatment being removed. In vivo , daily HBO provides a dose-dependent but modest improvement in murine IPA disease outcomes as measured by survival analysis. Intriguingly, no synergy was observed between subtherapeutic voriconazole or amphotericin B and HBO in vitro or in vivo with daily HBO dosing, though the loss of fungal superoxide dismutase genes enhanced HBO antifungal activity. Further studies are needed to optimize the HBO treatment regimen and better understand the effects of HBO on both the host and the pathogen during a pulmonary invasive fungal infection. Copyright © 2018 American Society for Microbiology.

Prophylactic Saccharomyces boulardii versus nystatin for the prevention of fungal colonization and invasive fungal infection in premature infants.

PubMed

Demirel, Gamze; Celik, Istemi Han; Erdeve, Omer; Saygan, Sibel; Dilmen, Ugur; Canpolat, Fuat Emre

2013-10-01

This study aims to compare the efficacy of orally administered Saccharomyces boulardii versus nystatin in prevention of fungal colonization and invasive fungal infections in very low birth weight infants. A prospective, randomized comparative study was conducted in preterm infants with a gestational age of ≤ 32 weeks and birth weight of ≤ 1,500 g. They were randomized into two groups, to receive S. boulardii or nystatin. Skin and stool cultures were performed for colonization and blood cultures for invasive infections, weekly. A total of 181 infants were enrolled (S. boulardii group, n = 91; nystatin group, n = 90). Fungal colonization of the skin (15.4 vs 18.9 %, p = 0.532) and the stool (32.2 vs 27 %, p = 0.441) were not different between the probiotic and nystatin groups. Two patients had Candida-positive blood culture in the nystatin group whereas none in the probiotic group. Feeding intolerance, clinical sepsis, and number of sepsis attacks were significantly lower in the probiotics group than in the nystatin group. Prophylactic S. boulardii supplementation is as effective as nystatin in reducing fungal colonization and invasive fungal infection, more effective in reducing the incidence of clinical sepsis and number of sepsis attacks and has favorable effect on feeding intolerance.

Invasive fungal infections during the neonatal period: diagnosis, treatment and prophylaxis.

PubMed

Tezer, Hasan; Canpolat, Fuat Emre; Dilmen, Uğur

2012-02-01

The incidence of preterm births seems to be increased in many countries around the world, in parallel to the advances in neonatal medicine. However, this has resulted in longer hospital stays and more exposure to invasive interventions, both of which can lead to an increase in late-onset nosocomial infections in the newborn period. In addition to bacteria, fungi are thought to be an important cause of hospital infections. The present article reviews the diagnosis, treatment and prophylaxis of invasive fungal infections (IFIs) during the neonatal period. IFIs are associated with high morbidity and mortality in preterm neonates. The main risk factors are multiple antibiotics, central venous catheters, parenteral nutrition, immunodepression, very low birth weight, and fungal colonization. Successful management of IFIs relies on early recognition and rapid initiation of effective treatment. Invasive-fungal-infection-related morbidity and mortality is a major concern for most neonatal intensive care units worldwide. Incidence rates are increasing for preterm neonates. Preterm infants display clinical characteristics that make them prone to fungal infections, and there is a high frequency of neurodevelopmental sequelae in those who survive after neonatal fungal infections. Specific prevention - rather than treatment - should be the optimal strategy. Both fluconazole and nystatin prophylaxis reduce the incidence of IFI and fungal colonization in very preterm infants.

Comparison of Non-Culture-Based Methods for Detection of Systemic Fungal Infections, with an Emphasis on Invasive Candida Infections

PubMed Central

White, P. Lewis; Archer, Alice E.; Barnes, Rosemary A.

2005-01-01

The accepted limitations associated with classic culture techniques for the diagnosis of invasive fungal infections have lead to the emergence of many non-culture-based methods. With superior sensitivities and quicker turnaround times, non-culture-based methods may aid the diagnosis of invasive fungal infections. In this review of the diagnostic service, we assessed the performances of two antigen detection techniques (enzyme-linked immunosorbent assay [ELISA] and latex agglutination) with a molecular method for the detection of invasive Candida infection and invasive aspergillosis. The specificities for all three assays were high (≥97%), although the Candida PCR method had enhanced sensitivity over both ELISA and latex agglutination with values of 95%, 75%, and 25%, respectively. However, calculating significant sensitivity values for the Aspergillus detection methods was not feasible due to a low number of proven/probable cases. Despite enhanced sensitivity, the PCR method failed to detect nucleic acid in a probable case of invasive Candida infection that was detected by ELISA. In conclusion, both PCR and ELISA techniques should be used in unison to aid the detection of invasive fungal infections. PMID:15872239

Plant hormones: a fungal point of view.

PubMed

Chanclud, Emilie; Morel, Jean-Benoit

2016-10-01

Most classical plant hormones are also produced by pathogenic and symbiotic fungi. The way in which these molecules favour the invasion of plant tissues and the development of fungi inside plant tissues is still largely unknown. In this review, we examine the different roles of such hormone production by pathogenic fungi. Converging evidence suggests that these fungal-derived molecules have potentially two modes of action: (i) they may perturb plant processes, either positively or negatively, to favour invasion and nutrient uptake; and (ii) they may also act as signals for the fungi themselves to engage appropriate developmental and physiological processes adapted to their environment. Indirect evidence suggests that abscisic acid, gibberellic acid and ethylene produced by fungi participate in pathogenicity. There is now evidence that auxin and cytokinins could be positive regulators required for virulence. Further research should establish whether or not fungal-derived hormones act like other fungal effectors. © 2016 The Authors. Molecular Plant Pathology Published by British Society for Plant Pathology and John Wiley & Sons Ltd.

Translational Development and Application of (1→3)-β-d-Glucan for Diagnosis and Therapeutic Monitoring of Invasive Mycoses

PubMed Central

McCarthy, Matthew W.; Petraitiene, Ruta; Walsh, Thomas J.

2017-01-01

Early diagnosis and prompt initiation of appropriate antimicrobial therapy are crucial steps in the management of patients with invasive fungal infections. However, the diagnosis of invasive mycoses remains a major challenge in clinical practice, because presenting symptoms may be subtle and non-invasive diagnostic assays often lack sensitivity and specificity. Diagnosis is often expressed on a scale of probability (proven, probable and possible) based on a constellation of imaging findings, microbiological tools and histopathology, as there is no stand-alone assay for diagnosis. Recent data suggest that the carbohydrate biomarker (1→3)-β-d-glucan may be useful in both the diagnosis and therapeutic monitoring of invasive fungal infections due to some yeasts, molds, and dimorphic fungi. In this paper, we review recent advances in the use of (1→3)-β-d-glucan to monitor clinical response to antifungal therapy and explore how this assay may be used in the future. PMID:28538702

Seed bank survival of an invasive species, but not of two native species, declines with invasion.

PubMed

Orrock, John L; Christopher, Cory C; Dutra, Humberto P

2012-04-01

Soil-borne seed pathogens may play an important role in either hindering or facilitating the spread of invasive exotic plants. We examined whether the invasive shrub Lonicera maackii (Caprifoliaceae) affected fungi-mediated mortality of conspecific and native shrub seeds in a deciduous forest in eastern Missouri. Using a combination of L. maackii removal and fungicide treatments, we found no effect of L. maackii invasion on seed viability of the native Symphoricarpos orbiculatus (Caprifoliaceae) or Cornus drummondii (Cornaceae). In contrast, fungi were significant agents of L. maackii seed mortality in invaded habitats. Losses of L. maackii to soil fungi were also significant in invaded habitats where L. maackii had been removed, although the magnitude of the effect of fungi was lower, suggesting that changes in soil chemistry or microhabitat caused by L. maackii were responsible for affecting fungal seed pathogens. Our work suggests that apparent competition via soil pathogens is not an important factor contributing to impacts of L. maackii on native shrubs. Rather, we found that fungal seed pathogens have density-dependent effects on L. maackii seed survival. Therefore, while fungal pathogens may provide little biotic resistance to early invasion by L. maackii, our study illustrates that more work is needed to understand how changes in fungal pathogens during the course of an invasion contribute to the potential for restoration of invaded systems. More generally, our study suggests that increased rates of fungal pathogen attack may be realized by invasive plants, such as L. maackii, that change the chemical or physical environment of the habitats they invade.

Early diagnosis of fungal infections in lung transplant recipients, colonization versus invasive disease?

PubMed

Herrera, Sabina; Husain, Shahid

2018-05-21

The diagnosis of invasive aspergillosis remains challenging in solid organ transplants in general, and in lung transplant recipients, in particular, because of colonization. Lung transplant recipients may be over treated with antifungal drugs because of the lack of appropriate diagnostic tools. A review of the new developments of diagnostic tools and whether this help distinguishing colonization from invasive disease is presented. Efforts are being made to develop new tools that will allow us to identify which patients will develop IPA, and those who will be able to control the disease.

Characterisation of Candida within the Mycobiome/Microbiome of the Lower Respiratory Tract of ICU Patients

PubMed Central

Krause, Robert; Halwachs, Bettina; Thallinger, Gerhard G.; Klymiuk, Ingeborg; Gorkiewicz, Gregor; Hoenigl, Martin; Prattes, Jürgen; Valentin, Thomas; Heidrich, Katharina; Buzina, Walter; Salzer, Helmut J. F.; Rabensteiner, Jasmin; Prüller, Florian; Raggam, Reinhard B.; Meinitzer, Andreas; Moissl-Eichinger, Christine; Högenauer, Christoph; Quehenberger, Franz; Kashofer, Karl; Zollner-Schwetz, Ines

2016-01-01

Whether the presence of Candida spp. in lower respiratory tract (LRT) secretions is a marker of underlying disease, intensive care unit (ICU) treatment and antibiotic therapy or contributes to poor clinical outcome is unclear. We investigated healthy controls, patients with proposed risk factors for Candida growth in LRT (antibiotic therapy, ICU treatment with and without antibiotic therapy), ICU patients with pneumonia and antibiotic therapy and candidemic patients (for comparison of truly invasive and colonizing Candida spp.). Fungal patterns were determined by conventional culture based microbiology combined with molecular approaches (next generation sequencing, multilocus sequence typing) for description of fungal and concommitant bacterial microbiota in LRT, and host and fungal biomarkes were investigated. Admission to and treatment on ICUs shifted LRT fungal microbiota to Candida spp. dominated fungal profiles but antibiotic therapy did not. Compared to controls, Candida was part of fungal microbiota in LRT of ICU patients without pneumonia with and without antibiotic therapy (63% and 50% of total fungal genera) and of ICU patients with pneumonia with antibiotic therapy (73%) (p<0.05). No case of invasive candidiasis originating from Candida in the LRT was detected. There was no common bacterial microbiota profile associated or dissociated with Candida spp. in LRT. Colonizing and invasive Candida strains (from candidemic patients) did not match to certain clades withdrawing the presence of a particular pathogenic and invasive clade. The presence of Candida spp. in the LRT rather reflected rapidly occurring LRT dysbiosis driven by ICU related factors than was associated with invasive candidiasis. PMID:27206014

Yeast central nervous system infection in a critically ill patient: a case report.

PubMed

Frantzeskaki, Frantzeska; Diakaki, Chryssi; Rizos, Michalis; Theodorakopoulou, Maria; Papadopoulos, Panagiotis; Antonopoulou, Anastasia; Nikitas, Nikitas; Lignos, Michail; Brountzos, Elias; Velegraki, Aristea; Paramythiotou, Elisabeth; Panagyotides, John; Armaganidis, Apostolos; Dimopoulos, George

2014-07-15

Invasive fungal infections are alarmingly common in intensive care unit patients; invasive fungal infections are associated with increased morbidity and mortality. Risk factors are the increased use of indwelling central venous catheters, the use of broad spectrum antibiotics, parenteral nutrition, renal replacement therapy and immunosuppression. Diagnosis of these infections might be complicated, requiring tissue cultures. In addition, therapy of invasive fungal infections might be difficult, given the rising resistance of fungi to antifungal agents. We describe the case of a 28-year-old Greek man with yeast central nervous system infection. Difficult-to-treat fungal infections may complicate the clinical course of critically ill patients and render their prognosis unfavorable. This report presents a case that was rare and difficult to treat, along with a thorough review of the investigation and treatment of these kinds of fungal infections in critically ill patients.

Modulation of Immune Signaling and Metabolism Highlights Host and Fungal Transcriptional Responses in Mouse Models of Invasive Pulmonary Aspergillosis.

PubMed

Kale, Shiv D; Ayubi, Tariq; Chung, Dawoon; Tubau-Juni, Nuria; Leber, Andrew; Dang, Ha X; Karyala, Saikumar; Hontecillas, Raquel; Lawrence, Christopher B; Cramer, Robert A; Bassaganya-Riera, Josep

2017-12-06

Incidences of invasive pulmonary aspergillosis, an infection caused predominantly by Aspergillus fumigatus, have increased due to the growing number of immunocompromised individuals. While A. fumigatus is reliant upon deficiencies in the host to facilitate invasive disease, the distinct mechanisms that govern the host-pathogen interaction remain enigmatic, particularly in the context of distinct immune modulating therapies. To gain insights into these mechanisms, RNA-Seq technology was utilized to sequence RNA derived from lungs of 2 clinically relevant, but immunologically distinct murine models of IPA on days 2 and 3 post inoculation when infection is established and active disease present. Our findings identify notable differences in host gene expression between the chemotherapeutic and steroid models at the interface of immunity and metabolism. RT-qPCR verified model specific and nonspecific expression of 23 immune-associated genes. Deep sequencing facilitated identification of highly expressed fungal genes. We utilized sequence similarity and gene expression to categorize the A. fumigatus putative in vivo secretome. RT-qPCR suggests model specific gene expression for nine putative fungal secreted proteins. Our analysis identifies contrasting responses by the host and fungus from day 2 to 3 between the two models. These differences may help tailor the identification, development, and deployment of host- and/or fungal-targeted therapeutics.

[Clinicopathologic study of invasive fungal rhinosinusitis caused by Aspergillus and Mucorales].

PubMed

He, Chun-yan; Piao, Ying-shi; Tian, Cheng; Li, Li-li; Liu, Hong-gang

2012-10-01

To compare the differences in clinicopathologic features of invasive fungal rhinosinusitis caused by Aspergillus and Mucorales, and to discuss the pathogenesis of tissue injury induced by these two kinds of fungi. The clinical and pathologic features of 19 patients with invasive fungal rhinosinusitis due to Aspergillus (group A) and 16 patients with invasive fungal rhinosinusitis due to Mucorales (group M) were retrospectively reviewed. HE, PAS and GMS stains were performed on all the paraffin-embedded tissues. The diagnosis was confirmed by histologic examination and microbiological culture results. Amongst the group A patients, the clinical course was acute in 4 cases and chronic in 15 cases. Thirteen cases had underlying predisposing conditions, including diabetes (number = 4), malignant tumor (number = 5), history of trauma (number = 1) and radical maxillary sinus surgery (number = 3). Follow-up information was available in 13 patients. Seven of them died, 4 due to fungal encephalopathy and 3 due to underlying diseases. Amongst the group M patients, the clinical course was acute in 14 cases and chronic in 2 cases. Fourteen cases had underlying predisposing conditions, including diabetes (number = 8), malignant tumor (number = 5) and history of wisdom tooth extraction (number = 1). Follow-up information was available in 14 patients. Four of them died of fungal encephalopathy. There was significant difference in clinical onset between the two groups (P = 0.01). There was however no difference in terms of underlying predisposing conditions and disease mortality. Histologically, the microorganisms in group A patients formed fungal masses and attached to the mucosal surface, resulting in necrotic bands (11/19). Epithelioid granulomas were conspicuous but multinucleated giant cells were relatively rare. Deep-seated necrosis, granulomatous inflammation against fungal organisms (3/19) and vasculitis with thrombosis (4/19) were not common. On the other hand, large areas of geographic necrosis involving deep-seated tissue could be seen in group M patients (13/16). Isolated multinucleated giant cells were commonly seen. Granulomatous inflammation against fungal organisms were identified (16/16). Vasculitis and thrombosis were also observed (10/16). The invasiveness of Mucorales is remarkable; and when it causes invasive fungal rhinosinusitis, the clinical course is often acute and large areas of tissue necrosis can be seen. The invasiveness of Aspergillus in tissue is relatively mild. Granulomas are more common and the disease often runs a chronic clinical course. There is however no significant difference in long-term mortality. The pathogenesis may be related to the different components of the fungi.

RNAi-mediated silencing of MAP kinase signalling genes (Fmk1, Hog1, and Pbs2) in Fusarium oxysporum reduces pathogenesis on tomato plants.

PubMed

Pareek, Manish; Rajam, Manchikatla Venkat

2017-09-01

Fusarium oxysporum is a soil-borne plant fungal pathogen, and causes colossal losses in several crop plants including tomato. Effective control measures include the use of harmful fungicides and resistant cultivars, but these methods have shown limited success. Conventional methods to validate fungal pathogenic genes are labour intensive. Therefore, an alternative strategy is required to efficiently characterize unknown pathogenic genes. RNA interference (RNAi) has emerged as a potential tool to functionally characterize novel fungal pathogenic genes and also to control fungal diseases. Here, we report an efficient method to produce stable RNAi transformants of F. oxysporum using Agrobacterium-mediated transformation (AMT). We have transformed F. oxysporum spores using RNAi constructs of Fmk1, Hog1, and Pbs2 MAP kinase signalling genes. Fmk1 RNAi fungal transformants showed loss of surface hydrophobicity, reduced invasive growth on tomato fruits and hypo-virulence on tomato seedlings. Hog1 and Pbs2 RNAi transformants showed altered conidial size, and reduced invasive growth and pathogenesis. These results showed that AMT using RNAi constructs is an effective approach for dissecting the role of genes involved in pathogenesis in F. oxysporum and this could be extended for other fungal systems. The obtained knowledge can be easily translated for developing fungal resistant crops by RNAi. Copyright © 2017 British Mycological Society. Published by Elsevier Ltd. All rights reserved.

Repurposing antipsychotic drugs into antifungal agents: Synergistic combinations of azoles and bromperidol derivatives in the treatment of various fungal infections.

PubMed

Holbrook, Selina Y L; Garzan, Atefeh; Dennis, Emily K; Shrestha, Sanjib K; Garneau-Tsodikova, Sylvie

2017-10-20

As the number of hospitalized and immunocompromised patients continues to rise, invasive fungal infections, such as invasive candidiasis and aspergillosis, threaten the life of millions of patients every year. The azole antifungals are currently the most prescribed drugs clinically that display broad-spectrum antifungal activity and excellent oral bioavailability. Yet, the azole antifungals have their own limitations and are unable to meet the challenges associated with increasing fungal infections and the accompanied development of resistance against azoles. Exploring combination therapy that involves the current azoles and another drug has been shown to be a promising strategy. Haloperidol and its derivative, bromperidol, were originally discovered as antipsychotics. Herein, we synthesize and report a series of bromperidol derivatives and their synergistic antifungal interactions in combination with a variety of current azole antifungals against a wide panel of fungal pathogens. We further select two representative combinations and confirm the antifungal synergy by performing time-kill assays. Furthermore, we evaluate the ability of selected combinations to destroy fungal biofilm. Finally, we perform mammalian cytotoxicity assays with the representative combinations against three mammalian cell lines. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

[Risk factors of invasive fungal infections in patients admitted to non- hematological oncology department and pediatric intensive care unit].

PubMed

Zhao, Cheng-song; Zhao, Shun-ying; Liu, Gang; Xi-Wei, Xu

2013-08-01

To determine risk factors of invasive fungal infections (IFI) in patients admitted to non-hematological oncology department and pediatric intensive care unit (PICU), in order to improve diagnostic level of invasive fungal infections. We retrospectively assessed 85 hospitalized pediatric patients with invasive fungal infections in Beijing Children's Hospital Affiliated to Capital Medical University from Jan.2007 to Nov.2012. All the cases were either from non-hematological oncology department or the PICU.We reviewed risk factors of invasive fungal infections. Among 85 patients, 42 had invasive candida infection, 20 invasive aspergillus infection, 21 cryptococcus infection, 1 Histoplasma capsulatum infection and 1 Mucor mucedo infection.In the 42 patients with invasive candida infection, 5 were young infants, 3 had combined immunodeficiency, 1 cellular immunodeficiency, 25 secondary infection due to long term use of corticosteroids and/or combined use of more than 2 kinds of antibiotics with primary disease, 5 prior intestinal tract surgery or chronic diarrheal disease, 1 reflux gastritis.In the 20 patients with invasive aspergillosis infection, 10 patients had chronic granulomatous disease, 5 long term use of corticosteroids ≥ 1 month, 3 long term use of corticosteroids and combined use of more than 2 kinds of antibiotics, 2 had no apparent host factors.In the 21 patients with cryptococcus infection, 2 patients had used corticosteroids ≥ 1 month, 2 had immunodeficiency mainly for lack of antibodies, while others had no apparent host factors. The child with Mucor mucedo infection had diabetes mellitus. And the one with Histoplasma capsulatum infection had immunodeficiency. High risk factors for IFI in patients admitted to non-hematological oncology department and PICU are primary immunodeficiency disease and long term use of corticosteroids and/or long term combined use of more than 2 kinds of antibiotics. Besides, young infant is also a high risk factor for invasive candida infection. Most of the cryptococcus infections and certain aspergillosis had no obvious host factors.

Diagnostic value of (1 → 3)-β-D-glucan in bronchoalveolar lavage fluid for invasive fungal disease: A meta-analysis.

PubMed

Shi, Xin-Yu; Liu, Yao; Gu, Xian-Min; Hao, Sheng-Yu; Wang, Yu-Hong; Yan, Di; Jiang, Shu-Juang

2016-08-01

The serum (1 → 3)-β-D-glucan (BG) assay has been approved for diagnosing invasive fungal diseases (IFDs). However, the performance of (1 → 3)-β-D-glucan assay in bronchoalveolar lavage (BAL) fluid is various among studies. The present study aimed to assess the accuracy of (1 → 3)-β-D-glucan assay in bronchoalveolar lavage fluid for the diagnosis of invasive fungal diseases by means of meta-analysis and systematic review of relevant studies. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (OR) and a summary receiver-operating characteristic curve of BAL-BG for diagnosing invasive fungal diseases were pooled using meta-analysis. We also performed meta-regression analysis. A total of 838 patients (138 with proven or probable invasive fungal diseases), included in 6 studies, were analyzed. The pooled sensitivity, specificity, PLR, NLR and diagnostic odds ratio were 0.52 (95%CI, 0.38-0.53), 0.58 (95%CI, 0.55-0.61), 1.34 (95%CI, 1.08-1.66), 0.82 (95% CI, 0.63-1.07) and 1.71 (95%CI, 1.01-2.92) respectively. The area under the summary receiver operating characteristic curve, with 95% confidence intervals was 0.61 (95%CI, 0.67-0.55). The accuracy of (1 → 3)-β-D-glucan test in bronchoalveolar lavage fluid is marginal, so that the results should not be interpreted alone but can be used as a part of full assessment with clinical features, image findings and other laboratory results for the diagnosis of invasive fungal diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Recent developments and current issues in the epidemiology, diagnosis, and management of bacterial and fungal neonatal sepsis.

PubMed

Shane, Andi L; Stoll, Barbara J

2013-02-01

Identifying neonates with sepsis is complicated by variability in clinical presentation. The incidence of early onset sepsis (EOS) resulting from invasive group B streptococcal (GBS) infections has been notably reduced by the widespread delivery of intrapartum antibiotic prophylaxis. Rates of EOS attributable to non-GBS etiologies have remained constant, and ampicillin-resistant Escherichia coli has become more prevalent. Late-onset sepsis (LOS) attributable to gram-positive organisms including coagulase-negative Staphylococci and Staphylococcus aureus is associated with increased morbidity and mortality among premature infants. Invasive candidiasis is an emerging cause of LOS, especially among infants who receive broad-spectrum antimicrobial agents. Prophylactic fluconazole administration to very low-birth-weight (VLBW) neonates during the first 6 weeks of life prevents invasive candidiasis in neonatal intensive care units (NICU) with high rates of fungal infections. Targeted fluconazole prophylaxis may be beneficial in VLBW neonates who receive care in NICUs with lower rates of invasive fungal infections. Assessment of immune function, neutrophil markers, acute phase reactants, and utilization of sepsis screening scores may contribute to the management of sepsis. Maternal decolonization, antimicrobial stewardship, early enteral feeding, and optimal infection control practices are potential practical strategies for reducing the burden of neonatal sepsis. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Host-Derived Leukotriene B4 Is Critical for Resistance against Invasive Pulmonary Aspergillosis.

PubMed

Caffrey-Carr, Alayna K; Hilmer, Kimberly M; Kowalski, Caitlin H; Shepardson, Kelly M; Temple, Rachel M; Cramer, Robert A; Obar, Joshua J

2017-01-01

Aspergillus fumigatus is a mold that causes severe pulmonary infections. Our knowledge of how immune competent hosts maintain control of fungal infections while constantly being exposed to fungi is rapidly emerging. It is known that timely neutrophil recruitment to and activation in the lungs is critical to the host defense against development of invasive pulmonary aspergillosis, but the inflammatory sequelae necessary remains to be fully defined. Here, we show that 5-Lipoxygenase (5-LO) and Leukotriene B 4 (LTB 4 ) are critical for leukocyte recruitment and resistance to pulmonary A. fumigatus challenge in a fungal-strain-dependent manner. 5-LO activity was needed in radiosensitive cells for an optimal anti-fungal response and in vivo LTB 4 production was at least partially dependent on myeloid-derived hypoxia inducible factor-1α. Overall, this study reveals a role for host-derived leukotriene synthesis in innate immunity to A. fumigatus .

An estimation of burden of serious fungal infections in France.

PubMed

Gangneux, J-P; Bougnoux, M-E; Hennequin, C; Godet, C; Chandenier, J; Denning, D W; Dupont, B

2016-12-01

An estimation of burden of serious fungal diseases in France is essential data to inform public health priorities on the importance of resources and research needed on these infections. In France, precise data are available for invasive fungal diseases but estimates for several other diseases such as chronic and immunoallergic diseases are by contrast less known. A systematic literature search was conducted using the Web of Science Platform. Published epidemiology papers reporting fungal infection rates from France were identified. Where no data existed, we used specific populations at risk and fungal infection frequencies in those populations to estimate national incidence or prevalence, depending on the condition. The model predicts high prevalences of severe asthma with fungal sensitization episodes (189 cases/100,000 adults per year), of allergic bronchopulmonary aspergillosis (145/100,000) and of chronic pulmonary aspergillosis (5.24/100,000). Besides, estimated incidence for invasive aspergillosis is 1.8/100,000 annually based on classical high risk factors. Estimates for invasive mucormycosis, pneumocystosis and cryptococcosis are 0.12/100,000, 1/100,000 and 0.2/100,000, respectively. Regarding invasive candidiasis, more than 10,000 cases per year are estimated, and a much higher number of recurrent vaginal candidiasis is probable but must be confirmed. Finally, this survey was an opportunity to report a first picture of the frequency of tinea capitis in France. Using local and literature data of the incidence or prevalence of fungal infections, approximately 1,000,000 (1.47%) people in France are estimated to suffer from serious fungal infections each year. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Sphingolipids as targets for treatment of fungal infections

PubMed Central

Rollin-Pinheiro, Rodrigo; Singh, Ashutosh; Barreto-Bergter, Eliana; Del Poeta, Maurizio

2016-01-01

Invasive fungal infections have significantly increased in the last few decades. Three classes of drugs are commonly used to treat these infections: polyenes, azoles and echinocandins. Unfortunately each of these drugs has drawbacks; polyenes are toxic, resistance against azoles is emerging and echinocandins have narrow spectrum of activity. Thus, the development of new antifungals is urgently needed. In this context, fungal sphingolipids have emerged as a potential target for new antifungals, because their biosynthesis in fungi is structurally different than in mammals. Besides, some fungal sphingolipids play an important role in the regulation of virulence in a variety of fungi. This review aims to highlight the diverse strategies that could be used to block the synthesis or/and function of fungal sphingolipids. PMID:27502288

II. Pathogens

Treesearch

Ned B. Klopfenstein; Brian W. Geils

2011-01-01

Invasive fungal pathogens have caused immeasurably large ecological and economic damage to forests. It is well known that invasive fungal pathogens can cause devastating forest diseases (e.g., white pine blister rust, chestnut blight, Dutch elm disease, dogwood anthracnose, butternut canker, Scleroderris canker of pines, sudden oak death, pine pitch canker) (Maloy 1997...

Performance of Panfungal- and Specific-PCR-Based Procedures for Etiological Diagnosis of Invasive Fungal Diseases on Tissue Biopsy Specimens with Proven Infection: a 7-Year Retrospective Analysis from a Reference Laboratory

PubMed Central

Bernal-Martinez, L.; Castelli, M. V.; Rodriguez-Tudela, J. L.; Cuenca-Estrella, M.

2014-01-01

A retrospective analysis of real-time PCR (RT-PCR) results for 151 biopsy samples obtained from 132 patients with proven invasive fungal diseases was performed. PCR-based techniques proved to be fast and sensitive and enabled definitive diagnosis in all cases studied, with detection of a total of 28 fungal species. PMID:24574295

Broad-Spectrum Molecular Detection of Fungal Nucleic Acids by PCR-Based Amplification Techniques.

PubMed

Czurda, Stefan; Lion, Thomas

2017-01-01

Over the past decade, the incidence of life-threatening invasive fungal infections has dramatically increased. Infections caused by hitherto rare and emerging fungal pathogens are associated with significant morbidity and mortality among immunocompromised patients. These observations render the coverage of a broad range of clinically relevant fungal pathogens highly important. The so-called panfungal or, perhaps more correctly, broad-range nucleic acid amplification techniques do not only facilitate sensitive detection of all clinically relevant fungal species but are also rapid and can be applied to analyses of any patient specimens. They have therefore become valuable diagnostic tools for sensitive screening of patients at risk of invasive fungal infections. This chapter summarizes the currently available molecular technologies employed in testing of a wide range of fungal pathogens, and provides a detailed workflow for patient screening by broad-spectrum nucleic acid amplification techniques.

Emerging IL-12 family cytokines in the fight against fungal infections.

PubMed

Thompson, Aiysha; Orr, Selinda J

2018-05-21

Invasive fungal infections cause approximately 1.5 million deaths per year worldwide and are a growing threat to human health. Current anti-fungal therapies are often insufficient, therefore studies into host-pathogen interactions are critical for the development of novel therapies to improve mortality rates. Myeloid cells, such as macrophages and dendritic cells, express pattern recognition receptor (PRRs), which are important for fungal recognition. Engagement of these PRRs by fungal pathogens induces multiple cytokines, which in turn activate T effector responses. Interleukin (IL)-12 family members (IL-12p70, IL-23, IL-27 and IL-35) link innate immunity with the development of adaptive immunity and are also important for regulating T cell responses. IL-12 and IL-23 have established roles during anti-fungal immunity, whereas emerging roles for IL-27 and IL-35 have recently been reported. Here, we discuss the IL-12 family, focusing on IL-27 and IL-35 during anti-fungal immune responses to pathogens such as Candida and Aspergillus. Copyright © 2018. Published by Elsevier Ltd.

Phylogenetics of a fungal invasion: origins and widespread dispersal of white-nose syndrome

Treesearch

Kevin P. Drees; Jeffrey M. Lorch; Sebastien J. Puechmaille; Katy L. Parise; Gudrun Wibbelt; Joseph R. Hoyt; Keping Sun; Ariunbold Jargalsaikhan; Munkhnast Dalannast; Jonathan M. Palmer; Daniel L. Lindner; A. Marm Kilpatrick; Talima Pearson; Paul S. Keim; David S. Blehert; Jeffrey T. Foster; Joseph Heitman

2017-01-01

Globalization has facilitated the worldwide movement and introduction of pathogens, but epizoological reconstructions of these invasions are often hindered by limited sampling and insufficient genetic resolution among isolates. Pseudogymnoascus destructans, a fungal pathogen causing the epizootic of white-nose syndrome in North American bats, has...

Inonotosis in Patient with Hematologic Malignancy

PubMed Central

Kwon, Mi; Guinea, Jesús; Escribano, Pilar; Jiménez, María del Carmen Martínez; Pulido, Ana; Parra, Verónica; Serrano, David; Gayoso, Jorge; Martín, José Luis Díez; Bouza, Emilio

2018-01-01

We report a lung-invasive fungal disease with possible cutaneous needle tract seeding in a patient with a febrile neutropenia caused by the Basidiomycetes mold Inonotus spp. Although rare, Inonotus spp. should be added to the list of microorganisms causing invasive fungal disease in neutropenic patients with hematologic malignancies. PMID:29260664

Invasive fungal infections in endogenous Cushing's syndrome

PubMed Central

Scheffel, Rafael Selbach; Dora, José Miguel; Weinert, Letícia Schwerz; Aquino, Valério; Maia, Ana Luiza; Canani, Luis Henrique; Goldani, Luciano Z.

2010-01-01

Cushing's syndrome is a condition characterized by elevated cortisol levels that can result from either augmented endogenous production or exogenous administration of corticosteroids. The predisposition to fungal infections among patients with hypercortisolemia has been noted since Cushing's original description of the disease. We describe here a patient with endogenous Cushing's syndrome secondary to an adrenocortical carcinoma, who developed concomitant disseminated cryptococcosis and candidiasis in the course of his disease. PMID:24470886

Genomes, free radicals and plant cell invasion: recent developments in plant pathogenic fungi.

PubMed

Egan, Martin J; Talbot, Nicholas J

2008-08-01

This review describes current advances in our understanding of fungal-plant interactions. The widespread application of whole genome sequencing to a diverse range of fungal species has allowed new insight into the evolution of fungal pathogenesis and the definition of the gene inventories associated with important plant pathogens. This has also led to functional genomic approaches to carry out large-scale gene functional analysis. There has also been significant progress in understanding appressorium-mediated plant infection by fungi and its underlying genetic basis. The nature of biotrophic proliferation of fungal pathogens in host tissue has recently revealed new potential mechanisms for cell-to-cell movement by invading pathogens.

Molecular mechanisms of cryptococcal meningitis

PubMed Central

Liu, Tong-Bao; Perlin, David; Xue, Chaoyang

2012-01-01

Fungal meningitis is a serious disease caused by a fungal infection of the central nervous system (CNS) mostly in individuals with immune system deficiencies. Fungal meningitis is often fatal without proper treatment, and the mortality rate remains unacceptably high even with antifungal drug interventions. Currently, cryptococcal meningitis is the most common fungal meningitis in HIV-1/AIDS, and its disease mechanism has been extensively studied. The key steps for fungi to infect brain and cause meningitis after establishment of local infection are the dissemination of fungal cells to the bloodstream and invasion through the blood brain barrier to reach the CNS. In this review, we use cryptococcal CNS infection as an example to describe the current molecular understanding of fungal meningitis, including the establishment of the infection, dissemination, and brain invasion. Host and microbial factors that contribute to these infection steps are also discussed. PMID:22460646

Identification of pathogenic fungi with an optoelectronic nose

PubMed Central

Zhang, Yinan; Askim, Jon R.; Zhong, Wenxuan; Orlean, Peter; Suslick, Kenneth S.

2014-01-01

Human fungal infections have gained recent notoriety following contamination of pharmaceuticals in the compounding process. Such invasive infections are a more serious global problem, especially for immunocompromised patients. While superficial fungal infections are common and generally curable, invasive fungal infections are often life-threatening and much harder to diagnose and treat. Despite the increasing awareness of the situation’s severity, currently available fungal diagnostic methods cannot always meet diagnostic needs, especially for invasive fungal infections. Volatile organic compounds produced by fungi provide an alternative diagnostic approach for identification of fungal strains. We report here an optoelectronic nose based on a disposable colorimetric sensor array capable of rapid differentiation and identification of pathogenic fungi based on their metabolic profiles of emitted volatiles. The sensor arrays were tested with 12 human pathogenic fungal strains grown on standard agar medium. Array responses were monitored with an ordinary flatbed scanner. All fungal strains gave unique composite responses within 3 hours and were correctly clustered using hierarchical cluster analysis. A standard jackknifed linear discriminant analysis gave a classification accuracy of 94% for 155 trials. Tensor discriminant analysis, which takes better advantage of the high dimensionality of the sensor array data, gave a classification accuracy of 98.1%. The sensor array is also able to observe metabolic changes in growth patterns upon the addition of fungicides, and this provides a facile screening tool for determining fungicide efficacy for various fungal strains in real time. PMID:24570999

Chronic Invasive Fungal Sinusitis Presenting as Inferior Altitudinal Visual Field Defect.

PubMed

Bansal, Reema; Takkar, Aastha; Lal, Vivek; Bal, Amanjit; Bansal, Sandeep

2017-06-01

A young male with acute blurring of vision (6/9) complained of an inferior altitudinal field defect in right eye. Clinical ophthalmological examination was normal. Magnetic resonance imaging (MRI) of the brain revealed the expansion and mucosal thickening of right posterior ethmoid and sphenoid sinuses and opacified right maxillary sinus. Surgical intervention (transethmoidal sphenoidotomy) and histopathological examination revealed chronic invasive granulomatous fungal sinusitis. Anti-fungal therapy led to resolution of visual complaints and restoration of visual field defects.

[Clinically documented fungal infections].

PubMed

Kakeya, Hiroshi; Kohno, Shigeru

2008-12-01

Proven fungal infections are diagnosed by histological/microbiological evidence of fungi at the site of infection and positive blood culture (fungemia). However, invasive diagnosing examinations are not always applied for all of immunocompromised patients. Clinically documented invasive fungal infections are diagnosed by typical radiological findings such as halo sign on chest CT plus positive serological/molecular evidence of fungi. Serological tests of Aspergillus galactomannan antigen and beta-glucan for aspergillosis and cryptococcal glucuronoxylomannan antigen for cryptococcosis are useful. Hence, none of reliable serological tests for zygomycosis are available so far. In this article, risk factors, sign and symptoms, and diagnostic methods for clinically documented cases of invasive aspergillosis, pulmonary cryptococcosis, and zygomycosis with diabates, are reviewed.

Recent developments in the management of invasive fungal infections in patients with oncohematological diseases.

PubMed

Ruhnke, Markus; Schwartz, Stefan

2016-12-01

Patients with hematological cancer have a high risk of invasive fungal diseases (IFDs). These infections are mostly life threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Most commonly, Aspergillus and Candida species are involved. However, other non- Aspergillus molds are increasingly be identified in cases of documented IFDs. Important risk factors are long lasting granulocytopenia with neutrophil counts below 500/μl for more than 10 days or graft- versus -host disease resulting from allogeneic stem-cell transplantation. For definite diagnosis of IFD, various diagnostic tools have to be applied, including conventional mycological culture and nonconventional microbiological tests such as antibody/antigen and molecular tests, as well as histopathology and radiology. In the last few years, various laboratory methods, like the Aspergillus GM immunoassay ( Aspergillus GM EIA), 1,3-ß-D-glucan (BG) assay or polymerase chain reaction (PCR) techniques have been developed for better diagnosis. Since no single indirect test, including radiological methods, provides the definite diagnosis of an invasive fungal infection, the combination of different diagnostic procedures, which include microbiological cultures, histological, serological and molecular methods like PCR together with the pattern of clinical presentation, may currently be the best strategy for the prompt diagnosis, initiation and monitoring of IFDs. Early start of antifungal therapy is mandatory, but clinical diagnostics often do not provide clear evidence of IFD. Integrated care pathways have been proposed for management and therapy of IFDs with either the diagnostic driven strategy using the preemptive antifungal therapy as opposed to the clinical or empirical driven strategy using the 'traditional' empirical antifungal therapy. Antifungal agents preferentially used for systemic therapy of invasive fungal infections are amphotericin B preparations, fluconazole, voriconazole, posaconazole, caspofungin, anidulafungin, micafungin, and most recently isavuconazole. Clinical decision making must consider licensing status, local experience and availability, pharmacological and economic aspects.

A breath fungal secondary metabolite signature to diagnose invasive aspergillosis.

PubMed

Koo, Sophia; Thomas, Horatio R; Daniels, S David; Lynch, Robert C; Fortier, Sean M; Shea, Margaret M; Rearden, Preshious; Comolli, James C; Baden, Lindsey R; Marty, Francisco M

2014-12-15

Invasive aspergillosis (IA) remains a leading cause of mortality in immunocompromised patients, in part due to the difficulty of diagnosing this infection. Using thermal desorption-gas chromatography/mass spectrometry, we characterized the in vitro volatile metabolite profile of Aspergillus fumigatus, the most common cause of IA, and other pathogenic aspergilli. We prospectively collected breath samples from patients with suspected invasive fungal pneumonia from 2011 to 2013, and assessed whether we could discriminate patients with proven or probable IA from patients without aspergillosis, as determined by European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions, by direct detection of fungal volatile metabolites in these breath samples. The monoterpenes camphene, α- and β-pinene, and limonene, and the sesquiterpene compounds α- and β-trans-bergamotene were distinctive volatile metabolites of A. fumigatus in vitro, distinguishing it from other pathogenic aspergilli. Of 64 patients with suspected invasive fungal pneumonia based on host risk factors, clinical symptoms, and radiologic findings, 34 were diagnosed with IA, whereas 30 were ultimately diagnosed with other causes of pneumonia, including other invasive mycoses. Detection of α-trans-bergamotene, β-trans-bergamotene, a β-vatirenene-like sesquiterpene, or trans-geranylacetone identified IA patients with 94% sensitivity (95% confidence interval [CI], 81%-98%) and 93% specificity (95% CI, 79%-98%). In patients with suspected fungal pneumonia, an Aspergillus secondary metabolite signature in breath can identify individuals with IA. These results provide proof-of-concept that direct detection of exogenous fungal metabolites in breath can be used as a novel, noninvasive, pathogen-specific approach to identifying the precise microbial cause of pneumonia. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The USDA Forest Service-RMRS forest fungi collection: Resource for fungal identification, developing biological controls, predicting invasive pathogens, and predicting potential impacts of climate change

Treesearch

Sara M. Ashiglar; John W. Hanna; Amy L. Ross-Davis; Ned B. Klopfenstein

2014-01-01

The Moscow Forestry Sciences Laboratory of the Rocky Mountain Research Station (RMRS) has a unique collection of forest/tree-associated fungi with over 15,000 living specimens. Based in Moscow, ID, this USDA APHIS-PPQ (Plant Protection and Quarantine) containment facility houses fungal archives from approximately 35 states and 30 countries. The collection involves the...

Fungal endophytes from seeds of invasive, non-native Phragmites australis and their potential role in germination and seedling growth

USGS Publications Warehouse

Shearin, Zackery R. C.; Filipek, Matthew; Desai, Rushvi; Bickford, Wesley A.; Kowalski, Kurt P.; Clay, Keith

2018-01-01

Background and aimsWe characterized fungal endophytes of seeds of invasive, non-native Phragmites from three sites in the Great Lakes region to determine if fungal symbiosis could contribute to invasiveness through their effects on seed germination and seedling growth.MethodsField-collected seeds were surface sterilized and plated on agar to culture endophytes for ITS sequencing. Prevalence of specific endophytes from germinated and non-germinated seeds, and from seedlings, was compared.ResultsOne-third of 740 seeds yielded endophyte isolates. Fifteen taxa were identified with Alternaria sp. representing 54% of all isolates followed by Phoma sp. (21%) and Penicillium corylophilum (12%). Overall germination of seeds producing an isolate (36%) was significantly higher than seeds not producing an isolate (20%). Penicillium in particular was strongly associated with increased germination of seeds from one site. Sixty-three isolates and 11 taxa were also obtained from 30 seedlings where Phoma, Penicillium and Alternaria respectively were most prevalent. There was a significant effect of isolating an endophyte from the seed on seedling growth.ConclusionsThese results suggest that many endophyte taxa are transmitted in seeds and can increase seed germination and seedling growth of invasive Phragmites. The role of fungal endophytes in host establishment, growth and invasiveness in nature requires further research.

Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi

PubMed Central

Parente-Rocha, Juliana Alves; Bailão, Alexandre Melo; Amaral, André Correa; Paccez, Juliano Domiraci; Borges, Clayton Luiz

2017-01-01

Diseases caused by fungi can occur in healthy people, but immunocompromised patients are the major risk group for invasive fungal infections. Cases of fungal resistance and the difficulty of treatment make fungal infections a public health problem. This review explores mechanisms used by fungi to promote fungal resistance, such as the mutation or overexpression of drug targets, efflux and degradation systems, and pleiotropic drug responses. Alternative novel drug targets have been investigated; these include metabolic routes used by fungi during infection, such as trehalose and amino acid metabolism and mitochondrial proteins. An overview of new antifungal agents, including nanostructured antifungals, as well as of repositioning approaches is discussed. Studies focusing on the development of vaccines against antifungal diseases have increased in recent years, as these strategies can be applied in combination with antifungal therapy to prevent posttreatment sequelae. Studies focused on the development of a pan-fungal vaccine and antifungal drugs can improve the treatment of immunocompromised patients and reduce treatment costs. PMID:28694566

Race and invasive fungal infection in solid organ transplant recipients.

PubMed

Boehme, Amelia K; McGwin, Gerald; Andes, David R; Lyon, G Marshall; Chiller, Tom; Pappas, Peter G; Baddley, John W

2014-01-01

Health disparities in access to solid organ transplantation (SOT) and graft survival are well recognized, but there are limited data on the relationship of race to risk of invasive fungal infection (IFI) among SOT recipients. We conducted a case-control study using data from the Transplant-Associated Infection Surveillance Network (TRANSNET) to investigate race and IFI. Cases (n = 1,214) and controls (n = 16,550) were compared on demographic variables using chi-square, and the relationship between race and IFI was assesses with unconditional logistic regression. Compared to White transplant patients, Blacks had similar odds of developing IFI (OR = .97, 95% Cl 0.82-1.15, P = .7125), while participants who identified as other ethnicity were less likely to develop IFI (OR = .56, 95% Cl .41-.75, P < .001). Blacks, when compared to White patients, were at increased odds of developing cryptococcal infection (OR 2.19, 95% CI 1.35-3.54, P = .002). Despite pharmacogenetic differences, Black transplant recipients were not more likely overall to develop IFI compared to White transplant recipients.

Clinical use of fungal PCR from deep tissue samples in the diagnosis of invasive fungal diseases: a retrospective observational study.

PubMed

Ala-Houhala, M; Koukila-Kähkölä, P; Antikainen, J; Valve, J; Kirveskari, J; Anttila, V-J

2018-03-01

To assess the clinical use of panfungal PCR for diagnosis of invasive fungal diseases (IFDs). We focused on the deep tissue samples. We first described the design of panfungal PCR, which is in clinical use at Helsinki University Hospital. Next we retrospectively evaluated the results of 307 fungal PCR tests performed from 2013 to 2015. Samples were taken from normally sterile tissues and fluids. The patient population was nonselected. We classified the likelihood of IFD according to the criteria of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG), comparing the fungal PCR results to the likelihood of IFD along with culture and microscopy results. There were 48 positive (16%) and 259 negative (84%) PCR results. The sensitivity and specificity of PCR for diagnosing IFDs were 60.5% and 91.7%, respectively, while the negative predictive value and positive predictive value were 93.4% and 54.2%, respectively. The concordance between the PCR and the culture results was 86% and 87% between PCR and microscopy, respectively. Of the 48 patients with positive PCR results, 23 had a proven or probable IFD. Fungal PCR can be useful for diagnosing IFDs in deep tissue samples. It is beneficial to combine fungal PCR with culture and microscopy. Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Clinical Utility of Fungal Screening Assays in Adults with Severe Burns

DTIC Science & Technology

2013-01-01

available test, FungitellTM Glucan Assay for (1,3) b D glucan (BG) in serum (Associates of Cape Cod Inc., East Falmouth, MA), is a qualitative...considered a positive test in the United States and was used as a positive value in this study. A positive test is reported with a b D glucan concentration... Glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous

The European Paediatric Mycology Network (EPMyN): Towards a Better Understanding and Management of Fungal Infections in Children.

PubMed

Warris, Adilia

The European Paediatric Mycology Network (EPMyN) was launched in 2014 to create a European platform for research and education in the field of paediatric mycology. The EPMyN aims to address the lack of paediatric specific evidence and knowledge needed to (1) improve the management and outcome of invasive fungal infections in children and neonates and to (2) enhance and develop paediatric antifungal stewardship programmes.

Neurons show the path: tip-to-nucleus communication in filamentous fungal development and pathogenesis.

PubMed

Etxebeste, Oier; Espeso, Eduardo A

2016-09-01

Multiple fungal species penetrate substrates and accomplish host invasion through the fast, permanent and unidirectional extension of filamentous cells known as hyphae. Polar growth of hyphae results, however, in a significant increase in the distance between the polarity site, which also receives the earliest information about ambient conditions, and nuclei, where adaptive responses are executed. Recent studies demonstrate that these long distances are overcome by signal transduction pathways which convey sensory information from the polarity site to nuclei, controlling development and pathogenesis. The present review compares the striking connections of the mechanisms for long-distance communication in hyphae with those from neurons, and discusses the importance of their study in order to understand invasion and dissemination processes of filamentous fungi, and design strategies for developmental control in the future. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Spontaneous fungal peritonitis: a rare but severe complication of liver cirrhosis.

PubMed

Gravito-Soares, Marta; Gravito-Soares, Elisa; Lopes, Sandra; Ribeiro, Graça; Figueiredo, Pedro

2017-09-01

Spontaneous bacterial peritonitis is the most common infectious complication in cirrhosis. Spontaneous fungal peritonitis is rare and remains unknown. In this work, spontaneous fungal peritonitis as well as risk factors and prognosis are characterized. A retrospective case-control study of 253 consecutive admissions by peritonitis in cirrhotic patients was carried out between 2006 and 2015. Comparison of patients with spontaneous fungal peritonitis (cases) and spontaneous bacterial peritonitis with positive microbiologic ascitic fluid culture (controls) was performed. Variables such as sociodemographic and clinical features, cirrhosis etiology, liver dysfunction scores, ascitic and laboratory parameters, invasive procedures, and prognosis were evaluated. Of the 231 patients, eight (3.5%) developed spontaneous fungal peritonitis, 62.5% of cases being coinfected with bacteria. Candida spp. was isolated in 87.5% of cases, mainly Candida albicans (37.5%) and C. krusei (25.0%). Patients with spontaneous fungal peritonitis had higher ascitic fluid lactate dehydrogenase (288.4±266.6 vs. 161.0±179.5; P=0.011), blood leukocyte count (15187.5±5432.3 vs. 10969.8±6949.5; P=0.028), blood urea nitrogen (69.8±3.1 vs. 36.3±25.5; P=0.001), higher number of invasive procedures (colonoscopy: 25.0 vs. 0.8%, P=0.001; urinary catheterization: 87.5 vs. 49.6%, P=0.038; nasogastric intubation: 87.5 vs. 26.9%, P=0.001), and longer duration of hospital stay (30.0±32.9 vs. 18.9±17.0 days; P=0.031). No statistical difference was found between the two groups for Model for End-Stage Liver Disease, Model for End-Stage Liver Disease-sodium, and Child-Pugh scores. Spontaneous fungal peritonitis was associated with a worse prognosis, particularly severe sepsis/septic shock (87.5 vs. 42.8%, P=0.023), admission in the gastroenterology intensive care unit (87.5 vs. 24.4%; P=0.001), and overall (62.5 vs. 31.9%; P=0.039) or 30-day mortality (50.0 vs. 24.4%; P=0.034), with a mean diagnosis-death time of 17.6±11.5 days. Despite being a rare condition, spontaneous fungal peritonitis was associated with worse prognosis and higher mortality than SBP. The ascitic fluid lactate dehydrogenase, blood leukocyte count and urea nitrogen, invasive procedures, and longer admission time were independent risk factors for spontaneous fungal peritonitis.

Integrated genomics of Mucorales reveals novel therapeutic targets

USDA-ARS?s Scientific Manuscript database

Mucormycosis is a life-threatening infection caused by Mucorales fungi. We sequenced 30 fungal genomes and performed transcriptomics with three representative Rhizopus and Mucor strains with human airway epithelial cells during fungal invasion to reveal key host and fungal determinants contributing ...

[Mixed invasive fungal infection due to Rhizomucor pusillus and Aspergillus niger in an immunocompetent patient].

PubMed

Pozo-Laderas, Juan Carlos; Pontes-Moreno, Antonio; Robles-Arista, Juan Carlos; Bautista-Rodriguez, M Dolores; Candau-Alvarez, Alberto; Caro-Cuenca, Maria Teresa; Linares-Sicilia, María José

2015-01-01

Mucormycosis infections are rare in immunocompetent patients, and very few cases of mucormycosis associated with aspergillosis in non-haematological patients have been reported. A 17-year-old male, immunocompetent and without any previously known risk factors, was admitted to hospital due to a seizure episode 11 days after a motorcycle accident. He had a complicated clinical course as he had a mixed invasive fungal infection with pulmonary involvement due to Aspergillus niger and disseminated mucormycosis due to Rhizomucor pusillus (histopathological and microbiological diagnosis in several non-contiguous sites). He was treated with liposomal amphotericin B for 7 weeks (total cumulative dose >10 g) and required several surgical operations. The patient survived and was discharged from ICU after 5 months and multiple complications. Treatment with liposomal amphotericin B and aggressive surgical management achieved the eradication of a mixed invasive fungal infection. However, we emphasise the need to maintain a higher level of clinical suspicion and to perform microbiological techniques for early diagnosis of invasive fungal infections in non-immunocompromised patients, in order to prevent spread of the disease and the poor prognosis associated with it. Copyright © 2013 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

British Society for Medical Mycology best practice recommendations for the diagnosis of serious fungal diseases.

PubMed

Schelenz, Silke; Barnes, Rosemary A; Barton, Richard C; Cleverley, Joanne R; Lucas, Sebastian B; Kibbler, Christopher C; Denning, David W

2015-04-01

Invasive fungal diseases are an important cause of morbidity and mortality in a wide range of patients, and early diagnosis and management are a challenge. We therefore did a review of the scientific literature to generate a series of key recommendations for the appropriate use of microbiological, histological, and radiological diagnostic methods for diagnosis of invasive fungal diseases. The recommendations emphasise the role of microscopy in rapid diagnosis and identification of clinically significant isolates to species level, and the need for susceptibility testing of all Aspergillus spp, if treatment is to be given. In this Review, we provide information to improve understanding of the importance of antigen detection for cryptococcal disease and invasive aspergillosis, the use of molecular (PCR) diagnostics for aspergillosis, and the crucial role of antibody detection for chronic and allergic aspergillosis. Furthermore, we consider the importance of histopathology reporting with a panel of special stains, and emphasise the need for urgent (<48 hours) and optimised imaging for patients with suspected invasive fungal infection. All 43 recommendations are auditable and should be used to ensure best diagnostic practice and improved outcomes for patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

Hypoxia enhances innate immune activation to Aspergillus fumigates through cell wall modulation

PubMed Central

Shepardson, Kelly M.; Ngo, Lisa Y.; Aimanianda, Vishukumar; Latge, Jean-Paul; Barker, Bridget M.; Blosser, Sara J.; Iwakura, Yoichiro; Hohl, Tobias M.; Cramer, Robert A.

2013-01-01

Infection by the human fungal pathogen Aspergillus fumigatus induces hypoxic microenvironments within the lung that can alter the course of fungal pathogenesis. How hypoxic microenvironments shape the composition and immune activating potential of the fungal cell wall remains undefined. Herein we demonstrate that hypoxic conditions increase the hyphal cell wall thickness and alter its composition particularly by augmenting total and surface-exposed β-glucan content. In addition, hypoxia-induced cell wall alterations increase macrophage and neutrophil responsiveness and antifungal activity as judged by inflammatory cytokine production and ability to induce hyphal damage. We observe that these effects are largely dependent on the mammalian β-glucan receptor dectin-1. In a corticosteroid model of invasive pulmonary aspergillosis, A. fumigatus β-glucan exposure correlates with the presence of hypoxia in situ. Our data suggest that hypoxia-induced fungal cell wall changes influence the activation of innate effector cells at sites of hyphal tissue invasion, which has potential implications for therapeutic outcomes of invasive pulmonary aspergillosis. PMID:23220005

Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis.

PubMed

Marty, Francisco M; Ostrosky-Zeichner, Luis; Cornely, Oliver A; Mullane, Kathleen M; Perfect, John R; Thompson, George R; Alangaden, George J; Brown, Janice M; Fredricks, David N; Heinz, Werner J; Herbrecht, Raoul; Klimko, Nikolai; Klyasova, Galina; Maertens, Johan A; Melinkeri, Sameer R; Oren, Ilana; Pappas, Peter G; Ráčil, Zdeněk; Rahav, Galia; Santos, Rodrigo; Schwartz, Stefan; Vehreschild, J Janne; Young, Jo-Anne H; Chetchotisakd, Ploenchan; Jaruratanasirikul, Sutep; Kanj, Souha S; Engelhardt, Marc; Kaufhold, Achim; Ito, Masanori; Lee, Misun; Sasse, Carolyn; Maher, Rochelle M; Zeiher, Bernhardt; Vehreschild, Maria J G T

2016-07-01

Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response-ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)-according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19-179, range 2-882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595). Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. Astellas Pharma Global Development, Basilea Pharmaceutica International. Copyright © 2016 Elsevier Ltd. All rights reserved.

Arbuscular and Ectomycorrhizal Fungi Associated with the Invasive Brazilian Pepper Tree (Schinus terebinthifolius) and Two Native Plants in South Florida

PubMed Central

Dawkins, Karim; Esiobu, Nwadiuto

2017-01-01

The potential role of soil fungi in the invasion of the Brazilian pepper tree (Schinus terebinthifolius—BP) in Florida is not known; although the low biotic resistance of Florida soils is often invoked to explain the prevalence of many invasive species. To gain an initial insight into BP's mycorrhizal associations, this study examined the rhizobiome of BP and two native plants (Hamelia patens and Bidens alba) across six locations. Arbuscular mycorrhizal fungi (AMF) associated with the roots of the target plants and bulk soil was characterized by spore morphotyping. Sequence analysis of metagenomic DNA from lateral roots/rhizosphere of BP (n = 52) and a native shrub H. patens (n = 37) on the same parcel yielded other fungal associates. Overall, the total population of AMF associated with BP was about two folds greater than that of the two native plants (p = 0.0001) growing on the same site. The dominant AMF under Schinus were members of the common Glomus and Rhizophagus spp. By contrast, the most prevalent AMF in the bulk soil and rhizosphere of the two Florida native plants, Acaulospora spp (29%) was sharply diminished (9%) under BP rhizosphere. Analysis of the ITS2 sequences also showed that Schinus rhizosphere had a high relative abundance of ectomycorrhizal fungi (76.5%) compared to the native H. patens (2.6%), with the species Lactifluus hygrophoroides (Basidiomycota) being the most prevalent at 61.5% (p < 0.05). Unlike the native plants where pathogenic fungi like Phyllosticta sp., Phoma sp., and Neofusicoccum andium were present (8.1% for H. patens), only one potentially pathogenic fungal taxon was detected (3.9%) under BP. The striking disparity in the relative abundance of AMF and other fungal types between BP and the native species is quite significant. Fungal symbionts could aide plant invasion via resource-use efficiency and other poorly defined mechanisms of protection from pathogens in their invaded range. This report exposes a potentially significant but previously unappreciated fungal dimension of a complex invasion system and underscores the need to characterize these fungal symbionts, their role and mode of action during invasion; with the goal of devising measures for invasion control and ecological restoration. PMID:28473811

Epidemiology of fungal infections in liver transplant recipients: a six-year study of a large Brazilian liver transplantation centre.

PubMed

Zicker, Michelle; Colombo, Arnaldo Lopes; Ferraz-Neto, Ben-Hur; Camargo, Luis Fernando Aranha

2011-05-01

Liver transplant seems to be an effective option to prolong survival in patients with end-stage liver disease, although it still can be followed by serious complications. Invasive fungal infections (ifi) are related to high rates of morbidity and mortality. The epidemiology of fungal infections in Brazilian liver transplant recipients is unknown. The aim of this observational and retrospective study was to determine the incidence and epidemiology of fungal infections in all patients who underwent liver transplantation at Albert Einstein Israeli Hospital between 2002-2007. A total of 596 liver transplants were performed in 540 patients. Overall, 77 fungal infections occurred in 68 (13%) patients. Among the 77 fungal infections, there were 40 IFI that occurred in 37 patients (7%). Candida and Aspergillus species were the most common etiologic agents. Candida species accounted for 82% of all fungal infections and for 67% of all IFI, while Aspergillus species accounted for 9% of all fungal infections and for 17% of all IFI. Non-albicans Candida species were the predominant Candida isolates. Invasive aspergillosis tended to occur earlier in the post-transplant period. These findings can contribute to improve antifungal prophylaxis and therapy practices in Brazilian centres.

Real-time visualization of immune cell clearance of Aspergillus fumigatus spores and hyphae.

PubMed

Knox, Benjamin P; Huttenlocher, Anna; Keller, Nancy P

2017-08-01

Invasive aspergillosis (IA) is a disease of the immunocompromised host and generally caused by the opportunistic fungal pathogen Aspergillus fumigatus. While both host and fungal factors contribute to disease severity and outcome, there are fundamental features of IA development including fungal morphological transition from infectious conidia to tissue-penetrating hyphae as well as host defenses rooted in mechanisms of innate phagocyte function. Here we address recent advances in the field and use real-time in vivo imaging in the larval zebrafish to visually highlight conserved vertebrate innate immune behaviors including macrophage phagocytosis of conidia and neutrophil responses post-germination. Copyright © 2017 Elsevier Inc. All rights reserved.

Ecthyma gangrenosum mimicking acute invasive fungal sinusitis in an immunocompromised patient.

PubMed

Hekiert, Adrianna M; Cohen, Michael B; Montone, Kathleen T; Palmer, James N; Govindaraj, Satish

2010-06-01

Ecthyma gangrenosum is a rare necrotizing cutaneous infection usually caused by Pseudomonas aeruginosa. We report a case of ecthyma gangrenosum presenting as a sinonasal eschar and mimicking acute invasive fungal sinusitis in an immunocompromised 39-year-old man with a hematologic malignancy. To the best of our knowledge, this represents the first case of ecthyma gangrenosum affecting the sinonasal mucosa to be reported in the literature.

Fungal endocarditis in paediatrics: a review of 192 cases (1971-2016).

PubMed

Ganesan, Vithiya; Ponnusamy, Shunmuga Sundaram; Sundaramurthy, Raja

2017-10-01

The aims of this article were to review the published literature on fungal endocarditis in children and to discuss the aetiology and diagnosis, with emphasis on non-invasive methods and various treatment regimes. We systematically reviewed published cases and case series of fungal endocarditis in children. We searched the literature, including PubMed and individual references for publications of original articles, single cases, or case series of paediatric fungal endocarditis, with the following keywords: "fungal endocarditis", "neonates", "infants", "child", and "cardiac vegetation". There have been 192 documented cases of fungal endocarditis in paediatrics. The highest number of cases was reported in infants (93/192, 48%) including 60 in neonates. Of the neonatal cases, 57 were premature with a median gestational age of 27 weeks and median birth weight of 860 g. Overall, 120 yeast - fungus that grows as a single cell - infections and 43 mould - fungus that grows in multicellular filaments, hyphae - infections were reported. With increasing age, there was an increased infection rate with moulds. All the yeast infections were detected by blood culture. In cases with mould infection, diagnosis was mainly established by culture or histology of emboli or infected valves after invasive surgical procedures. There have been a few recent cases of successful early diagnosis by non-invasive methods such as blood polymerase chain reaction (PCR) for moulds. The overall mortality for paediatric fungal endocarditis was 56.25%. The most important cause of death was cardiac complications due to heart failure. Among the various treatment regimens used, none of them was significantly associated with better outcome. Non-invasive methods such as PCR tests can be used to improve the chances of detecting and identifying the aetiological agent in a timely manner. Delays in the diagnosis of these infections may result in high mortality and morbidity. No significant difference was noted between combined surgical and medical therapy over exclusively combined medical therapy.

Drugs currently under investigation for the treatment of invasive candidiasis.

PubMed

McCarthy, Matthew W; Walsh, Thomas J

2017-07-01

The widespread implementation of immunosuppressants, immunomodulators, hematopoietic stem cell transplantation and solid organ transplantation in clinical practice has led to an expanding population of patients who are at risk for invasive candidiasis, which is the most common form of fungal disease among hospitalized patients in the developed world. The emergence of drug-resistant Candida spp. has added to the morbidity associated with invasive candidiasis and novel therapeutic strategies are urgently needed. Areas covered: In this paper, we explore investigational agents for the treatment of invasive candidiasis, with particular attention paid to compounds that have recently entered phase I or phase II clinical trials. Expert opinion: The antifungal drug development pipeline has been severely limited due to regulatory hurdles and a systemic lack of investment in novel compounds. However, several promising drug development strategies have recently emerged, including chemical screens involving Pathogen Box compounds, combination antifungal therapy, and repurposing of existing agents that were initially developed to treat other conditions, all of which have the potential to redefine the treatment of invasive candidiasis.

High-Throughput Sequencing Reveals Drastic Changes in Fungal Communities in the Phyllosphere of Norway Spruce (Picea abies) Following Invasion of the Spruce Bud Scale (Physokermes piceae).

PubMed

Menkis, Audrius; Marčiulynas, Adas; Gedminas, Artūras; Lynikienė, Jūratė; Povilaitienė, Aistė

2015-11-01

The aim of this study was to assess the diversity and composition of fungal communities in damaged and undamaged shoots of Norway spruce (Picea abies) following recent invasion of the spruce bud scale (Physokermes piceae) in Lithuania. Sampling was done in July 2013 and included 50 random lateral shoots from ten random trees in each of five visually undamaged and five damaged 40-50-year-old pure stands of P. abies. DNA was isolated from 500 individual shoots, subjected to amplification of the internal transcribed spacer of fungal ribosomal DNA (ITS rDNA), barcoded and sequenced. Clustering of 149,426 high-quality sequences resulted in 1193 non-singleton contigs of which 1039 (87.1 %) were fungal. In total, there were 893 fungal taxa in damaged shoots and 608 taxa in undamaged shoots (p < 0.0001). Furthermore, 431 (41.5 %) fungal taxa were exclusively in damaged shoots, 146 (14.0 %) were exclusively in undamaged shoots, and 462 (44.5 %) were common to both types of samples. Correspondence analysis showed that study sites representing damaged and undamaged shoots were separated from each other, indicating that in these fungal communities, these were largely different and, therefore, heavily affected by P. piceae. In conclusion, the results demonstrated that invasive alien tree pests may have a profound effect on fungal mycobiota associated with the phyllosphere of P. abies, and therefore, in addition to their direct negative effect owing physical damage of the tissue, they may also indirectly determine health, sustainability and, ultimately, distribution of the forest tree species.

CARD9-Dependent Neutrophil Recruitment Protects against Fungal Invasion of the Central Nervous System

PubMed Central

Swamydas, Muthulekha; Rodriguez, Carlos A.; Lim, Jean K.; Mendez, Laura M.; Fink, Danielle L.; Hsu, Amy P.; Zhai, Bing; Karauzum, Hatice; Mikelis, Constantinos M.; Rose, Stacey R.; Ferre, Elise M. N.; Yockey, Lynne; Lemberg, Kimberly; Kuehn, Hye Sun; Rosenzweig, Sergio D.; Lin, Xin; Chittiboina, Prashant; Datta, Sandip K.; Belhorn, Thomas H.; Weimer, Eric T.; Hernandez, Michelle L.; Hohl, Tobias M.; Kuhns, Douglas B.; Lionakis, Michail S.

2015-01-01

Candida is the most common human fungal pathogen and causes systemic infections that require neutrophils for effective host defense. Humans deficient in the C-type lectin pathway adaptor protein CARD9 develop spontaneous fungal disease that targets the central nervous system (CNS). However, how CARD9 promotes protective antifungal immunity in the CNS remains unclear. Here, we show that a patient with CARD9 deficiency had impaired neutrophil accumulation and induction of neutrophil-recruiting CXC chemokines in the cerebrospinal fluid despite uncontrolled CNS Candida infection. We phenocopied the human susceptibility in Card9 -/- mice, which develop uncontrolled brain candidiasis with diminished neutrophil accumulation. The induction of neutrophil-recruiting CXC chemokines is significantly impaired in infected Card9 -/- brains, from both myeloid and resident glial cellular sources, whereas cell-intrinsic neutrophil chemotaxis is Card9-independent. Taken together, our data highlight the critical role of CARD9-dependent neutrophil trafficking into the CNS and provide novel insight into the CNS fungal susceptibility of CARD9-deficient humans. PMID:26679537

[Iron and invasive fungal infection].

PubMed

Álvarez, Florencio; Fernández-Ruiz, Mario; Aguado, José María

2013-01-01

Iron is an essential factor for both the growth and virulence of most of microorganisms. As a part of the innate (or nutritional) immune system, mammals have developed different mechanisms to store and transport this element in order to limit free iron bioavailability. To survive in this hostile environment, pathogenic fungi have specific uptake systems for host iron sources, one of the most important of which is based on the synthesis of siderophores-soluble, low-molecular-mass, high-affinity iron chelators. The increase in free iron that results from iron-overload conditions is a well-established risk factor for invasive fungal infection (IFI) such as mucormycosis or aspergillosis. Therefore, iron chelation may be an appealing therapeutic option for these infections. Nevertheless, deferoxamine -the first approved iron chelator- paradoxically increases the incidence of IFI, as it serves as a xeno-siderophore to Mucorales. On the contrary, the new oral iron chelators (deferiprone and deferasirox) have shown to exert a deleterious effect on fungal growth both in vitro and in animal models. The present review focuses on the role of iron metabolism in the pathogenesis of IFI and summarises the preclinical data, as well as the limited clinical experience so far, in the use of new iron chelators as treatment for mucormycosis and invasive aspergillosis. Copyright © 2012 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

[Invasive fungal disease due to Scedosporium, Fusarium and mucorales].

PubMed

Pemán, Javier; Salavert, Miguel

2014-01-01

The number of emerging organisms causing invasive fungal infections has increased in the last decades. These etiological agents include Scedosporium, Fusarium and mucorales. All of them can cause disseminated, virulent, and difficult-to treat infections in immunosuppressed patients, the most affected, due to their resistance to most available antifungal agents. Current trends in transplantation including the use of new immunosuppressive treatments, the common prescription of antifungal agents for prophylaxis, and new ecological niches could explain the emergence of these fungal pathogens. These pathogens can also affect immunocompetent individuals, especially after natural disasters (earthquakes, floods, tsunamis), combat wounds or near drowning. All the invasive infections caused by Scedosporium, Fusarium, and mucorales are potentially lethal and a favourable outcome is associated with rapid diagnosis by direct microscopic examination of the involved tissue, wide debridement of infected material, early use of antifungal agents including combination therapy, and an improvement in host defenses, especially neutropenia. Copyright © 2014. Published by Elsevier Espana.

Diagnosis of invasive fungal infections using real-time PCR assay in paediatric acute leukaemia induction.

PubMed

Mandhaniya, Sushil; Iqbal, Sobuhi; Sharawat, Surender Kumar; Xess, Immaculata; Bakhshi, Sameer

2012-07-01

Invasive fungal infections (IFI) lead to morbidity and mortality in neutropenic patients and in allogenic stem cell transplantation. Serum-based fungal detection assays have limitation of specificity or sensitivity. Studies on fungal DNA detection using real-time PCR in childhood leukaemia are lacking. The aim of this study was to develop sensitive and specific diagnostic tools for IFI in paediatric acute leukaemia patients using real-time PCR. Of 100 randomised paediatric acute leukaemia patients receiving antifungal prophylaxis with voriconazole/amphotericin B, single peripheral whole blood sample in EDTA was used for Pan-AC real-time PCR assay (detects nine Candida and six Aspergillus species) in patients who failed prophylaxis due to proven, probable, possible or suspected fungal infections. PCR results were retrospectively correlated with clinical profile. Real-time PCR test was positive in 18/29 (62%) patients who failed prophylaxis. The only patient with proven IFI (mucormycosis), real-time PCR assay was negative. Real-time PCR was positive in 2/4 (50%) patients with possible and 16/24 (66.6%) suspected IFI and 5/10 (50%) patients with pneumonia. By applying method A/B, sensitivity and positive predictive value could not be commented due to unproven Aspergillus or Candida infections; specificity and negative predictive values (NPV) were 41% and 100% respectively; by method C (included episodes of possible IFI as true positive), sensitivity, specificity, PPV and NPV were 50%, 36%, 11% and 81% respectively. In those with suspected IFI, 8/24 (33.3%) were PCR negative and unnecessarily received empirical antifungal therapy (EAFT). Real-time PCR is a practical, rapid, non-invasive screening test for excluding IFI in paediatric leukaemia. The high NPV makes real-time PCR a promising tool to use this prior to initiating EAFT in antibiotic-resistant febrile neutropenic patients; this would avoid toxicity, cost and hospitalisation for EAFT (ClinicalTrials.gov identifier:NCT00624143). © 2011 Blackwell Verlag GmbH.

The rationale of combination antifungal therapy in severely immunocompromised patients: empiricism versus evidence-based medicine.

PubMed

Chamilos, Georgios; Kontoyiannis, Dimitrios P

2006-08-01

Despite expansion of the antifungal armamentarium over the past decade, the mortality rate for invasive fungal infections remains high in severely immunocompromised patients. Furthermore, in recent years, difficult-to-treat invasive infections caused by rare molds and yeasts have emerged in high-risk patients receiving antifungal prophylaxis or empirical treatment. Antifungal combinations are increasingly used in clinical practice to improve outcomes for refractory mycoses because of the suboptimal efficacy of current antifungal agents. Herein we review recent advances in the area of antifungal combinations in high-risk patients to separate empiricism from evidence-based medicine. Thus far, the benefits of combination antifungal therapy have been difficult to prove for invasive fungal infections other than cryptococcal meningitis. The recent introduction of a new class of antifungal agents (the echinocandins) and extended-spectrum triazoles has rejuvenated interest in studying those combinations for difficult-to-treat aspergillosis, as recent observational studies show promise. In view of the evolving epidemiology of invasive fungal infections, combination antifungal therapy could be most valuable in preemptive management of carefully selected high-risk patients; however, this should be studied in appropriate trials.

[Significance of MUC5B antibody in differential diagnosis between Aspergillus species and Mucorales of fungal sinusitis].

PubMed

Piao, Ying-shi; Liu, Hong-gang; Liu, Xian-jun

2008-04-01

To differentiate between Aspergillus species and Mucorales of fungal sinusitis by immunohistochemistry. Formalin-fixed paraffin-embedded tissue blocks of 66 cases of fungal sinusitis were retrieved from the archival files of Department of Pathology of Beijing Tongren Hospital during the period from 2001 to 2006. The samples included 29 cases of fungal balls, 12 cases of allergic fungal sinusitis, 24 cases of chronic invasive fungal sinusitis and 1 case of acute invasive fungal sinusitis. The types of fungi were 44 Aspergillus species (31 cases of A. fumigatus, 7 cases of A. flavus and 6 cases of A. terreus) and 22 Mucorales (14 cases of Mucor species and 8 cases of Rhizopus species). Immunohistochemistry was performed with MUC2, MUC5AC and MUC5B antibodies. The results were compared with histochemical study for periodic acid-Schiff (PAS) and Grocott methenamine silver (GMS) stains. Immunohistochemical study for MUC5B showed that the positive rate of Aspergillus species was 90.9%, in contrast to 4.5% in Mucorales (P < 0.001). The expression of MUC2 and MUC5AC was completely negative, whereas PAS and GMS stains were positive in all cases. MUC5B antibody appears to be a useful immunohistochemical marker for identifying fungal types in tissue sections, especially in distinguishing between Aspergillus species and Mucorales in fungal sinusitis.

Advances in the diagnosis and treatment of fungal infections of the CNS.

PubMed

Schwartz, Stefan; Kontoyiannis, Dimitrios P; Harrison, Thomas; Ruhnke, Markus

2018-04-01

Fungal infections of the CNS are challenging to treat and their optimal management requires knowledge of their epidemiology, host characteristics, diagnostic criteria, and therapeutic options. Aspergillus and Cryptococcus species predominate among fungal infections of the CNS. Most of these fungi are ubiquitous, but some have restricted geographical distribution. Fungal infections of the CNS usually originate from primary sites outside the CNS (eg, fungal pneumonia) or occur after inoculation (eg, invasive procedures). Most patients with these infections have immunodeficiencies, but immunocompetent individuals can also be infected through heavy exposure. The infecting fungi can be grouped into moulds, yeasts, and dimorphic fungi. Substantial progress has been made with new diagnostic approaches and the introduction of novel antifungal drugs, but fungal infections of the CNS are frequently lethal because of diagnostic delays, impaired drug penetration, resistance to antifungal treatments, and inadequate restoration of immune function. To improve outcomes, future research should advance diagnostic methods (eg, molecular detection and fungus identification), develop antifungal compounds with enhanced CNS-directed efficacy, and further investigate crucial host defence mechanisms. Copyright © 2018 Elsevier Ltd. All rights reserved.

Resistant ticks inhibit Metarhizium infection prior to hemocoel invasion by reducing fungal viability on the cuticle surface

USDA-ARS?s Scientific Manuscript database

We studied disease progression of, and host responses to, four species in the M. anisopliae complex expressing green fluorescent protein (GFP). We compared development and determined their relative levels of virulence against two susceptible arthropods, the cattle tick Rhipicephalus annulatus and th...

A Spectral Mapping Signature for the Rapid Ohia Death (ROD) Pathogen in Hawaiian Forests

USDA-ARS?s Scientific Manuscript database

Pathogenic invasions are a major disruptive source of change in both agricultural and natural ecosystems. In forests, fungal pathogens can kill habitat-generating plant species such as canopy trees, but methods for remote detection, mapping and monitoring of such outbreaks are poorly developed. Cera...

Improved lure for redbay ambrosia beetle developed by enrichment of a-copaene content

USDA-ARS?s Scientific Manuscript database

Over the past decade, the exotic redbay ambrosia beetle, Xyleborus glabratus Eichhoff, has become a serious invasive pest in the USA, now established in seven southeastern states. Females are the primary vectors of a fungal pathogen, Raffaelea lauricola, that causes laurel wilt, a lethal disease of...

Co-incidental Plasmodium Knowlesi and Mucormycosis infections presenting with acute kidney injury and lower gastrointestinal bleeding.

PubMed

Ramaswami, Arunachalam; Pisharam, Jayakrishnan K; Aung, Hla; Ghazala, Kafeel; Maboud, Khalil; Chong, Vui Heng; Tan, Jackson

2013-01-01

Plasmodium knowlesi is frequently reported in Southeast Asian countries and is now widely regarded as the fifth malarial parasite. Mucormycosis is a rare fungal infection that can occur in patients with a weakened immune system. We report a case of acute kidney injury secondary to Plasmodium knowlesi malaria infection and mucormycosis fungal infection. In addition, the patient also had lower gastrointestinal bleeding from invasive gastrointestinal mucormycosis. P. knowlesi infection was diagnosed by blood film and mucormycosis was diagnosed by histopathological examination of biopsy specimen of the colon. The patient recovered with antimalarial treatment (Quinine), antifungal treatment (Lipophilic Amphotericin), and supportive hemodialysis treatment. We hypothesize that P. knowlesi malarial infection can lower the immunologic threshold and predisposes vulnerable individuals to rare disseminated fungal infections. To the best of our knowledge, this is the first P. Knowlesi malaria-associated invasive fungal infection reported in the literature.

Long-distance endosome trafficking drives fungal effector production during plant infection

PubMed Central

Bielska, Ewa; Higuchi, Yujiro; Schuster, Martin; Steinberg, Natascha; Kilaru, Sreedhar; Talbot, Nicholas J.; Steinberg, Gero

2014-01-01

To cause plant disease, pathogenic fungi can secrete effector proteins into plant cells to suppress plant immunity and facilitate fungal infection. Most fungal pathogens infect plants using very long strand-like cells, called hyphae, that secrete effectors from their tips into host tissue. How fungi undergo long-distance cell signalling to regulate effector production during infection is not known. Here we show that long-distance retrograde motility of early endosomes (EEs) is necessary to trigger transcription of effector-encoding genes during plant infection by the pathogenic fungus Ustilago maydis. We demonstrate that motor-dependent retrograde EE motility is necessary for regulation of effector production and secretion during host cell invasion. We further show that retrograde signalling involves the mitogen-activated kinase Crk1 that travels on EEs and participates in control of effector production. Fungal pathogens therefore undergo long-range signalling to orchestrate host invasion. PMID:25283249

Long-distance endosome trafficking drives fungal effector production during plant infection.

PubMed

Bielska, Ewa; Higuchi, Yujiro; Schuster, Martin; Steinberg, Natascha; Kilaru, Sreedhar; Talbot, Nicholas J; Steinberg, Gero

2014-10-06

To cause plant disease, pathogenic fungi can secrete effector proteins into plant cells to suppress plant immunity and facilitate fungal infection. Most fungal pathogens infect plants using very long strand-like cells, called hyphae, that secrete effectors from their tips into host tissue. How fungi undergo long-distance cell signalling to regulate effector production during infection is not known. Here we show that long-distance retrograde motility of early endosomes (EEs) is necessary to trigger transcription of effector-encoding genes during plant infection by the pathogenic fungus Ustilago maydis. We demonstrate that motor-dependent retrograde EE motility is necessary for regulation of effector production and secretion during host cell invasion. We further show that retrograde signalling involves the mitogen-activated kinase Crk1 that travels on EEs and participates in control of effector production. Fungal pathogens therefore undergo long-range signalling to orchestrate host invasion.

[Nosocomial infection due to Trichosporon asahii in a critical burned patient].

PubMed

Tamayo Lomas, Luis; Domínguez-Gil González, Marta; Martín Luengo, Ana Isabel; Eiros Bouza, José María; Piqueras Pérez, José María

2015-01-01

Invasive fungal infection is an important cause of morbimortality in patients with severe burns. The advances in burn care therapy have considerably extended the survival of seriously burned patients, exposing them to infectious complications, notably fungal infections, with increased recognition of invasive infections caused by Candida species. However, some opportunistic fungi, like Trichosporon asahii, have emerged as important causes of nosocomial infection. A case of nosocomial infection due to T. asahii in a severely ill burned patient successfully treated with voriconazole is presented. The management of invasive fungal infections in burned patients, from diagnosis to selection of the therapeutic protocol, is often a challenge. Early diagnosis and treatment are associated with a better prognosis. In this case report, current treatment options are discussed, and a review of previously published cases is presented. Due to the difficulty in the diagnosis of invasive mycoses and their high associated mortality rates, it is advisable to keep a high degree of clinical suspicion of trichosporonosis in susceptible patients, including burned patients. The isolation of T. asahii in clinical specimens of this type of host must raise clinical alert, since it may precede an invasive infection. Copyright © 2014 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

ImmunoPET/MR imaging allows specific detection of Aspergillus fumigatus lung infection in vivo

PubMed Central

Rolle, Anna-Maria; Hasenberg, Mike; Thornton, Christopher R.; Solouk-Saran, Djamschid; Männ, Linda; Weski, Juliane; Maurer, Andreas; Fischer, Eliane; Spycher, Philipp R.; Schibli, Roger; Boschetti, Frederic; Stegemann-Koniszewski, Sabine; Bruder, Dunja; Severin, Gregory W.; Autenrieth, Stella E.; Krappmann, Sven; Davies, Genna; Pichler, Bernd J.; Gunzer, Matthias; Wiehr, Stefan

2016-01-01

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease caused by the fungus Aspergillus fumigatus, and is a leading cause of invasive fungal infection-related mortality and morbidity in patients with hematological malignancies and bone marrow transplants. We developed and tested a novel probe for noninvasive detection of A. fumigatus lung infection based on antibody-guided positron emission tomography and magnetic resonance (immunoPET/MR) imaging. Administration of a [64Cu]DOTA-labeled A. fumigatus-specific monoclonal antibody (mAb), JF5, to neutrophil-depleted A. fumigatus-infected mice allowed specific localization of lung infection when combined with PET. Optical imaging with a fluorochrome-labeled version of the mAb showed colocalization with invasive hyphae. The mAb-based newly developed PET tracer [64Cu]DOTA-JF5 distinguished IPA from bacterial lung infections and, in contrast to [18F]FDG-PET, discriminated IPA from a general increase in metabolic activity associated with lung inflammation. To our knowledge, this is the first time that antibody-guided in vivo imaging has been used for noninvasive diagnosis of a fungal lung disease (IPA) of humans, an approach with enormous potential for diagnosis of infectious diseases and with potential for clinical translation. PMID:26787852

Transcriptomic Crosstalk between Fungal Invasive Pathogens and Their Host Cells: Opportunities and Challenges for Next-Generation Sequencing Methods

PubMed Central

Enguita, Francisco J.; Costa, Marina C.; Fusco-Almeida, Ana Marisa; Mendes-Giannini, Maria José; Leitão, Ana Lúcia

2016-01-01

Fungal invasive infections are an increasing health problem. The intrinsic complexity of pathogenic fungi and the unmet clinical need for new and more effective treatments requires a detailed knowledge of the infection process. During infection, fungal pathogens are able to trigger a specific transcriptional program in their host cells. The detailed knowledge of this transcriptional program will allow for a better understanding of the infection process and consequently will help in the future design of more efficient therapeutic strategies. Simultaneous transcriptomic studies of pathogen and host by high-throughput sequencing (dual RNA-seq) is an unbiased protocol to understand the intricate regulatory networks underlying the infectious process. This protocol is starting to be applied to the study of the interactions between fungal pathogens and their hosts. To date, our knowledge of the molecular basis of infection for fungal pathogens is still very limited, and the putative role of regulatory players such as non-coding RNAs or epigenetic factors remains elusive. The wider application of high-throughput transcriptomics in the near future will help to understand the fungal mechanisms for colonization and survival, as well as to characterize the molecular responses of the host cell against a fungal infection. PMID:29376924

Fatal disseminated Rasamsonia infection in cystic fibrosis post-lung transplantation.

PubMed

Hong, Gina; White, Marissa; Lechtzin, Noah; West, Natalie E; Avery, Robin; Miller, Heather; Lee, Richard; Lovari, Robert J; Massire, Christian; Blyn, Lawrence B; Liang, Xinglun; Sutton, Deanna A; Fu, Jianmin; Wickes, Brian L; Wiederhold, Nathan P; Zhang, Sean X

2017-03-01

Disseminated fungal infections are a known serious complication in individuals with cystic fibrosis (CF) following orthotopic lung transplantation. Aspergillus fumigatus and Scedosporium species are among the more common causes of invasive fungal infection in this population. However, it is also important for clinicians to be aware of other emerging fungal species which may require markedly different antifungal therapies. We describe the first laboratory-documented case of a fatal disseminated fungal infection caused by Rasamsonia aegroticola in a 21-year-old female CF patient status post-bilateral lung transplantation, which was only identified post-mortem. Molecular analysis revealed the presence of the identical Rasamsonia strains in the patient's respiratory cultures preceding transplantation. We propose that the patient's disseminated fungal disease and death occurred as a result of recrudescence of Rasamsonia infection from her native respiratory system in the setting of profound immunosuppression post-operatively. Since Rasamsonia species have been increasingly recovered from the respiratory tract of CF patients, we further review the literature on these fungi and discuss their association with invasive fungal infections in the CF lung transplant host. Our report suggests Rasamsonia species may be important fungal pathogens that may have fatal consequences in immunosuppressed CF patients after solid organ transplantation. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Cellular and Molecular Defects Underlying Invasive Fungal Infections—Revelations from Endemic Mycoses

PubMed Central

Lee, Pamela P.; Lau, Yu-Lung

2017-01-01

The global burden of fungal diseases has been increasing, as a result of the expanding number of susceptible individuals including people living with human immunodeficiency virus (HIV), hematopoietic stem cell or organ transplant recipients, patients with malignancies or immunological conditions receiving immunosuppressive treatment, premature neonates, and the elderly. Opportunistic fungal pathogens such as Aspergillus, Candida, Cryptococcus, Rhizopus, and Pneumocystis jiroveci are distributed worldwide and constitute the majority of invasive fungal infections (IFIs). Dimorphic fungi such as Histoplasma capsulatum, Coccidioides spp., Paracoccidioides spp., Blastomyces dermatiditis, Sporothrix schenckii, Talaromyces (Penicillium) marneffei, and Emmonsia spp. are geographically restricted to their respective habitats and cause endemic mycoses. Disseminated histoplasmosis, coccidioidomycosis, and T. marneffei infection are recognized as acquired immunodeficiency syndrome (AIDS)-defining conditions, while the rest also cause high rate of morbidities and mortalities in patients with HIV infection and other immunocompromised conditions. In the past decade, a growing number of monogenic immunodeficiency disorders causing increased susceptibility to fungal infections have been discovered. In particular, defects of the IL-12/IFN-γ pathway and T-helper 17-mediated response are associated with increased susceptibility to endemic mycoses. In this review, we put together the various forms of endemic mycoses on the map and take a journey around the world to examine how cellular and molecular defects of the immune system predispose to invasive endemic fungal infections, including primary immunodeficiencies, individuals with autoantibodies against interferon-γ, and those receiving biologic response modifiers. Though rare, these conditions provide importance insights to host defense mechanisms against endemic fungi, which can only be appreciated in unique climatic and geographical regions. PMID:28702025

[Molecular techniques in mycology].

PubMed

Rodríguez-Tudela, Juan Luis; Cuesta, Isabel; Gómez-López, Alicia; Alastruey-Izquierdo, Ana; Bernal-Martínez, Leticia; Cuenca-Estrella, Manuel

2008-11-01

An increasing number of molecular techniques for the diagnosis of fungal infections have been developed in the last few years, due to the growing prevalence of mycoses and the length of time required for diagnosis when classical microbiological methods are used. These methods are designed to resolve the following aspects of mycological diagnosis: a) Identification of fungi to species level by means of sequencing relevant taxonomic targets; b) early clinical diagnosis of invasive fungal infections; c) detection of molecular mechanisms of resistance to antifungal agents; and d) molecular typing of fungi. Currently, these methods are restricted to highly developed laboratories. However, some of these techniques will probably be available in daily clinical practice in the near future.

Invasive Fungal Infections after Natural Disasters

PubMed Central

Benedict, Kaitlin

2014-01-01

The link between natural disasters and subsequent fungal infections in disaster-affected persons has been increasingly recognized. Fungal respiratory conditions associated with disasters include coccidioidomycosis, and fungi are among several organisms that can cause near-drowning pneumonia. Wound contamination with organic matter can lead to post-disaster skin and soft tissue fungal infections, notably mucormycosis. The role of climate change in the environmental growth, distribution, and dispersal mechanisms of pathogenic fungi is not fully understood; however, ongoing climate change could lead to increased disaster-associated fungal infections. Fungal infections are an often-overlooked clinical and public health issue, and increased awareness by health care providers, public health professionals, and community members regarding disaster-associated fungal infections is needed. PMID:24565446

Invasive fungal infections after natural disasters.

PubMed

Benedict, Kaitlin; Park, Benjamin J

2014-03-01

The link between natural disasters and subsequent fungal infections in disaster-affected persons has been increasingly recognized. Fungal respiratory conditions associated with disasters include coccidioidomycosis, and fungi are among several organisms that can cause near-drowning pneumonia. Wound contamination with organic matter can lead to post-disaster skin and soft tissue fungal infections, notably mucormycosis. The role of climate change in the environmental growth, distribution, and dispersal mechanisms of pathogenic fungi is not fully understood; however, ongoing climate change could lead to increased disaster-associated fungal infections. Fungal infections are an often-overlooked clinical and public health issue, and increased awareness by health care providers, public health professionals, and community members regarding disaster-associated fungal infections is needed.

Chest CT scans are frequently abnormal in asymptomatic patients with newly diagnosed acute myeloid leukemia.

PubMed

Vallipuram, Janaki; Dhalla, Sidika; Bell, Chaim M; Dresser, Linda; Han, Heekyung; Husain, Shahid; Minden, Mark D; Paul, Narinder S; So, Miranda; Steinberg, Marilyn; Vallipuram, Mayuran; Wong, Gary; Morris, Andrew M

2017-04-01

Chest computed tomography (CT) findings of nodules, ground glass opacities, and consolidations are often interpreted as representing invasive fungal infection in individuals with febrile neutropenia. We assessed whether these CT findings were present in asymptomatic individuals with acute myeloid leukemia (AML) at low risk of invasive fungal disease. A retrospective study of consecutive asymptomatic adult patients with newly diagnosed AML over a 2-year period was performed at a tertiary care oncology center. Radiology reports of baseline chest CTs were reviewed. Of 145 CT scans, the majority (88%) had pulmonary abnormalities. Many (70%) had one or both of unspecified opacities (52%) and nodules (49%). Ground glass opacities (18%) and consolidations (12%) occurred less frequently. Radiologists suggested pneumonia as a possible diagnosis in 32% (n = 47) of scans. Chest CT may result in over-diagnosis of invasive fungal disease in individuals with febrile neutropenia if interpreted without correlation to the patients' clinical status.

Defining Responses to Therapy and Study Outcomes in Clinical Trials of Invasive Fungal Diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer Consensus Criteria

PubMed Central

Segal, Brahm H.; Herbrecht, Raoul; Stevens, David A.; Ostrosky-Zeichner, Luis; Sobel, Jack; Viscoli, Claudio; Walsh, Thomas J.; Maertens, Johan; Patterson, Thomas F.; Perfect, John R.; Dupont, Bertrand; Wingard, John R.; Calandra, Thierry; Kauffman, Carol A.; Graybill, John R.; Baden, Lindsey R.; Pappas, Peter G.; Bennett, John E.; Kontoyiannis, Dimitrios P.; Cordonnier, Catherine; Viviani, Maria Anna; Bille, Jacques; Almyroudis, Nikolaos G.; Wheat, L. Joseph; Graninger, Wolfgang; Bow, Eric J.; Holland, Steven M.; Kullberg, Bart-Jan; Dismukes, William E.; De Pauw, Ben E.

2009-01-01

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge. PMID:18637757

Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants.

PubMed

Marr, Kieren A; Crippa, Fulvio; Leisenring, Wendy; Hoyle, Maggie; Boeckh, Michael; Balajee, S Arunmozhi; Nichols, W Garrett; Musher, Benjamin; Corey, Lawrence

2004-02-15

Prophylactic fluconazole prevents candidiasis; however, this drug has no activity against molds. We performed a randomized trial to determine whether prophylactic itraconazole prevents invasive mold infections (IMIs). A total of 304 patients receiving allogeneic stem cell transplants (SCT) were randomized to receive fluconazole (400 mg/d) or itraconazole (oral solution 2.5 mg/kg 3 times daily, or intravenous 200 mg daily) for 180 days after SC transplantation, or until 4 weeks after discontinuation of graft-versus-host disease (GVHD) therapy. Proven or probable invasive fungal infections (IFI) were evaluated by intent-to-treat and "on-treatment" analyses. More patients in the itraconazole arm developed hepatotoxicities, and more patients were discontinued from itraconazole because of toxicities or gastrointestinal (GI) intolerance (36% versus 16%, P <.001). Intent-to-treat analysis demonstrated no difference in the incidence of IFI during the intended study period (fluconazole 16% versus itraconazole 13%, P =.46); however, fewer patients in the itraconazole arm developed IFI on treatment (fluconazole 15% versus itraconazole 7%, P =.03). Itraconazole provided better protection against IMI (fluconazole 12% versus itraconazole 5%, P =.03), but similar protection against candidiasis (3% versus 2%, P =.69). There was no difference in overall or fungal-free survival. Itraconazole appears to prevent IMI in the subset of patients who tolerate the drug; however, toxicities and poor tolerability limit its success as prophylactic therapy.

Pharmacoeconomic evaluations of antifungal therapies.

PubMed

Hennen, Cynthia R

2009-07-01

Invasive fungal infections are a growing source of morbidity and mortality in the United States and are associated with excess hospital stay and costs. Although clinicians now have more effective and safe treatment options for invasive candidiasis, evidence confirming the pharmacoeconomic benefits of newer treatment options such as the echinocandins is scarce as few rigorous pharmacoeconomic studies have been completed in the arena of invasive fungal infections. Beyond the cost of drug acquisition, costs associated with ineffective treatment and significant drug-related side-effects must be factored into pharmacoeconomic analysis. Additional administrative costs may need to be considered when a formulary medication switch is undertaken, including those involved with re-education of clinicians unfamiliar with the newer product.

QPCR detection of Mucorales DNA in bronchoalveolar lavage fluid to diagnose pulmonary mucormycosis.

PubMed

Scherer, Emeline E; Iriart, Xavier; Bellanger, Anne Pauline; Dupont, Damien; Guitard, Juliette; Gabriel, Frederic; Cassaing, Sophie; Charpentier, Eléna; Guenounou, Sarah; Cornet, Murielle; Botterel, Françoise; Rocchi, Steffi; Berceanu, Ana; Millon, Laurence

2018-06-06

Early diagnosis and treatment are essential to improving the outcome of mucormycosis. The aim of this retrospective study was to assess the contribution of quantitative PCR detection of Mucorales DNA in bronchoalveolar lavage fluids for early diagnosis of pulmonary mucormycosis.Bronchoalveolar lavage fluids (n=450) from 374 patients with pneumonia and immunosuppressive conditions were analyzed using a combination of 3 quantitative PCR assays targeting the main genera involved in mucormycosis in France ( Rhizomucor, Mucor/Rhizopus, Lichtheimia ).Among these 374 patients, 24 had at least one bronchoalveolar lavage with a positive PCR; 23/24 patients had radiological criteria for invasive fungal infections according to consensual criteria : 10 patients with probable or proven mucormycosis, and 13 additional patients with other invasive fungal infections (4 probable aspergillosis, 1 proven fusariosis, and 8 possible invasive fungal infections). Only 2/24 patients with a positive PCR on bronchoalveolar lavage had a positive Mucorales culture.PCR was also positive on serum in 17/24 patients. In most cases, PCR was first detected positive on sera (15/17). However, a positive PCR on bronchoalveolar lavage was the earliest and/or the only biological test revealing mucormycosis in 4 patients with a final diagnosis of probable or proven mucormycosis, 3 patients with probable aspergillosis and one patient with a possible invasive fungal infection.Mucorales PCR performed on bronchoalveolar lavage could provide additional arguments for earlier administration of Mucorales-directed antifungal therapy, thus improving the outcome of lung mucormycosis. Copyright © 2018 American Society for Microbiology.

Development of a kairomone-based monitoring tool for the invasive redbay ambrosia beetle

USDA-ARS?s Scientific Manuscript database

The redbay ambrosia beetle, Xyleborus glabratus Eichhoff, is an exotic wood-borer that vectors the fungal agent responsible for laurel wilt. This disease has had severe impact on forest ecosystems, and has spread to eight states in the southeastern US since the first detection of the beetle in Georg...

Development of host-based lures for detection of redbay ambrosia beetle, Xyleborus glabratus

USDA-ARS?s Scientific Manuscript database

The redbay ambrosia beetle, Xyleborus glabratus Eichhoff, is native to Southeast Asia, but since its initial detection near Savannah, Georgia in 2002, it has become a serious invasive pest in the USA, now established in seven southeastern states. Females are the primary vectors of a fungal pathogen...

Call for Action: Invasive Fungal Infections Associated With Ibrutinib and Other Small Molecule Kinase Inhibitors Targeting Immune Signaling Pathways.

PubMed

Chamilos, Georgios; Lionakis, Michail S; Kontoyiannis, Dimitrios P

2018-01-06

Opportunistic infections caused by Pneumocystis jirovecii, Cryptococcus neoformans, and ubiquitous airborne filamentous fungi have been recently reported in patients with hematological cancers historically considered at low risk for invasive fungal infections (IFIs), after receipt of the Bruton tyrosine kinase inhibitor ibrutinib. The spectrum and severity of IFIs often observed in these patients implies the presence of a complex immunodeficiency that may not be solely attributed to mere inhibition of Bruton tyrosine kinase. In view of the surge in development of small molecule kinase inhibitors for treatment of malignant and autoimmune diseases, it is possible that there would be an emergence of IFIs associated with the effects of these molecules on the immune system. Preclinical assessment of the immunosuppressive effects of kinase inhibitors and human studies aimed at improving patient risk stratification for development of IFIs could lead to prevention, earlier diagnosis, and better outcomes in affected patients. © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Risk Factors Associated with Invasive Fungal Infections in Combat Trauma

PubMed Central

Rodriguez, Carlos J.; Weintrob, Amy C.; Shah, Jinesh; Malone, Debra; Dunne, James R.; Weisbrod, Allison B.; Lloyd, Bradley A.; Warkentien, Tyler E.; Murray, Clinton K.; Wilkins, Kenneth; Shaikh, Faraz; Carson, M. Leigh; Aggarwal, Deepak

2014-01-01

Abstract Background: In recent years, invasive fungal infections (IFI) have complicated the clinical course of patients with combat-related injuries. Commonalities in injury patterns and characteristics among patients with IFI led to the development of a Joint Trauma System (JTS) clinical practice guideline (CPG) for IFI management. We performed a case-control study to confirm and further delineate risk factors associated with IFI development in combat casualties with the objective of generating data to refine the CPG and promote timelier initiation of treatment. Methods: Data were collected retrospectively for United States (U.S.) military personnel injured during deployment in Afghanistan from June 2009 through August 2011. Cases were identified as IFI based upon wound cultures with fungal growth and/or fungal elements seen on histology, in addition to the presence of recurrent wound necrosis. Controls were matched using date of injury (±3 mo) and injury severity score (±10). Risk factor parameters analyzed included injury circumstances, blood transfusion requirements, amputations after first operative intervention, and associated injuries. Data are expressed as multivariate odds ratios (OR; 95% confidence interval [CI]). Results: Seventy-six IFI cases were identified from 1,133 U.S. military personnel wounded in Afghanistan and matched to 150 controls. Parameters associated significantly with the development of IFI multivariate analysis were blast injuries (OR: 5.7; CI: 1.1–29.6), dismounted at time of injury (OR: 8.5; CI: 1.2–59.8); above the knee amputations (OR: 4.1; CI: 1.3-12.7), and large-volume packed red blood cell (PRBC; >20 U) transfusions within first 24 h (OR: 7.0; CI: 2.5-19.7). Conclusions: Our analysis indicates that dismounted blast injuries, resulting in above the knee amputations, and requirement of large volume PRBC transfusions are independent predictors of IFI development. These data confirm all the preliminary risk factors, except for genitalia/perineal injuries, utilized by JTS in their IFI CPG. Model validation is necessary for further risk factor specification. PMID:24821267

Universal antifungal therapy is not needed in persistent febrile neutropenia: a tailored diagnostic and therapeutic approach

PubMed Central

Aguilar-Guisado, Manuela; Martín-Peña, Almudena; Espigado, Ildefonso; Ruiz Pérez de Pipaon, Maite; Falantes, José; de la Cruz, Fátima; Cisneros, José M.

2012-01-01

Background Giving antifungal therapy exclusively to selected patients with persistent febrile neutropenia may avoid over-treatment without increasing mortality. The aim of this study was to validate an innovative diagnostic and therapeutic approach based on assessing patients’ risk profile and clinical criteria in order to select those patients requiring antifungal therapy. The efficacy of this approach was compared to that of universal empirical antifungal therapy. Design and Methods This was a prospective study which included all consecutive adult hematology patients with neutropenia and fever refractory to 5 days of empirical antibacterial therapy admitted to a teaching hospital in Spain over a 2-year period. A diagnostic and therapeutic approach based on clinical criteria and risk profile was applied in order to select patients for antifungal therapy. The sensitivity, specificity and negative predictive value of this approach and also the overall success rate, according to the same criteria of efficacy described in classical clinical trials, were analyzed. Results Eighty-five episodes were included, 35 of them (41.2%) in patients at high risk of invasive fungal infections. Antifungal therapy was not indicated in 33 episodes (38.8%). The overall incidence of proven and probable invasive fungal infections was 14.1%, all of which occurred in patients who had received empirical antifungal therapy. The 30-day crude mortality rate was 15.3% and the invasive fungal infection-related mortality rate was 2.8% (2/72). The overall success rate following the diagnostic and therapeutic approach was 36.5% compared with 33.9% and 33.7% obtained in the trial by Walsh et al. The sensitivity, specificity and negative predictive value of the study approach were 100%, 52.4% and 100%, respectively. Conclusions Based on the high negative predictive value of this diagnostic and therapeutic approach in persistent febrile neutropenia patients with hematologic malignancies or patients who have received a hematopoietic stem cell transplant, the approach is useful for identifying patients who are not likely to develop invasive fungal infection and do not, therefore, require antifungal therapy. The effectiveness of the strategy is similar to that of universal empirical antifungal therapy reported in controlled trials. PMID:22058202

Thigmo Responses: The Fungal Sense of Touch.

PubMed

Almeida, Mariana Cruz; Brand, Alexandra C

2017-04-01

The growth and development of most fungi take place on a two-dimensional surface or within a three-dimensional matrix. The fungal sense of touch is therefore critical for fungi in the interpretation of their environment and often signals the switch to a new developmental state. Contact sensing, or thigmo-based responses, include thigmo differentiation, such as the induction of invasion structures by plant pathogens in response to topography; thigmonasty, where contact with a motile prey rapidly triggers its capture; and thigmotropism, where the direction of hyphal growth is guided by physical features in the environment. Like plants and some bacteria, fungi grow as walled cells. Despite the well-demonstrated importance of thigmo responses in numerous stages of fungal growth and development, it is not known how fungal cells sense contact through the relatively rigid structure of the cell wall. However, while sensing mechanisms at the molecular level are not entirely understood, the downstream signaling pathways that are activated by contact sensing are being elucidated. In the majority of cases, the response to contact is complemented by chemical cues and both are required, either sequentially or simultaneously, to elicit normal developmental responses. The importance of a sense of touch in the lifestyles and development of diverse fungi is highlighted in this review, and the candidate molecular mechanisms that may be involved in fungal contact sensing are discussed.

An annotated bibliography of invasive tree pathogens Sirococcus clavigignenti-juglandacearum, Phytophthora alni, and Phytophthora quercina and a regulatory policy and management practices for invasive species

Treesearch

T.M. Seeland; M.E. Ostry; R. Venette; J. Juzwik

2006-01-01

Provides a database of selected literature pertaining to the prevention, early detection and rapid response, control and management, and rehabilitation and restoration related to three invasive fungal pathogens of forest trees. Literature addressing regulatory policy and management practices for invasive species is also included.

Evaluation of fluorescence in situ hybridisation (FISH) for the detection of fungi directly from blood cultures and cerebrospinal fluid from patients with suspected invasive mycoses.

PubMed

Da Silva, Roberto Moreira; Da Silva Neto, João Ricardo; Santos, Carla Silvana; Frickmann, Hagen; Poppert, Sven; Cruz, Kátia Santana; Koshikene, Daniela; De Souza, João Vicente Braga

2015-01-31

The aim of this study was to evaluate the diagnostic performance of in-house FISH (fluorescence in situ hybridisation) procedures for the direct identification of invasive fungal infections in blood cultures and cerebrospinal fluid (CSF) samples and to compare these FISH results with those obtained using traditional microbiological techniques and PCR targeting of the ITS1 region of the rRNA gene. In total, 112 CSF samples and 30 positive blood cultures were investigated by microscopic examination, culture, PCR-RFLP and FISH. The sensitivity of FISH for fungal infections in CSF proved to be slightly better than that of conventional microscopy (India ink) under the experimental conditions, detecting 48 (instead of 46) infections in 112 samples. The discriminatory powers of traditional microbiology, PCR-RFLP and FISH for fungal bloodstream infections were equivalent, with the detection of 14 fungal infections in 30 samples. However, the mean times to diagnosis after the detection of microbial growth by automated blood culture systems were 5 hours, 20 hours and 6 days for FISH, PCR-RFLP and traditional microbiology, respectively. The results demonstrate that FISH is a valuable tool for the identification of invasive mycoses that can be implemented in the diagnostic routine of hospital laboratories.

Imaging O2 changes induced in tomato roots by fungal pathogen

NASA Astrophysics Data System (ADS)

Rubol, S.; Turco, E.; Rodeghiero, M.; Bellin, A.

2014-12-01

In the last decade, planar optodes have demonstrated to be a useful non-invasive tool to monitor real time oxygen concentrations in a wide range of applications. However, only limited investigations have been carried out to explore the use of optodes in plant respiration studies. In particular, their use to study plant-pathogen interactions has been not deeply investigated. Here, we present for the first time an in vitro experimental setup capable to depict the dynamical effects of the fungal pathogen Fusarium oxysporum f.sp. lycopersici (Fol) on tomato roots by the use of a recently developed optical non-invasive optode oxygen sensor (Visisens, Presens, Germany). Fol is a soil-borne pathogen and the causal agent of wilt in tomato plants, a destructive worldwide disease. The interaction Fol-tomato is widely accepted as a model system in plant pathology. In this work, oxygen concentrations are monitored continuously in time and considered a proxy for root respiration and metabolic activity. The experimental procedure reveals three different dynamic stages: 1) a uniform oxygen consumption in tomato roots earlier before pathogen colonization, 2) a progressive decrease in the oxygen concentration indicating a high metabolic activity as soon as the roots were surrounded and colonized by the fungal mycelium, and 3) absence of root respiration, as a consequence of root death. Our results suggest the ability of the fungal mycelium to move preferentially towards and along the root as a consequence of the recognition event.

Risk factors for invasive fungal disease in critically ill adult patients: a systematic review.

PubMed

Muskett, Hannah; Shahin, Jason; Eyres, Gavin; Harvey, Sheila; Rowan, Kathy; Harrison, David

2011-01-01

Over 5,000 cases of invasive Candida species infections occur in the United Kingdom each year, and around 40% of these cases occur in critical care units. Invasive fungal disease (IFD) in critically ill patients is associated with increased morbidity and mortality at a cost to both the individual and the National Health Service. In this paper, we report the results of a systematic review performed to identify and summarise the important risk factors derived from published multivariable analyses, risk prediction models and clinical decision rules for IFD in critically ill adult patients to inform the primary data collection for the Fungal Infection Risk Evaluation Study. An internet search was performed to identify articles which investigated risk factors, risk prediction models or clinical decisions rules for IFD in critically ill adult patients. Eligible articles were identified in a staged process and were assessed by two investigators independently. The methodological quality of the reporting of the eligible articles was assessed using a set of questions addressing both general and statistical methodologies. Thirteen articles met the inclusion criteria, of which eight articles examined risk factors, four developed a risk prediction model or clinical decision rule and one evaluated a clinical decision rule. Studies varied in terms of objectives, risk factors, definitions and outcomes. The following risk factors were found in multiple studies to be significantly associated with IFD: surgery, total parenteral nutrition, fungal colonisation, renal replacement therapy, infection and/or sepsis, mechanical ventilation, diabetes, and Acute Physiology and Chronic Health Evaluation II (APACHE II) or APACHE III score. Several other risk factors were also found to be statistically significant in single studies only. Risk factor selection process and modelling strategy also varied across studies, and sample sizes were inadequate for obtaining reliable estimates. This review shows a number of risk factors to be significantly associated with the development of IFD in critically ill adults. Methodological limitations were identified in the design and conduct of studies in this area, and caution should be used in their interpretation.

Risk factors for invasive fungal disease in critically ill adult patients: a systematic review

PubMed Central

2011-01-01

Introduction Over 5,000 cases of invasive Candida species infections occur in the United Kingdom each year, and around 40% of these cases occur in critical care units. Invasive fungal disease (IFD) in critically ill patients is associated with increased morbidity and mortality at a cost to both the individual and the National Health Service. In this paper, we report the results of a systematic review performed to identify and summarise the important risk factors derived from published multivariable analyses, risk prediction models and clinical decision rules for IFD in critically ill adult patients to inform the primary data collection for the Fungal Infection Risk Evaluation Study. Methods An internet search was performed to identify articles which investigated risk factors, risk prediction models or clinical decisions rules for IFD in critically ill adult patients. Eligible articles were identified in a staged process and were assessed by two investigators independently. The methodological quality of the reporting of the eligible articles was assessed using a set of questions addressing both general and statistical methodologies. Results Thirteen articles met the inclusion criteria, of which eight articles examined risk factors, four developed a risk prediction model or clinical decision rule and one evaluated a clinical decision rule. Studies varied in terms of objectives, risk factors, definitions and outcomes. The following risk factors were found in multiple studies to be significantly associated with IFD: surgery, total parenteral nutrition, fungal colonisation, renal replacement therapy, infection and/or sepsis, mechanical ventilation, diabetes, and Acute Physiology and Chronic Health Evaluation II (APACHE II) or APACHE III score. Several other risk factors were also found to be statistically significant in single studies only. Risk factor selection process and modelling strategy also varied across studies, and sample sizes were inadequate for obtaining reliable estimates. Conclusions This review shows a number of risk factors to be significantly associated with the development of IFD in critically ill adults. Methodological limitations were identified in the design and conduct of studies in this area, and caution should be used in their interpretation. PMID:22126425

Starvation and imidacloprid exposure influence immune response by Anoplophora glabripennis (Coleoptera: Cerambycidae) to a fungal pathogen

USDA-ARS?s Scientific Manuscript database

In several insect systems, fungal entomopathogens synergize with neonicotinoid insecticides which results in accelerated host death. Using the Asian longhorned beetle, Anoplophora glabripennis (Motschulsky), an invasive woodborer inadvertently introduced into North America and Europe, we investigate...

Burden of serious fungal infections in the Czech Republic.

PubMed

Chrdle, Aleš; Mallátová, Nad'a; Vašáková, Martina; Haber, Jan; Denning, David W

2015-10-01

We have estimated the number of serious fungal infections in the Czech Republic. All published epidemiology papers reporting Czech fungal infection rates were identified. Where no data existed, we used specific populations at risk and fungal infection frequencies in those populations. Population statistics were obtained from the 2011 Census data, prevalence and incidence data for at-risk conditions were obtained from publicly accessible healthcare statistics and relevant surveys. We estimate that 152,840 Czech women suffer with recurrent vaginal thrush. Allergic bronchopulmonary aspergillosis is likely in 4739 adults and 6581 more have severe asthma with fungal sensitisation. Hypersensitivity pneumonitits secondary to fungi is estimated in 1050 cases and 365 people may have chronic pulmonary aspergillosis. Oesophageal candidiasis is estimated in 210 HIV-positive people. There are 12 cases of Pneumocystis pneumonia in HIV population and 60 more cases in non-HIV population. There are an estimated 526 cases of candidaemia, 79 cases of Candida peritonitis and 297 cases of invasive aspergillosis a year. About 176,000 (1.67%) Czech people suffer from severe fungal infections each year, predominantly from recurrent vaginitis and allergic respiratory conditions. Substantial uncertainty surrounds these estimates except for invasive aspergillosis in haematology and candidaemia in critical care. © 2015 Blackwell Verlag GmbH.

Fungal Disease Prevention in Seedlings of Rice (Oryza sativa) and Other Grasses by Growth-Promoting Seed-Associated Endophytic Bacteria from Invasive Phragmites australis

PubMed Central

Verma, Satish K.; Kingsley, Kathryn L.; Bergen, Marshall S.; White, James F.

2018-01-01

Non-cultivated plants carry microbial endophytes that may be used to enhance development and disease resistance of crop species where growth-promoting and protective microbes may have been lost. During seedling establishment, seedlings may be infected by several fungal pathogens that are seed or soil borne. Several species of Fusarium, Pythium and other water moulds cause seed rots during germination. Fusarium blights of seedlings are also very common and significantly affect seedling development. In the present study we screened nine endophytic bacteria isolated from the seeds of invasive Phragmites australis by inoculating onto rice, Bermuda grass (Cynodon dactylon), or annual bluegrass (Poa annua) seeds to evaluate plant growth promotion and protection from disease caused by Fusarium oxysporum. We found that three bacteria belonging to genus Pseudomonas spp. (SLB4-P. fluorescens, SLB6-Pseudomonas sp. and SY1-Pseudomonas sp.) promoted seedling development, including enhancement of root and shoot growth, and stimulation of root hair formation. These bacteria were also found to increase phosphate solubilization in in vitro experiments. Pseudomonas sp. (SY1) significantly protected grass seedlings from Fusarium infection. In co-culture experiments, strain SY1 strongly inhibited fungal pathogens with 85.71% growth inhibition of F. oxysporum, 86.33% growth inhibition of Curvularia sp. and 82.14% growth inhibition of Alternaria sp. Seedlings previously treated with bacteria were found much less infected by F. oxysporum in comparison to non-treated controls. On microscopic observation we found that bacteria appeared to degrade fungal mycelia actively. Metabolite products of strain SY1 in agar were also found to inhibit fungal growth on nutrient media. Pseudomonas sp. (SY1) was found to produce antifungal volatiles. Polymerase chain reaction (PCR) amplification using specific primers for pyrrolnitirin synthesis and HCN (hydrogen cyanide) production suggested presence of genes for both compounds in the genome of SY1. HCN was detected in cultures of SY1. We conclude that microbes from non-cultivated plants may provide disease protection and promote growth of crop plants. PMID:29518024

Fungal Disease Prevention in Seedlings of Rice (Oryza sativa) and Other Grasses by Growth-Promoting Seed-Associated Endophytic Bacteria from Invasive Phragmites australis.

PubMed

Verma, Satish K; Kingsley, Kathryn L; Bergen, Marshall S; Kowalski, Kurt P; White, James F

2018-03-08

Non-cultivated plants carry microbial endophytes that may be used to enhance development and disease resistance of crop species where growth-promoting and protective microbes may have been lost. During seedling establishment, seedlings may be infected by several fungal pathogens that are seed or soil borne. Several species of Fusarium , Pythium and other water moulds cause seed rots during germination. Fusarium blights of seedlings are also very common and significantly affect seedling development. In the present study we screened nine endophytic bacteria isolated from the seeds of invasive Phragmites australis by inoculating onto rice, Bermuda grass ( Cynodon dactylon ), or annual bluegrass ( Poa annua ) seeds to evaluate plant growth promotion and protection from disease caused by Fusarium oxysporum . We found that three bacteria belonging to genus Pseudomonas spp. (SLB4- P. fluorescens , SLB6- Pseudomonas sp. and SY1- Pseudomonas sp.) promoted seedling development, including enhancement of root and shoot growth, and stimulation of root hair formation. These bacteria were also found to increase phosphate solubilization in in vitro experiments. Pseudomonas sp. (SY1) significantly protected grass seedlings from Fusarium infection. In co-culture experiments, strain SY1 strongly inhibited fungal pathogens with 85.71% growth inhibition of F. oxysporum , 86.33% growth inhibition of Curvularia sp. and 82.14% growth inhibition of Alternaria sp. Seedlings previously treated with bacteria were found much less infected by F. oxysporum in comparison to non-treated controls. On microscopic observation we found that bacteria appeared to degrade fungal mycelia actively. Metabolite products of strain SY1 in agar were also found to inhibit fungal growth on nutrient media. Pseudomonas sp. (SY1) was found to produce antifungal volatiles. Polymerase chain reaction (PCR) amplification using specific primers for pyrrolnitirin synthesis and HCN (hydrogen cyanide) production suggested presence of genes for both compounds in the genome of SY1. HCN was detected in cultures of SY1. We conclude that microbes from non-cultivated plants may provide disease protection and promote growth of crop plants.

Fungal disease prevention in seedlings of rice (Oryza sativa) and other grasses by growth-promoting seed-associated endophytic bacteria from invasive Phragmites australis

USGS Publications Warehouse

Verma, Satish K.; Kingsley, Kathryn L.; Bergen, Marshall S.; Kowalski, Kurt P.; White, James F.

2018-01-01

Non-cultivated plants carry microbial endophytes that may be used to enhance development and disease resistance of crop species where growth-promoting and protective microbes may have been lost. During seedling establishment, seedlings may be infected by several fungal pathogens that are seed or soil borne. Several species of Fusarium, Pythium and other water moulds cause seed rots during germination. Fusariumblights of seedlings are also very common and significantly affect seedling development. In the present study we screened nine endophytic bacteria isolated from the seeds of invasive Phragmites australis by inoculating onto rice, Bermuda grass (Cynodon dactylon), or annual bluegrass (Poa annua) seeds to evaluate plant growth promotion and protection from disease caused by Fusarium oxysporum. We found that three bacteria belonging to genus Pseudomonas spp. (SLB4-P. fluorescens, SLB6-Pseudomonas sp. and SY1-Pseudomonassp.) promoted seedling development, including enhancement of root and shoot growth, and stimulation of root hair formation. These bacteria were also found to increase phosphate solubilization in in vitro experiments. Pseudomonas sp. (SY1) significantly protected grass seedlings from Fusarium infection. In co-culture experiments, strain SY1 strongly inhibited fungal pathogens with 85.71% growth inhibition of F. oxysporum, 86.33% growth inhibition of Curvularia sp. and 82.14% growth inhibition of Alternaria sp. Seedlings previously treated with bacteria were found much less infected by F. oxysporum in comparison to non-treated controls. On microscopic observation we found that bacteria appeared to degrade fungal mycelia actively. Metabolite products of strain SY1 in agar were also found to inhibit fungal growth on nutrient media. Pseudomonas sp. (SY1) was found to produce antifungal volatiles. Polymerase chain reaction (PCR) amplification using specific primers for pyrrolnitirin synthesis and HCN (hydrogen cyanide) production suggested presence of genes for both compounds in the genome of SY1. HCN was detected in cultures of SY1. We conclude that microbes from non-cultivated plants may provide disease protection and promote growth of crop plants.

Aspergillosis and stem cell transplantation: An overview of experimental pathogenesis studies.

PubMed

Al-Bader, Nadia; Sheppard, Donald C

2016-11-16

Invasive aspergillosis is a life-threatening infection caused by the opportunistic filamentous fungus Aspergillus fumigatus. Patients undergoing haematopoietic stem cell transplant (HSCT) for the treatment of hematological malignancy are at particularly high risk of developing this fatal infection. The susceptibility of HSCT patients to infection with A. fumigatus is a consequence of a complex interplay of both fungal and host factors. Here we review our understanding of the host-pathogen interactions underlying the susceptibility of the immunocompromised host to infection with A. fumigatus with a focus on the experimental validation of fungal and host factors relevant to HSCT patients. These include fungal factors such as secondary metabolites, cell wall constituents, and metabolic adaptations that facilitate immune evasion and survival within the host microenvironment, as well as the innate and adaptive immune responses involved in host defense against A. fumigatus.

Secondary free-flap reconstruction following ablation for acute invasive fungal sinusitis.

PubMed

Allensworth, Jordan J; Troob, Scott H; Weaver, Tyler S; Gonzalez, Javier D; Petrisor, Daniel; Wax, Mark K

2017-04-01

Acute invasive fungal sinusitis (AIFS) is a frequently fatal infection for which extensive and debilitating surgical debridement is a mainstay of therapy. Resulting defects are often composite in nature, mandating free tissue-transfer reconstruction. Outcomes data for free flap reconstruction are limited. The purpose of this study was to examine surgical outcomes and survival in patients undergoing free flap transfer following invasive fungal sinusitis. Retrospective case series. Between 1995 and 2015, patients undergoing operative debridement for AIFS were identified. Surgical records were used to identify survivors of acute infection who subsequently underwent free flap reconstructive surgery. Patient demographics, cause of immune compromise, defect description, flap type, perioperative complications, indications for revision surgery, functional outcomes, and long-term survival were reviewed. Forty-four patients were treated for AIFS, of those, 30 (68%) survived acute infection. Ten patients underwent maxillectomy, six with orbital exenteration, and were designated candidates for reconstruction. Eight patients underwent reconstruction. Median time from debridement to reconstruction was 67.5 days. Flap types included latissimus dorsi, scapula, anterolateral thigh, rectus, radial forearm, and fibula. Median follow-up was 7.7 months. No perioperative complications were encountered, and all subjects remained disease-free, able to speak and eat normally without prosthetic supplementation. Seven patients (87%) are currently alive. Reconstruction of defects left by invasive fungal sinusitis using free-tissue transfer resulted in successful flap survival, with no disease recurrence for all defects and flap types reviewed. Survivors of AIFS are able to tolerate midface reconstruction, with favorable functional outcomes and survival rates. 4. Laryngoscope, 127:815-819, 2017. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

Improving early diagnosis of pulmonary infections in patients with febrile neutropenia using low-dose chest computed tomography.

PubMed

Gerritsen, M G; Willemink, M J; Pompe, E; van der Bruggen, T; van Rhenen, A; Lammers, J W J; Wessels, F; Sprengers, R W; de Jong, P A; Minnema, M C

2017-01-01

We performed a prospective study in patients with chemotherapy induced febrile neutropenia to investigate the diagnostic value of low-dose computed tomography compared to standard chest radiography. The aim was to compare both modalities for detection of pulmonary infections and to explore performance of low-dose computed tomography for early detection of invasive fungal disease. The low-dose computed tomography remained blinded during the study. A consensus diagnosis of the fever episode made by an expert panel was used as reference standard. We included 67 consecutive patients on the first day of febrile neutropenia. According to the consensus diagnosis 11 patients (16.4%) had pulmonary infections. Sensitivity, specificity, positive predictive value and negative predictive value were 36%, 93%, 50% and 88% for radiography, and 73%, 91%, 62% and 94% for low-dose computed tomography, respectively. An uncorrected McNemar showed no statistical difference (p = 0.197). Mean radiation dose for low-dose computed tomography was 0.24 mSv. Four out of 5 included patients diagnosed with invasive fungal disease had radiographic abnormalities suspect for invasive fungal disease on the low-dose computed tomography scan made on day 1 of fever, compared to none of the chest radiographs. We conclude that chest radiography has little value in the initial assessment of febrile neutropenia on day 1 for detection of pulmonary abnormalities. Low-dose computed tomography improves detection of pulmonary infiltrates and seems capable of detecting invasive fungal disease at a very early stage with a low radiation dose.

Improving early diagnosis of pulmonary infections in patients with febrile neutropenia using low-dose chest computed tomography

PubMed Central

Pompe, E.; van der Bruggen, T.; van Rhenen, A.; Lammers, J. W. J.; Wessels, F.; Sprengers, R. W.; de Jong, P. A.; Minnema, M. C.

2017-01-01

We performed a prospective study in patients with chemotherapy induced febrile neutropenia to investigate the diagnostic value of low-dose computed tomography compared to standard chest radiography. The aim was to compare both modalities for detection of pulmonary infections and to explore performance of low-dose computed tomography for early detection of invasive fungal disease. The low-dose computed tomography remained blinded during the study. A consensus diagnosis of the fever episode made by an expert panel was used as reference standard. We included 67 consecutive patients on the first day of febrile neutropenia. According to the consensus diagnosis 11 patients (16.4%) had pulmonary infections. Sensitivity, specificity, positive predictive value and negative predictive value were 36%, 93%, 50% and 88% for radiography, and 73%, 91%, 62% and 94% for low-dose computed tomography, respectively. An uncorrected McNemar showed no statistical difference (p = 0.197). Mean radiation dose for low-dose computed tomography was 0.24 mSv. Four out of 5 included patients diagnosed with invasive fungal disease had radiographic abnormalities suspect for invasive fungal disease on the low-dose computed tomography scan made on day 1 of fever, compared to none of the chest radiographs. We conclude that chest radiography has little value in the initial assessment of febrile neutropenia on day 1 for detection of pulmonary abnormalities. Low-dose computed tomography improves detection of pulmonary infiltrates and seems capable of detecting invasive fungal disease at a very early stage with a low radiation dose. PMID:28235014

Predicting Invasive Fungal Pathogens Using Invasive Pest Assemblages: Testing Model Predictions in a Virtual World

PubMed Central

Paini, Dean R.; Bianchi, Felix J. J. A.; Northfield, Tobin D.; De Barro, Paul J.

2011-01-01

Predicting future species invasions presents significant challenges to researchers and government agencies. Simply considering the vast number of potential species that could invade an area can be insurmountable. One method, recently suggested, which can analyse large datasets of invasive species simultaneously is that of a self organising map (SOM), a form of artificial neural network which can rank species by establishment likelihood. We used this method to analyse the worldwide distribution of 486 fungal pathogens and then validated the method by creating a virtual world of invasive species in which to test the SOM. This novel validation method allowed us to test SOM's ability to rank those species that can establish above those that can't. Overall, we found the SOM highly effective, having on average, a 96–98% success rate (depending on the virtual world parameters). We also found that regions with fewer species present (i.e. 1–10 species) were more difficult for the SOM to generate an accurately ranked list, with success rates varying from 100% correct down to 0% correct. However, we were able to combine the numbers of species present in a region with clustering patterns in the SOM, to further refine confidence in lists generated from these sparsely populated regions. We then used the results from the virtual world to determine confidences for lists generated from the fungal pathogen dataset. Specifically, for lists generated for Australia and its states and territories, the reliability scores were between 84–98%. We conclude that a SOM analysis is a reliable method for analysing a large dataset of potential invasive species and could be used by biosecurity agencies around the world resulting in a better overall assessment of invasion risk. PMID:22016773

Predicting invasive fungal pathogens using invasive pest assemblages: testing model predictions in a virtual world.

PubMed

Paini, Dean R; Bianchi, Felix J J A; Northfield, Tobin D; De Barro, Paul J

2011-01-01

Predicting future species invasions presents significant challenges to researchers and government agencies. Simply considering the vast number of potential species that could invade an area can be insurmountable. One method, recently suggested, which can analyse large datasets of invasive species simultaneously is that of a self organising map (SOM), a form of artificial neural network which can rank species by establishment likelihood. We used this method to analyse the worldwide distribution of 486 fungal pathogens and then validated the method by creating a virtual world of invasive species in which to test the SOM. This novel validation method allowed us to test SOM's ability to rank those species that can establish above those that can't. Overall, we found the SOM highly effective, having on average, a 96-98% success rate (depending on the virtual world parameters). We also found that regions with fewer species present (i.e. 1-10 species) were more difficult for the SOM to generate an accurately ranked list, with success rates varying from 100% correct down to 0% correct. However, we were able to combine the numbers of species present in a region with clustering patterns in the SOM, to further refine confidence in lists generated from these sparsely populated regions. We then used the results from the virtual world to determine confidences for lists generated from the fungal pathogen dataset. Specifically, for lists generated for Australia and its states and territories, the reliability scores were between 84-98%. We conclude that a SOM analysis is a reliable method for analysing a large dataset of potential invasive species and could be used by biosecurity agencies around the world resulting in a better overall assessment of invasion risk.

Invasive forms of Candida and Aspergillus in sputum samples of pulmonary tuberculosis patients attending the tuberculosis reference laboratory in Ghaemshahr, Northern Iran: An analysis of samples collected during the past 10years.

PubMed

Jabbari Amiri, Mohammad Reza; Aghili, Seyed Reza; Shokohi, Tahereh; Hedayati, Mohammad Taghi; Abastabar, Mahdi; Aliyali, Masoud; Jabbari Amiri, Masoumeh; Hasanpour, Hamid

2016-12-01

Tuberculosis (TB) continues to be a major public health problem worldwide. This is especially true in Northern Iran, which has high TB prevalence. The chronic nature of this disease is further exacerbated if it is accompanied by fungal infection, which usually remains undiagnosed and thus untreated. Thus, mycotic infections add fatal dimensions to pulmonary TB. Our objective was to determine the prevalence of invasive forms of fungal elements in sputum samples collected from patients with pulmonary TB at a reference laboratory in Ghaemshahr, Northern Iran, during the past 10years. In this retrospective study, sputum samples collected from 430 patients were examined. Pulmonary TB in patients was confirmed in our laboratory, and samples obtained during the period from March 2006 to February 2016 were analyzed. The sputum samples were subjected to biological (bacterial) staining (Ziehl-Neelsen and fluorochrome) and mycological investigation using KOH + Calcofluor White (Sigma-Aldrich, India) by fluorescent microscopy and fungal culture on Sabouraud dextrose agar (Sigma-Aldrich, India) and CHROMagar (Paris, France). Invasive forms of fungal pathogens were observed as co-infection with Mycobacterium tuberculosis in 28/430 cases (6.51%). The frequency of Aspergillus, both branching and dichotomous infection, accounted for 3.72% (16/430): Aspergillus flavus, 1.63%; Aspergillus fumigatus, 1.16%; Aspergillus niger, 0.69%; and Aspergillus oryzae, 0.23%, respectively. Blastoconidia and pseudohyphae forms of yeast were observed as co-infection with M. tuberculosis in 2.79% (12/430) of the cases: Candida albicans, 1.86%; Candida krusei, 0.46%; and other Candida species, 0.46%, respectively. Northern Iran is a critical region in the TB world and multidrug-resistant TB is a serious problem in this region. Although it is believed that there exists a commensal relationship between fungus and TB infections, the invasive forms of fungal pathogens and their co-infection can be caused by increasing disability and failure of treatment. Diagnosis of secondary or co-existing fungal infections in TB is most important for reducing the mortality and morbidity of these patients. Copyright © 2016.

Rare fungal infectious agents: a lurking enemy

PubMed Central

Skiada, Anna; Pavleas, Ioannis; Drogari-Apiranthitou, Maria

2017-01-01

In the expanding population of immunocompromised patients and those treated in intensive care units, rare fungal infectious agents have emerged as important pathogens, causing invasive infections associated with high morbidity and mortality. These infections may present either as de novo or as breakthrough invasive infections in high-risk patients with hematologic malignancies receiving prophylactic or empirical antifungal therapy or in patients with central venous catheters. Diagnosis and treatment are challenging. Physicians should have a high index of suspicion because early diagnosis is of paramount importance. Conventional diagnostic methods such as cultures and histopathology are still essential, but rapid and more specific molecular techniques for both detection and identification of the infecting pathogens are being developed and hopefully will lead to early targeted treatment. The management of invasive fungal infections is multimodal. Reversal of risk factors, if feasible, should be attempted. Surgical debridement is recommended in localized mold infections. The efficacy of various antifungal drugs is not uniform. Amphotericin B is active against most yeasts, except Trichosporon, as well as against Mucorales, Fusarium, and some species of Paecilomyces and dimorphic fungi. The use of voriconazole is suggested for the treatment of trichosporonosis and scedosporiosis. Combination treatment, though recommended as salvage therapy in some infections, is controversial in most cases. Despite the use of available antifungals, mortality remains high. The optimization of molecular-based techniques, with expansion of reference libraries and the possibility for direct detection of resistance mechanisms, is awaited with great interest in the near future. Further research is necessary, however, in order to find the best ways to confront and destroy these lurking enemies. PMID:29152230

Prospecting fungal parasites of the potato cyst nematode Globodera pallida using a rapid screening technique.

PubMed

Kooliyottil, Rinu; Dandurand, Louise-Marie; Knudsen, Guy R

2017-05-01

Seven filamentous fungal species were isolated from individual eggs of Globodera pallida cysts collected from infested fields in Shelley Idaho, USA and identified as Chaetomium globosum, Fusarium oxysporum, Fusarium solani, Fusarium tricinctum, Microdochium bolleyi, Purpureocillium lilacinum, and Plectosphaerella cucumerina. Their ability to reduce infection by G. pallida in planta were assessed in simple, reproducible micro-rhizosphere chambers (micro-ROCs). All fungi reduced G. pallida infection in potato, but greatest reduction was observed with C. globosum at an average reduction of 76%. Further non-destructive methods were developed to rapidly assess biological control potential of putative fungal strains by staining the infectious second stage juveniles of G. pallida with the live fluorescent stain PKH26. In comparisons between the standard, invasive acid fuchsin method and use of the live stain PKH26, no significant difference in infection level of G. pallida was observed whether roots were stained with PKH26 or acid fuchsin. For both methods, a similar reduction (77% for acid fuchsin, and 78% for PKH26 stain) in invasion of infectious stage of G. pallida was observed when potato plants were inoculated with C. globosum compared to non-inoculated potato. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Use of (1→3)-β-D-Glucan for diagnosis and management of invasive mycoses in HIV-infected patients.

PubMed

Farhour, Zahra; Mehraj, Vikram; Chen, Jun; Ramendra, Rayoun; Lu, Hongzhou; Routy, Jean-Pierre

2018-05-31

People living with HIV (PLHIV) are highly vulnerable to invasive fungal infections (IFIs) due to their immune dysfunction. Diagnosis and treatment of IFIs remain challenging due to the requirement of deep tissue sampling to visualize and culture fungi before initiating treatment. Such techniques are less practical in resource-limited settings due to their cost and requirement of relatively invasive procedures. Hence, identification of surrogate markers for the early diagnosis and therapeutic monitoring of IFIs is required. Recent studies have shown that (1→3)-β-D-Glucan (BDG), a major fungal cell wall antigen, represents a promising soluble marker for the presumptive diagnosis and therapeutic monitoring of IFIs in HIV-infected patients. Herein, we review findings on the merits of BDG assays in the diagnosis of IFIs and monitoring of antifungal therapies for PLHIV. Conversely to other types of immunocompromised patients, HIV infection is associated with gut damage and subsequent bacterial and fungal translocation leading to elevated BDG plasma levels. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

PCR Followed by Electrospray Ionization Mass Spectrometry for Broad-Range Identification of Fungal Pathogens

PubMed Central

Massire, Christian; Buelow, Daelynn R.; Zhang, Sean X.; Lovari, Robert; Matthews, Heather E.; Toleno, Donna M.; Ranken, Raymond R.; Hall, Thomas A.; Metzgar, David; Sampath, Rangarajan; Blyn, Lawrence B.; Ecker, David J.; Gu, Zhengming; Walsh, Thomas J.

2013-01-01

Invasive fungal infections are a significant cause of morbidity and mortality among immunocompromised patients. Early and accurate identification of these pathogens is central to direct therapy and to improve overall outcome. PCR coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) was evaluated as a novel means for identification of fungal pathogens. Using a database grounded by 60 ATCC reference strains, a total of 394 clinical fungal isolates (264 molds and 130 yeasts) were analyzed by PCR/ESI-MS; results were compared to phenotypic identification, and discrepant results were sequence confirmed. PCR/ESI-MS identified 81.4% of molds to either the genus or species level, with concordance rates of 89.7% and 87.4%, respectively, to phenotypic identification. Likewise, PCR/ESI-MS was able to identify 98.4% of yeasts to either the genus or species level, agreeing with 100% of phenotypic results at both the genus and species level. PCR/ESI-MS performed best with Aspergillus and Candida isolates, generating species-level identification in 94.4% and 99.2% of isolates, respectively. PCR/ESI-MS is a promising new technology for broad-range detection and identification of medically important fungal pathogens that cause invasive mycoses. PMID:23303501

The role of fungi in diseases of the nose and sinuses

PubMed Central

Schlosser, Rodney J.

2012-01-01

Background: Human exposure to fungal elements is inevitable, with normal respiration routinely depositing fungal hyphae within the nose and paranasal sinuses. Fungal species can cause sinonasal disease, with clinical outcomes ranging from mild symptoms to intracranial invasion and death. There has been much debate regarding the precise role fungal species play in sinonasal disease and optimal treatment strategies. Methods: A literature review of fungal diseases of the nose and sinuses was conducted. Results: Presentation, diagnosis, and current management strategies of each recognized form of fungal rhinosinusitis was reviewed. Conclusion: Each form of fungal rhinosinusitis has a characteristic presentation and clinical course, with the immune status of the host playing a critical pathophysiological role. Accurate diagnosis and targeted treatment strategies are necessary to achieve optimal outcomes. PMID:23168148

Histopathologic criteria to confirm white-nose syndrome in bats

USGS Publications Warehouse

Meteyer, Carol U.; Buckles, Elizabeth L.; Blehert, David S.; Hicks, Alan C.; Green, David E.; Shearn-Bochsler, Valerie I.; Thomas, Nancy J.; Gargas, Andrea; Behr, Melissa

2009-01-01

White-nose syndrome (WNS) is a cutaneous fungal disease of hibernating bats associated with a novel Geomyces sp. fungus. Currently, confirmation of WNS requires histopathologic examination. Invasion of living tissue distinguishes this fungal infection from those caused by conventional transmissible dermatophytes. Although fungal hyphae penetrate the connective tissue of glabrous skin and muzzle, there is typically no cellular inflammatory response in hibernating bats. Preferred tissue samples to diagnose this fungal infection are rostral muzzle with nose and wing membrane fixed in 10% neutral buffered formalin. To optimize detection, the muzzle is trimmed longitudinally, the wing membrane is rolled, and multiple cross-sections are embedded to increase the surface area examined. Periodic acid-Schiff stain is essential to discriminate the nonpigmented fungal hyphae and conidia. Fungal hyphae form cup-like epidermal erosions and ulcers in the wing membrane and pinna with involvement of underlying connective tissue. In addition, fungal hyphae are present in hair follicles and in sebaceous and apocrine glands of the muzzle with invasion of tissue surrounding adnexa. Fungal hyphae in tissues are branching and septate, but the diameter and shape of the hyphae may vary from parallel walls measuring 2 ??m in diameter to irregular walls measuring 3-5 ??m in diameter. When present on short aerial hyphae, curved conidia are approximately 2.5 ??m wide and 7.5 ??m in curved length. Conidia have a more deeply basophilic center, and one or both ends are usually blunt. Although WNS is a disease of hibernating bats, severe wing damage due to fungal hyphae may be seen in bats that have recently emerged from hibernation. These recently emerged bats also have a robust suppurative inflammatory response.

Histopathologic criteria to confirm white-nose syndrome in bats.

PubMed

Meteyer, Carol Uphoff; Buckles, Elizabeth L; Blehert, David S; Hicks, Alan C; Green, D Earl; Shearn-Bochsler, Valerie; Thomas, Nancy J; Gargas, Andrea; Behr, Melissa J

2009-07-01

White-nose syndrome (WNS) is a cutaneous fungal disease of hibernating bats associated with a novel Geomyces sp. fungus. Currently, confirmation of WNS requires histopathologic examination. Invasion of living tissue distinguishes this fungal infection from those caused by conventional transmissible dermatophytes. Although fungal hyphae penetrate the connective tissue of glabrous skin and muzzle, there is typically no cellular inflammatory response in hibernating bats. Preferred tissue samples to diagnose this fungal infection are rostral muzzle with nose and wing membrane fixed in 10% neutral buffered formalin. To optimize detection, the muzzle is trimmed longitudinally, the wing membrane is rolled, and multiple cross-sections are embedded to increase the surface area examined. Periodic acid-Schiff stain is essential to discriminate the nonpigmented fungal hyphae and conidia. Fungal hyphae form cup-like epidermal erosions and ulcers in the wing membrane and pinna with involvement of underlying connective tissue. In addition, fungal hyphae are present in hair follicles and in sebaceous and apocrine glands of the muzzle with invasion of tissue surrounding adnexa. Fungal hyphae in tissues are branching and septate, but the diameter and shape of the hyphae may vary from parallel walls measuring 2 microm in diameter to irregular walls measuring 3-5 microm in diameter. When present on short aerial hyphae, curved conidia are approximately 2.5 microm wide and 7.5 microm in curved length. Conidia have a more deeply basophilic center, and one or both ends are usually blunt. Although WNS is a disease of hibernating bats, severe wing damage due to fungal hyphae may be seen in bats that have recently emerged from hibernation. These recently emerged bats also have a robust suppurative inflammatory response.

Soil Bacteria and Fungi Respond on Different Spatial Scales to Invasion by the Legume Lespedeza cuneata.

PubMed

Yannarell, Anthony C; Busby, Ryan R; Denight, Michael L; Gebhart, Dick L; Taylor, Steven J

2011-01-01

The spatial scale on which microbial communities respond to plant invasions may provide important clues as to the nature of potential invader-microbe interactions. Lespedeza cuneata (Dum. Cours.) G. Don is an invasive legume that may benefit from associations with mycorrhizal fungi; however, it has also been suggested that the plant is allelopathic and may alter the soil chemistry of invaded sites through secondary metabolites in its root exudates or litter. Thus, L. cuneata invasion may interact with soil microorganisms on a variety of scales. We investigated L. cuneata-related changes to soil bacterial and fungal communities at two spatial scales using multiple sites from across its invaded N. American range. Using whole-community DNA fingerprinting, we characterized microbial community variation at the scale of entire invaded sites and at the scale of individual plants. Based on permutational multivariate analysis of variance, soil bacterial communities in heavily invaded sites were significantly different from those of uninvaded sites, but bacteria did not show any evidence of responding at very local scales around individual plants. In contrast, soil fungi did not change significantly at the scale of entire sites, but there were significant differences between fungal communities of native versus exotic plants within particular sites. The differential scaling of bacterial and fungal responses indicates that L. cuneata interacts differently with soil bacteria and soil fungi, and these microorganisms may play very different roles in the invasion process of this plant.

Fungal decomposers of leaf litter from an invaded and native mountain forest of NW Argentina.

PubMed

Fernandez, Romina Daiana; Bulacio, Natalia; Álvarez, Analía; Pajot, Hipólito; Aragón, Roxana

2017-09-01

The impact of plant species invasions on the abundance, composition and activity of fungal decomposers of leaf litter is poorly understood. In this study, we isolated and compared the relative abundance of ligninocellulolytic fungi of leaf litter mixtures from a native forest and a forest invaded by Ligustrum lucidum in a lower mountain forest of Tucuman, Argentina. In addition, we evaluated the relationship between the relative abundance of ligninocellulolytic fungi and properties of the soil of both forest types. Finally, we identified lignin degrading fungi and characterized their polyphenol oxidase activities. The relative abundance of ligninocellulolytic fungi was higher in leaf litter mixtures from the native forest. The abundance of cellulolytic fungi was negatively related with soil pH while the abundance of ligninolytic fungi was positively related with soil humidity. We identified fifteen genera of ligninolytic fungi; four strains were isolated from both forest types, six strains only from the invaded forest and five strains were isolated only from the native forest. The results found in this study suggest that L. Lucidum invasion could alter the abundance and composition of fungal decomposers. Long-term studies that include an analysis of the nutritional quality of litter are needed, for a more complete overview of the influence of L. Lucidum invasion on fungal decomposers and on leaf litter decomposition.

Integrated inference and evaluation of host–fungi interaction networks

PubMed Central

Remmele, Christian W.; Luther, Christian H.; Balkenhol, Johannes; Dandekar, Thomas; Müller, Tobias; Dittrich, Marcus T.

2015-01-01

Fungal microorganisms frequently lead to life-threatening infections. Within this group of pathogens, the commensal Candida albicans and the filamentous fungus Aspergillus fumigatus are by far the most important causes of invasive mycoses in Europe. A key capability for host invasion and immune response evasion are specific molecular interactions between the fungal pathogen and its human host. Experimentally validated knowledge about these crucial interactions is rare in literature and even specialized host–pathogen databases mainly focus on bacterial and viral interactions whereas information on fungi is still sparse. To establish large-scale host–fungi interaction networks on a systems biology scale, we develop an extended inference approach based on protein orthology and data on gene functions. Using human and yeast intraspecies networks as template, we derive a large network of pathogen–host interactions (PHI). Rigorous filtering and refinement steps based on cellular localization and pathogenicity information of predicted interactors yield a primary scaffold of fungi–human and fungi–mouse interaction networks. Specific enrichment of known pathogenicity-relevant genes indicates the biological relevance of the predicted PHI. A detailed inspection of functionally relevant subnetworks reveals novel host–fungal interaction candidates such as the Candida virulence factor PLB1 and the anti-fungal host protein APP. Our results demonstrate the applicability of interolog-based prediction methods for host–fungi interactions and underline the importance of filtering and refinement steps to attain biologically more relevant interactions. This integrated network framework can serve as a basis for future analyses of high-throughput host–fungi transcriptome and proteome data. PMID:26300851

Use of external ventriculostomy and intrathecal anti-fungal treatment in cerebral mucormycotic abscess.

PubMed

Grannan, Benjamin L; Yanamadala, Vijay; Venteicher, Andrew S; Walcott, Brian P; Barr, John C

2014-10-01

Mucormycosis is an invasive fungal infection associated with a high mortality. Cerebral mucor abscesses can result secondary to rhinocerebral or hematogenous spread. Amphotericin B, posaconazole, and aggressive surgical resection are the hallmarks of treatment. While amphotericin is typically administered intravenously, less is known about the use of intrathecal amphotericin B. We describe a 42-year-old man who developed a cerebellar mucor abscess after undergoing hematopoietic stem cell transplant for the treatment of myelodysplastic syndrome. In the post-operative period he was admitted to the neurocritical care unit and received liposomal amphotericin B intravenously and through an external ventricular drain. This patient demonstrates that utilization of an external ventricular drain for intrathecal antifungal therapy in the post-operative period may warrant further study in patients with difficult to treat intracranial fungal abscesses. Copyright © 2014. Published by Elsevier Ltd.

Modification of a pollen trap design to capture airborne conidia of Entomophaga maimaiga and detection of conidia by quantitative PCR

Treesearch

Tonya D. Bittner; Ann E. Hajek; Andrew M. Liebhold; Harold Thistle; Dan Cullen

2017-01-01

The goal of this study was to develop effective and practical field sampling methods for quantification of aerial deposition of airborne conidia of Entomophaga maimaiga over space and time. This important fungal pathogen is a major cause of larval death in invasive gypsy moth (Lymantria dispar) populations in the United States...

Effects of early enteral nutrition on the gastrointestinal motility and intestinal mucosal barrier of patients with burn-induced invasive fungal infection

PubMed Central

Zhang, Yu; Gu, Fang; Wang, Fengxian; Zhang, Yuanda

2016-01-01

Objective: To evaluate the effects of early enteral nutrition on the gastrointestinal motility and intestinal mucosal barrier of patients with burn-induced invasive fungal infection. Methods: A total of 120 patients with burn-induced invasive fungal infection were randomly divided into an early enteral nutrition (EN) group and a parenteral nutrition (PN) group (n=60). The patients were given nutritional support intervention for 14 days, and the expression levels of serum transferrin, albumin, total protein, endotoxin, D-lactic acid and inflammatory cytokines were detected on the 1st, 7th and 14th days respectively. Results: As the treatment progressed, the levels of serum transferrin, albumin and total protein of the EN group were significantly higher than those of the PN group (P<0.05), while the levels of serum endotoxin and D-lactic acid of the form group were significantly lower (P<0.05). After treatment, the expression levels of IL-6 and TNF-α were decreased in the EN group, which were significantly different from those of the PN group (P<0.05). During treatment, the incidence rates of complications such as abdominal distension, diarrhea, sepsis, nausea, vomiting and gastric retention were similar. The mean healing time of wound surface was 9.34±0.78 days in the EN group and 12.46±2.19 days in the PN group, i.e. such time of the former was significantly shorter than that of the latter (P<0.05). Conclusion: Treating patients having burn-induced invasive fungal infection by early enteral nutrition support with arginine can safely alleviate malnutrition and stress reaction, strengthen cellular immune function and promote wound healing, thereby facilitating the recovery of gastrointestinal motility and the function of intestinal mucosal barrier. PMID:27375697

Ustilago echinata: Infection in a Mixed Martial Artist Following an Open Fracture.

PubMed

Stewart, Ethan; Waldman, Sarah; Sutton, Deanna A; Sanders, Carmita; Lindner, Jonathan; Fan, Hongxin; Wiederhold, Nathan P; Thompson, George R

2016-04-01

Ustilago, a common fungal parasite of grains, is infrequently isolated as a pathogen in humans. We describe a case of Ustilago echinata infection following an open distal tibia fracture, review the current literature of this genus as a cause of invasive fungal infection in humans, and discuss management issues.

Molecular diagnostic methods for invasive fungal disease: the horizon draws nearer?

PubMed

Halliday, C L; Kidd, S E; Sorrell, T C; Chen, S C-A

2015-04-01

Rapid, accurate diagnostic laboratory tests are needed to improve clinical outcomes of invasive fungal disease (IFD). Traditional direct microscopy, culture and histological techniques constitute the 'gold standard' against which newer tests are judged. Molecular diagnostic methods, whether broad-range or fungal-specific, have great potential to enhance sensitivity and speed of IFD diagnosis, but have varying specificities. The use of PCR-based assays, DNA sequencing, and other molecular methods including those incorporating proteomic approaches such as matrix-assisted laser desorption ionisation-time of flight mass spectroscopy (MALDI-TOF MS) have shown promising results. These are used mainly to complement conventional methods since they require standardisation before widespread implementation can be recommended. None are incorporated into diagnostic criteria for defining IFD. Commercial assays may assist standardisation. This review provides an update of molecular-based diagnostic approaches applicable to biological specimens and fungal cultures in microbiology laboratories. We focus on the most common pathogens, Candida and Aspergillus, and the mucormycetes. The position of molecular-based approaches in the detection of azole and echinocandin antifungal resistance is also discussed.

Endophytic fungal communities of Bromus tectorum: Mutualisms, community assemblages and implications for invasion

Treesearch

Melissa A. Baynes

2011-01-01

Exotic plant invasions are of serious economic, social and ecological concern worldwide. Although many promising hypotheses have been posited in attempt to explain the mechanism(s) by which plant invaders are successful, there is no single explanation for all invasions and often no single explanation for the success of an individual species. Cheatgrass (Bromus tectorum...

Gymnemic Acids Inhibit Hyphal Growth and Virulence in Candida albicans

PubMed Central

Vediyappan, Govindsamy; Dumontet, Vincent; Pelissier, Franck; d’Enfert, Christophe

2013-01-01

Candida albicans is an opportunistic and polymorphic fungal pathogen that causes mucosal, disseminated and invasive infections in humans. Transition from the yeast form to the hyphal form is one of the key virulence factors in C. albicans contributing to macrophage evasion, tissue invasion and biofilm formation. Nontoxic small molecules that inhibit C. albicans yeast-to-hypha conversion and hyphal growth could represent a valuable source for understanding pathogenic fungal morphogenesis, identifying drug targets and serving as templates for the development of novel antifungal agents. Here, we have identified the triterpenoid saponin family of gymnemic acids (GAs) as inhibitor of C. albicans morphogenesis. GAs were isolated and purified from Gymnema sylvestre leaves, the Ayurvedic traditional medicinal plant used to treat diabetes. Purified GAs had no effect on the growth and viability of C. albicans yeast cells but inhibited its yeast-to-hypha conversion under several hypha-inducing conditions, including the presence of serum. Moreover, GAs promoted the conversion of C. albicans hyphae into yeast cells under hypha inducing conditions. They also inhibited conidial germination and hyphal growth of Aspergillus sp. Finally, GAs inhibited the formation of invasive hyphae from C. albicans-infected Caenorhabditis elegans worms and rescued them from killing by C. albicans. Hence, GAs could be useful for various antifungal applications due to their traditional use in herbal medicine. PMID:24040201

An integrated genomic and transcriptomic survey of mucormycosis-causing fungi

PubMed Central

Chibucos, Marcus C.; Soliman, Sameh; Gebremariam, Teclegiorgis; Lee, Hongkyu; Daugherty, Sean; Orvis, Joshua; Shetty, Amol C.; Crabtree, Jonathan; Hazen, Tracy H.; Etienne, Kizee A.; Kumari, Priti; O'Connor, Timothy D.; Rasko, David A.; Filler, Scott G.; Fraser, Claire M.; Lockhart, Shawn R.; Skory, Christopher D.; Ibrahim, Ashraf S.; Bruno, Vincent M.

2016-01-01

Mucormycosis is a life-threatening infection caused by Mucorales fungi. Here we sequence 30 fungal genomes, and perform transcriptomics with three representative Rhizopus and Mucor strains and with human airway epithelial cells during fungal invasion, to reveal key host and fungal determinants contributing to pathogenesis. Analysis of the host transcriptional response to Mucorales reveals platelet-derived growth factor receptor B (PDGFRB) signaling as part of a core response to divergent pathogenic fungi; inhibition of PDGFRB reduces Mucorales-induced damage to host cells. The unique presence of CotH invasins in all invasive Mucorales, and the correlation between CotH gene copy number and clinical prevalence, are consistent with an important role for these proteins in mucormycosis pathogenesis. Our work provides insight into the evolution of this medically and economically important group of fungi, and identifies several molecular pathways that might be exploited as potential therapeutic targets. PMID:27447865

[Prevention and control of nosocomial and health-care facilities associated infections caused by species of Candida and other yeasts].

PubMed

Pemán, Javier; Zaragoza, Rafael; Salavert, Miguel

2013-12-01

Knowledge of the epidemiology of invasive fungal diseases caused by yeasts (Candida spp., especially) in health care settings allows the establishment of the levels necessary for its prevention. A first step is to identify groups of patients at high risk of nosocomial invasive fungal infections, establish accurate risk factors, observing the periods of greatest risk, and analyze the epidemiological profile in genera and species as well as the patterns of antifungal resistance. Secondly, mechanisms to avoid persistent exposure to potential fungal pathogens must be programed, protecting areas and recommending measures such as the control of the quality of the air and water, inside and outside the hospital, and other products or substances able to cause outbreaks. Finally, apart from the correct implementation of these measures, in selected patients at very high risk, the use of antifungal prophylaxis should be considered following the guidelines published.

[Antifungals cellular targets and mechanisms of resistance].

PubMed

Accoceberry, Isabelle; Noël, Thierry

2006-01-01

Antifungals of systemic use for the treatment of invasive fungal infections belong to four main chemical families which have globally three cellular targets in fungal cells: fluorinated pyrimidines act on deoxyribonucleic acid (DNA) replication and protein synthesis; polyenes and azoles are toxic for ergosterol and its biosynthetic pathway; lipopeptides inhibit the synthesis of cell wall beta glucans. The resistance mechanisms that are developed by some fungi begin to be well understood particularly in Candida yeasts. The underlying bases of these mechanisms are either mutations that modify the antifungal target, or that block access to the target, and, on the other hand, the overexpression of genes encoding the target, or some membrane proteins involved in the active efflux of antifungal drugs.

Potential involvement of Aspergillus flavus laccases in peanut invasion at low water potential

USDA-ARS?s Scientific Manuscript database

Aspergillus flavus (Link) accumulates aflatoxins in peanuts, mainly affecting immature kernels during drought. Peanut invasion by A. flavus induces synthesis of phytoalexins, mostly stilbenoids, as a plant defense mechanism. Fungal laccases are often related to pathogenicity, and among other subst...

Loss of functional diversity and network modularity in introduced plant–fungal symbioses

PubMed Central

Cooper, Jerry A.; Bufford, Jennifer L.; Hulme, Philip E.; Bates, Scott T.

2017-01-01

The introduction of alien plants into a new range can result in the loss of co-evolved symbiotic organisms, such as mycorrhizal fungi, that are essential for normal plant physiological functions. Prior studies of mycorrhizal associations in alien plants have tended to focus on individual plant species on a case-by-case basis. This approach limits broad scale understanding of functional shifts and changes in interaction network structure that may occur following introduction. Here we use two extensive datasets of plant–fungal interactions derived from fungal sporocarp observations and recorded plant hosts in two island archipelago nations: New Zealand (NZ) and the United Kingdom (UK). We found that the NZ dataset shows a lower functional diversity of fungal hyphal foraging strategies in mycorrhiza of alien when compared with native trees. Across species this resulted in fungal foraging strategies associated with alien trees being much more variable in functional composition compared with native trees, which had a strikingly similar functional composition. The UK data showed no functional difference in fungal associates of alien and native plant genera. Notwithstanding this, both the NZ and UK data showed a substantial difference in interaction network structure of alien trees compared with native trees. In both cases, fungal associates of native trees showed strong modularity, while fungal associates of alien trees generally integrated into a single large module. The results suggest a lower functional diversity (in one dataset) and a simplification of network structure (in both) as a result of introduction, potentially driven by either limited symbiont co-introductions or disruption of habitat as a driver of specificity due to nursery conditions, planting, or plant edaphic-niche expansion. Recognizing these shifts in function and network structure has important implications for plant invasions and facilitation of secondary invasions via shared mutualist populations. PMID:28039116

[Invasive fungal infections in immunocompromised patients with focus on aspergillosis and its causative agents].

PubMed

Paloušová, Dita; Lengerová, Martina; Volfová, Pavlína; Bejdák, Petr; Kocmanová, Iva; Mayer, Jiří; Ráčil, Zdeněk

2012-08-01

Invasive fungal diseases (IFD) are a life-threatening infectious complications in immunocompromised patients and are associated with high rate of morbidity and mortality. The most common invasive mycosis in patients who underwent an allogeneic hematopoietic stem cell transplantation is invasive aspergilosis (IA), most frequently caused by the clinically dominant species Aspergillus fumigatus and, rarely, also by Aspergillus flavus, Aspergillus terreus and Aspergillus niger. In recent years, other related Aspergillus species were also reported to cause IFD, phenotypically similar to A. fumigatus and moreover, frequently exhibiting resistance towards various antifungals. For example, it is Aspergillus lentulus, Aspergillus viridinutans, Neosartoya fischeri, etc. Classical microbiological methods such as direct microscopy or culture are usually used for the identification of Aspergillus species. The application of PCR-based molecular techniques and monitoring of secondary metabolites production enable detection and identification of species, which are not distinguishable solely by their morphology. PCR methods are also useful for molecular strain typing of aspergilli and can reveal the genetic diversity of isolates.

Differences in stability of seed-associated microbial assemblages in response to invasion by phytopathogenic microorganisms.

PubMed

Rezki, Samir; Campion, Claire; Iacomi-Vasilescu, Beatrice; Preveaux, Anne; Toualbia, Youness; Bonneau, Sophie; Briand, Martial; Laurent, Emmanuelle; Hunault, Gilles; Simoneau, Philippe; Jacques, Marie-Agnès; Barret, Matthieu

2016-01-01

Seeds are involved in the vertical transmission of microorganisms from one plant generation to another and consequently act as reservoirs for the plant microbiota. However, little is known about the structure of seed-associated microbial assemblages and the regulators of assemblage structure. In this work, we have assessed the response of seed-associated microbial assemblages of Raphanus sativus to invading phytopathogenic agents, the bacterial strain Xanthomonas campestris pv. campestris (Xcc) 8004 and the fungal strain Alternaria brassicicola Abra43. According to the indicators of bacterial (16S rRNA gene and gyrB sequences) and fungal (ITS1) diversity employed in this study, seed transmission of the bacterial strain Xcc 8004 did not change the overall composition of resident microbial assemblages. In contrast seed transmission of Abra43 strongly modified the richness and structure of fungal assemblages without affecting bacterial assemblages. The sensitivity of seed-associated fungal assemblage to Abra43 is mostly related to changes in relative abundance of closely related fungal species that belong to the Alternaria genus. Variation in stability of the seed microbiota in response to Xcc and Abra43 invasions could be explained by differences in seed transmission pathways employed by these micro-organisms, which ultimately results in divergence in spatio-temporal colonization of the seed habitat.

Differences in stability of seed-associated microbial assemblages in response to invasion by phytopathogenic microorganisms

PubMed Central

Rezki, Samir; Campion, Claire; Iacomi-Vasilescu, Beatrice; Preveaux, Anne; Toualbia, Youness; Bonneau, Sophie; Briand, Martial; Laurent, Emmanuelle; Hunault, Gilles; Simoneau, Philippe; Jacques, Marie-Agnès

2016-01-01

Seeds are involved in the vertical transmission of microorganisms from one plant generation to another and consequently act as reservoirs for the plant microbiota. However, little is known about the structure of seed-associated microbial assemblages and the regulators of assemblage structure. In this work, we have assessed the response of seed-associated microbial assemblages of Raphanus sativus to invading phytopathogenic agents, the bacterial strain Xanthomonas campestris pv. campestris (Xcc) 8004 and the fungal strain Alternaria brassicicola Abra43. According to the indicators of bacterial (16S rRNA gene and gyrB sequences) and fungal (ITS1) diversity employed in this study, seed transmission of the bacterial strain Xcc 8004 did not change the overall composition of resident microbial assemblages. In contrast seed transmission of Abra43 strongly modified the richness and structure of fungal assemblages without affecting bacterial assemblages. The sensitivity of seed-associated fungal assemblage to Abra43 is mostly related to changes in relative abundance of closely related fungal species that belong to the Alternaria genus. Variation in stability of the seed microbiota in response to Xcc and Abra43 invasions could be explained by differences in seed transmission pathways employed by these micro-organisms, which ultimately results in divergence in spatio-temporal colonization of the seed habitat. PMID:27077013

Epidemiology of invasive fungal diseases among patients with haematological disorders in the Asia-Pacific: a prospective observational study.

PubMed

Hsu, L Y; Lee, D G; Yeh, S P; Bhurani, D; Khanh, B Q; Low, C Y; Norasetthada, L; Chan, T; Kwong, Y L; Vaid, A K; Alejandria, I; Mendoza, M; Chen, C Y; Johnson, A; Tan, T Y

2015-06-01

We conducted a 2-year multicentre prospective observational study to determine the epidemiology of and mortality associated with invasive fungal diseases (IFDs) among patients with haematological disorders in Asia. Eleven institutions from 8 countries/regions participated, with 412 subjects (28.2% possible, 38.3% probable and 33.5% proven IFDs) recruited. The epidemiology of IFDs in participating institutions was similar to Western centres, with Aspergillus spp. (65.9%) or Candida spp. (26.7%) causing the majority of probable and proven IFDs. The overall 30-day mortality was 22.1%. Progressive haematological disorder (odds ratio [OR] 5.192), invasive candidiasis (OR 3.679), and chronic renal disease (OR 6.677) were independently associated with mortality. Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Emerging Fungal Threats to Plants and Animals Challenge Agriculture and Ecosystem Resilience.

PubMed

Fones, Helen N; Fisher, Matthew C; Gurr, Sarah J

2017-03-01

While fungi can make positive contributions to ecosystems and agro-ecosystems, for example, in mycorrhizal associations, they can also have devastating impacts as pathogens of plants and animals. In undisturbed ecosystems, most such negative interactions will be limited through the coevolution of fungi with their hosts. In this article, we explore what happens when pathogenic fungi spread beyond their natural ecological range and become invasive on naïve hosts in new ecosystems. We will see that such invasive pathogens have been problematic to humans and their domesticated plant and animal species throughout history, and we will discuss some of the most pressing fungal threats of today.

Candida albicans-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers

PubMed Central

2018-01-01

ABSTRACT Life-threatening systemic infections often occur due to the translocation of pathogens across the gut barrier and into the bloodstream. While the microbial and host mechanisms permitting bacterial gut translocation are well characterized, these mechanisms are still unclear for fungal pathogens such as Candida albicans, a leading cause of nosocomial fungal bloodstream infections. In this study, we dissected the cellular mechanisms of translocation of C. albicans across intestinal epithelia in vitro and identified fungal genes associated with this process. We show that fungal translocation is a dynamic process initiated by invasion and followed by cellular damage and loss of epithelial integrity. A screen of >2,000 C. albicans deletion mutants identified genes required for cellular damage of and translocation across enterocytes. Correlation analysis suggests that hypha formation, barrier damage above a minimum threshold level, and a decreased epithelial integrity are required for efficient fungal translocation. Translocation occurs predominantly via a transcellular route, which is associated with fungus-induced necrotic epithelial damage, but not apoptotic cell death. The cytolytic peptide toxin of C. albicans, candidalysin, was found to be essential for damage of enterocytes and was a key factor in subsequent fungal translocation, suggesting that transcellular translocation of C. albicans through intestinal layers is mediated by candidalysin. However, fungal invasion and low-level translocation can also occur via non-transcellular routes in a candidalysin-independent manner. This is the first study showing translocation of a human-pathogenic fungus across the intestinal barrier being mediated by a peptide toxin. PMID:29871918

[Localized invasive intracranial aspergillosis with multiple cranial nerve failure -- case report and review of the literature].

PubMed

Winkler, F; Seelos, K; Hempel, J M; Pfister, H-W

2002-12-01

Contrary to the more frequent hematogenously spread cerebral aspergillosis, localized invasive intracranial aspergillosis is a fungal infection that can also occur in patients who are not severely immunosuppressed. This illness can be effectively treated in some of these patients by early and rigorous therapy. Localized invasion of the fungus, generally from one of the nasal sinuses, causes intracranial growth mainly along the base of the skull and larger vessels,where fibrous, granulomatous tissue develops. This generally leads to damage of the cranial nerves (primarily I-VI) as well as localized pain syndromes. We report on the clinical course documented by MRI of a patient with localized invasive intracranial aspergillosis who had multiple failure of cranial nerves following surgery for an aspergilloma of the maxillary sinus. Clinical course, imaging findings, and treatment of the illness are discussed with a review of the relevant literature.

[Favorable Outcome of Hepatosplenic Candidiasis in a Patient with Acute Leukemia].

PubMed

Čolović, Nataša; Arsenijević, Valentina Arsić; Suvajdžić, Nada; Djunić, Irena; Tomin, Dragica

2015-01-01

Acute leukemias treatment requires strong chemotherapy. Patients that develop bone marrow aplasia become immunocompromised, thus becoming liable to bacterial and fungal infections. Fungal infections caused by Candida are frequent. Hepatosplenic candidiasis (HSC) is a frequent consequence of invasive candidiasis which is clinically presented with prolonged febrility unresponsive to antibiotics. A 53-year-old patient with acute myeloid leukemia was submitted to standard chemotherapy "3+7" regimen (daunoblastine 80 mg i.v. on days 1 to 3, cytarabine 2 x 170 mg i.v. during 7 days) and achieved complete remission. However, during remission he developed febrility unresponsive to antibiotics. Computerised tomography (CT) of the abdomen showed multiple hypodense lesions within the liver and spleen. Haemocultures on fungi were negative. However, seroconversion of biomarkers for invasive fungal infection (FI) (Candida and Aspergillus antigen/Ag and antibody/Ab) indicated possible HSC. Only high positivity of anti-Candida IgG antibodies, positivity of mannan and CT finding we regarded sufficient for the diagnosis and antimycotic therapy.Three months of treatment with different antimycotics were necessary for complete disappearance of both clinical symptoms and CT findings. In patients with prolonged febrile neutropenia IFI has to be strongly suspected. If imaging techniques show multiple hypodense lesions within liver and spleen, HSC has to be taken seriously into consideration. We believe that, along with CT finding, positive laboratory Candida biomarkers (mannan and IgG antibodies) should be considered sufficient for"probable HSC" and commencement of antifungal therapy, which must be long enough, i.e. until complete disappearance of clinical symptoms and CT findings are achieved.

Update on mucormycosis pathogenesis.

PubMed

Ibrahim, Ashraf S; Kontoyiannis, Dimitrios P

2013-12-01

Mucormycosis is an increasingly common fungal infection with unacceptably high mortality. The recent sequencing genome projects of Mucorales and the development of gene manipulation have enabled significant advances in understanding the pathogenesis of mucormycosis. Therefore, we review the pathogenesis of mucormycosis and highlight potential development of novel diagnostic and therapeutic modalities against this lethal disease. Much of the work has been focused on the role of iron uptake in the virulence of Mucorales. Additionally, host receptors and fungal ligands involved in the process of tissue invasion as well as sporangiospore size and sex loci and their contribution to virulence of Mucorales are discussed. Finally, the role of innate and adaptive immunity in protection against Mucorales and new evidence about drug-induced apoptosis in these fungi are discussed. Recent discoveries introduce several potentially novel diagnostic and therapeutic modalities, which are likely to improve management and outcome for mucormycosis. Future preclinical and clinical research is warranted to develop these diagnostic and therapeutic strategies.

Invasive Fungal Infections Acquired from Contaminated Food or Nutritional Supplements: A Review of the Literature.

PubMed

Benedict, Kaitlin; Chiller, Tom M; Mody, Rajal K

2016-07-01

Fungi are an integral part of the natural environment and, therefore, play many roles in relation to food: some fungi are used in food production, some are food sources themselves, and some are agents of food spoilage. Some fungi that contaminate food can also be harmful to human health. The harmful but noninfectious health consequences of mycotoxins have been well-characterized, but the extent to which fungi in food pose a risk for invasive infections is unknown. We conducted a literature review to identify cases of invasive fungal infections (IFIs) believed to have resulted from ingestion or inhalation of food, beverages, or dietary supplements (excluding Saccharomyces infections). We identified 11 publications describing cases or small outbreaks of IFIs related to foods or beverages and three describing IFIs related to dietary supplements. These food-associated IFIs were predominantly mold infections, and the few yeast infections were associated with dairy products. Suspected foodborne IFIs appear to be rare, but are increasingly described in the electronically searchable literature. They are associated with a variety of foods, are due to a variety of fungal pathogens, and primarily occur in persons with immunosuppressive conditions or other predisposing factors. Various guidelines for high-risk patients recommend avoidance of certain food products that may contain high levels of fungi, but further work is needed to evaluate the effectiveness of these restrictive diets in preventing fungal infections. The relationships between food spoilage, food insecurity, and IFI risk are another area that may warrant further exploration.

Effects of tree phytochemistery on the interactions among endophloedic fungi associated with the southern pine beetle

Treesearch

R. W. Hofstetter; Jolie B. Mahfouz; Kier D. Klepzig; M. P. Ayres

2005-01-01

We examined the interaction between host trees and fungi associated with a tree-killing bark beetle, Dendroctonus frontalis. We evaluated (1) the response of four Pinus species to fungal invasion and (2) the effects of plant secondary metabolites on primary growth of and secondary colonization of three consistent fungal associates...

Evaluating the virulence and longevity of non-woven fiber bands impregnated with Metarhizium anisopliae against the Asian longhorned beetle, Anoplophora glabripennis (Coleoptera: Cerambycidae)

Treesearch

Ryan P. Shanley; Melody Keena; Micheal M. Wheeler; Jarrod Leland; Ann E. Hajek

2009-01-01

Fiber bands impregnated with entomopathogenic fungi (=fungal bands) provide an effective method for controlling the invasive Asian longhorned beetle, Anoplophora glabripennis (Motschulsky) (Coleoptera: Cerambycidae). In this study we investigated the effective longevity of fungal bands for use against A. glabripennis, using...

Invasion dynamics of white-nose syndrome fungus, midwestern United States, 2012-2014.

PubMed

Langwig, Kate E; Hoyt, Joseph R; Parise, Katy L; Kath, Joe; Kirk, Dan; Frick, Winifred F; Foster, Jeffrey T; Kilpatrick, A Marm

2015-06-01

White-nose syndrome has devastated bat populations in eastern North America. In Midwestern United States, prevalence increased quickly in the first year of invasion (2012-13) but with low population declines. In the second year (2013-14), environmental contamination led to earlier infection and high population declines. Interventions must be implemented before or soon after fungal invasion to prevent population collapse.

Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Malignancies.

PubMed

Varughese, Tilly; Taur, Ying; Cohen, Nina; Palomba, M Lia; Seo, Susan K; Hohl, Tobias M; Redelman-Sidi, Gil

2018-03-02

Ibrutinib is a Bruton's tyrosine kinase inhibitor that is used for the treatment of lymphoid malignancies, including chronic lymphocytic leukemia (CLL), Waldenström's macroglobulinemia and mantle cell lymphoma (MCL). Several case series have described opportunistic infections among ibrutinib recipients, but the full extent of these infections is unknown. We sought to determine the spectrum of serious infections associated with ibrutinib treatment. We reviewed the electronic medical records of patients with lymphoid malignancies at Memorial Sloan Kettering Cancer Center who received ibrutinib during a five-year period from January 1, 2012 to December 31, 2016. Serious infections were identified by review of the relevant microbiology, clinical laboratory, and radiology data. Risk factors for infection were determined by univariate and multivariate analyses. 378 patients with lymphoid malignancies who received ibrutinib were analyzed. The most common underlying malignancies were CLL and MCL. 84% of patients received ibrutinib as monotherapy. Serious infection developed in 43 patients (11.4%), primarily during the first year of ibrutinib treatment. Of these, 23 (53.5%) developed invasive bacterial infections, and 16 (37.2%) developed invasive fungal infections (IFI). The majority of those who developed IFI on ibrutinib therapy (62.5%) lacked classical clinical risk factors for fungal infection (i.e., neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in six of the 43 patients (14%). Patients with lymphoid malignancies receiving ibrutinib treatment are at risk for serious infections, including IFI.

Structures of Cryptococcus neoformans Protein Farnesyltransferase Reveal Strategies for Developing Inhibitors That Target Fungal Pathogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hast, Michael A.; Nichols, Connie B.; Armstrong, Stephanie M.

Cryptococcus neoformans is a fungal pathogen that causes life-threatening infections in immunocompromised individuals, including AIDS patients and transplant recipients. Few antifungals can treat C. neoformans infections, and drug resistance is increasing. Protein farnesyltransferase (FTase) catalyzes post-translational lipidation of key signal transduction proteins and is essential in C. neoformans. We present a multidisciplinary study validating C. neoformans FTase (CnFTase) as a drug target, showing that several anticancer FTase inhibitors with disparate scaffolds can inhibit C. neoformans and suggesting structure-based strategies for further optimization of these leads. Structural studies are an essential element for species-specific inhibitor development strategies by revealing similarities andmore » differences between pathogen and host orthologs that can be exploited. We, therefore, present eight crystal structures of CnFTase that define the enzymatic reaction cycle, basis of ligand selection, and structurally divergent regions of the active site. Crystal structures of clinically important anticancer FTase inhibitors in complex with CnFTase reveal opportunities for optimization of selectivity for the fungal enzyme by modifying functional groups that interact with structurally diverse regions. A substrate-induced conformational change in CnFTase is observed as part of the reaction cycle, a feature that is mechanistically distinct from human FTase. Our combined structural and functional studies provide a framework for developing FTase inhibitors to treat invasive fungal infections.« less

Successful management of a renal fungal ball in a pretermature neonate: A case report and review of literature

PubMed Central

Raghunath, B. V.; Gowrishankar, B. C.; Narendrababu, M.; Ramesh, S.

2013-01-01

Invasive fungal infection is common in the present day NICUs - generally manifesting as candiduria or candida sepsis. Fungal balls in the kidneys are very uncommon and most are amenable to higher antifungal agents. However, we had a child who did not respond to such measures and ultimately needed a surgical removal of the fungal ball in his kidney. We report this case along with a review of literature to highlight about this uncommon, but an important cause of persistent sepsis in pre-term infants and to review the treatment options including a surgical removal. PMID:24019645

Invasive Fungal Infections in Patients with Hematological Malignancies: Emergence of Resistant Pathogens and New Antifungal Therapies

PubMed Central

Gamaletsou, Maria N.; Walsh, Thomas J.; Sipsas, Nikolaos V.

2018-01-01

Invasive fungal infections caused by drug-resistant organisms are an emerging threat to heavily immunosuppressed patients with hematological malignancies. Modern early antifungal treatment strategies, such as prophylaxis and empirical and preemptive therapy, result in long-term exposure to antifungal agents, which is a major driving force for the development of resistance. The extended use of central venous catheters, the nonlinear pharmacokinetics of certain antifungal agents, neutropenia, other forms of intense immunosuppression, and drug toxicities are other contributing factors. The widespread use of agricultural and industrial fungicides with similar chemical structures and mechanisms of action has resulted in the development of environmental reservoirs for some drug-resistant fungi, especially azole-resistant Aspergillus species, which have been reported from four continents. The majority of resistant strains have the mutation TR34/L98H, a finding suggesting that the source of resistance is the environment. The global emergence of new fungal pathogens with inherent resistance, such as Candida auris, is a new public health threat. The most common mechanism of antifungal drug resistance is the induction of efflux pumps, which decrease intracellular drug concentrations. Overexpression, depletion, and alteration of the drug target are other mechanisms of resistance. Mutations in the ERG11 gene alter the protein structure of C-demethylase, reducing the efficacy of antifungal triazoles. Candida species become echinocandin-resistant by mutations in FKS genes. A shift in the epidemiology of Candida towards resistant non-albicans Candida spp. has emerged among patients with hematological malignancies. There is no definite association between antifungal resistance, as defined by elevated minimum inhibitory concentrations, and clinical outcomes in this population. Detection of genes or mutations conferring resistance with the use of molecular methods may offer better predictive values in certain cases. Treatment options for resistant fungal infections are limited and new drugs with novel mechanisms of actions are needed. Prevention of resistance through antifungal stewardship programs is of paramount importance. PMID:29391334

Application of an oligonucleotide microarray-based nano-amplification technique for the detection of fungal pathogens.

PubMed

Lu, Weiping; Gu, Dayong; Chen, Xingyun; Xiong, Renping; Liu, Ping; Yang, Nan; Zhou, Yuanguo

2010-10-01

The traditional techniques for diagnosis of invasive fungal infections in the clinical microbiology laboratory need improvement. These techniques are prone to delay results due to their time-consuming process, or result in misidentification of the fungus due to low sensitivity or low specificity. The aim of this study was to develop a method for the rapid detection and identification of fungal pathogens. The internal transcribed spacer two fragments of fungal ribosomal DNA were amplified using a polymerase chain reaction for all samples. Next, the products were hybridized with the probes immobilized on the surface of a microarray. These species-specific probes were designed to detect nine different clinical pathogenic fungi including Candida albicans, Candida tropocalis, Candida glabrata, Candida parapsilosis, Candida krusei, Candida lusitaniae, Candida guilliermondii, Candida keyfr, and Cryptococcus neoformans. The hybridizing signals were enhanced with gold nanoparticles and silver deposition, and detected using a flatbed scanner or visually. Fifty-nine strains of fungal pathogens, including standard and clinically isolated strains, were correctly identified by this method. The sensitivity of the assay for Candida albicans was 10 cells/mL. Ten cultures from clinical specimens and 12 clinical samples spiked with fungi were also identified correctly. This technique offers a reliable alternative to conventional methods for the detection and identification of fungal pathogens. It has higher efficiency, specificity and sensitivity compared with other methods commonly used in the clinical laboratory.

Annual brome control using a native fungal seed pathogen

Treesearch

Susan E. Meyer; Suzette Clement; Julie Beckstead

2013-01-01

Formulations having a selective, mycoherbicide activity for killing ungerminated seeds of invasive grass species are provided. An agricultural, mycoherbicide formulation is taught for killing ungerminated seeds of invasive grass species. The formulations can comprise, for example, a slow-growing strain of Pyrenophora semeniperda, a fast-growing strain of Pyrenophora...

Lack of resistance development in Bemisia tabaci to Isaria fumosorosea after multiple generations of selection

NASA Astrophysics Data System (ADS)

Gao, Tianni; Wang, Zhaolei; Huang, Yü; Keyhani, Nemat O.; Huang, Zhen

2017-02-01

The emergence of insecticide resistant insect pests is of significant concern worldwide. The whitefly, Bemisia tabaci, is an important agricultural pest and has shown incredible resilience developing resistance to a number of chemical pesticides. Entomopathogenic fungi such as Isaria fumosorosea offer an attractive alternative to chemical pesticides for insect control, and this fungus has been shown to be an effective pathogen of B. tabaci. Little is known concerning the potential for the development of resistance to I. fumosorosea by B. tabaci. Five generations of successive survivors of B. tabaci infected by I. fumosorosea were assayed with I. fumosorosea. No significant differences in susceptibility to I. fumosorosea, number of ovarioles, or ovipostioning were seen between any of the generations tested. Effects of I. fumosorosea and cell-free ethyl acetate fractions derived from the fungus on the B. tabaci fat body, ovary, and vitellogenin were also investigated. These data revealed significant deformation and degradation of ovary tissues and associated vitellogenin by the fungal mycelium as well as by cell-free ethyl acetate fungal extracts. These data indicate the lack of the emergence of resistance to I. fumosorosea under the conditions tested and demonstrate invasion of the insect reproductive tissues during fungal infection.

Assessing the advantage of morphological changes in Candida albicans: a game theoretical study

PubMed Central

Tyc, Katarzyna M.; Kühn, Clemens; Wilson, Duncan; Klipp, Edda

2014-01-01

A range of attributes determines the virulence of human pathogens. During interactions with their hosts, pathogenic microbes often undergo transitions between distinct stages, and the ability to switch between these can be directly related to the disease process. Understanding the mechanisms and dynamics of these transitions is a key factor in understanding and combating infectious diseases. The human fungal pathogen Candida albicans exhibits different morphotypes at different stages during the course of infection (candidiasis). For example, hyphae are considered to be the invasive form, which causes tissue damage, while yeast cells are predominant in the commensal stage. Here, we described interactions of C. albicans with its human host in a game theoretic model. In the game, players are fungal cells. Each fungal cell can adopt one of the two strategies: to exist as a yeast or hyphal cell. We characterized the ranges of model parameters in which the coexistence of both yeast and hyphal forms is plausible. Stability analysis of the system showed that, in theory, a reduced ability of the host to specifically recognize yeast and hyphal cells can result in bi-stability of the microbial populations' profile. Inspired by the model analysis we reasoned that the types of microbial interactions can change during invasive candidiasis. We found that positive cooperation among fungal cells occurs in mild infections and an enhanced tendency to invade the host is associated with negative cooperation. The model can easily be extended to multi-player systems with direct application to identifying individuals that enhance either positive or negative cooperation. Results of the modeling approach have potential application in developing treatment strategies. PMID:24567730

Designing a SCAR molecular marker for monitoring Trichoderma cf. harzianum in experimental communities.

PubMed

Pérez, Gabriel; Verdejo, Valentina; Gondim-Porto, Clarissa; Orlando, Julieta; Carú, Margarita

2014-11-01

Several species of the fungal genus Trichoderma establish biological interactions with various micro- and macro-organisms. Some of these interactions are relevant in ecological terms and in biotechnological applications, such as biocontrol, where Trichoderma could be considered as an invasive species that colonizes a recipient community. The success of this invasion depends on multiple factors, which can be assayed using experimental communities as study models. Therefore, the aim of this work is to develop a species-specific sequence-characterized amplified region (SCAR) marker to monitor the colonization and growth of T. cf. harzianum when it invades experimental communities. For this study, 16 randomly amplified polymorphic DNA (RAPD) primers of 10-mer were used to generate polymorphic patterns, one of which generated a band present only in strains of T. cf. harzianum. This band was cloned, sequenced, and five primers of 20-23 mer were designed. Primer pairs 2F2/2R2 and 2F2/2R3 successfully and specifically amplified fragments of 278 and 448 bp from the T. cf. harzianum BpT10a strain DNA, respectively. Both primer pairs were also tested against the DNA from 14 strains of T. cf. harzianum and several strains of different fungal genera as specificity controls. Only the DNA from the strains of T. cf. harzianum was successfully amplified. Moreover, primer pair 2F2/2R2 was assessed by quantitative real-time polymerase chain reaction (PCR) using fungal DNA mixtures and DNA extracted from fungal experimental communities as templates. T. cf. harzianum was detectable even when as few as 100 copies of the SCAR marker were available or even when its population represented only 0.1% of the whole community.

Designing a SCAR molecular marker for monitoring Trichoderma cf. harzianum in experimental communities* #

PubMed Central

Pérez, Gabriel; Verdejo, Valentina; Gondim-Porto, Clarissa; Orlando, Julieta; Carú, Margarita

2014-01-01

Several species of the fungal genus Trichoderma establish biological interactions with various micro- and macro-organisms. Some of these interactions are relevant in ecological terms and in biotechnological applications, such as biocontrol, where Trichoderma could be considered as an invasive species that colonizes a recipient community. The success of this invasion depends on multiple factors, which can be assayed using experimental communities as study models. Therefore, the aim of this work is to develop a species-specific sequence-characterized amplified region (SCAR) marker to monitor the colonization and growth of T. cf. harzianum when it invades experimental communities. For this study, 16 randomly amplified polymorphic DNA (RAPD) primers of 10-mer were used to generate polymorphic patterns, one of which generated a band present only in strains of T. cf. harzianum. This band was cloned, sequenced, and five primers of 20–23 mer were designed. Primer pairs 2F2/2R2 and 2F2/2R3 successfully and specifically amplified fragments of 278 and 448 bp from the T. cf. harzianum BpT10a strain DNA, respectively. Both primer pairs were also tested against the DNA from 14 strains of T. cf. harzianum and several strains of different fungal genera as specificity controls. Only the DNA from the strains of T. cf. harzianum was successfully amplified. Moreover, primer pair 2F2/2R2 was assessed by quantitative real-time polymerase chain reaction (PCR) using fungal DNA mixtures and DNA extracted from fungal experimental communities as templates. T. cf. harzianum was detectable even when as few as 100 copies of the SCAR marker were available or even when its population represented only 0.1% of the whole community. PMID:25367789

Mucormycosis in Children: Review and Recommendations for Management.

PubMed

Francis, Joshua R; Villanueva, Paola; Bryant, Penelope; Blyth, Christopher C

2018-05-15

Mucormycosis represents the third most common invasive fungal infection in children, and recent studies have suggested a rising incidence. Its case fatality rate is high, especially for neonates. Clinical presentation is influenced by underlying risk factors; associations with immunosuppression, neutropenia, diabetes, and prematurity have been described. It has been implicated in several hospital outbreaks. Diagnosis requires a high index of suspicion and evaluation with histopathology, culture, and, increasingly, molecular identification. Surgical debridement and antifungal therapies are the cornerstone for combatting invasive mucormycosis. However, the severity and relative rarity of this disease make comparative clinical trials for evaluating antifungal therapies in children difficult to conduct. Hence, therapeutic decisions are derived mainly from retrospective case series, in vitro data, and animal models. In this review, we summarize the literature on the epidemiology and diagnosis of this invasive fungal infection and provide suggestions on the management of mucormycosis in children.

Burden of serious fungal infections in Ukraine.

PubMed

Osmanov, Ali; Denning, David W

2015-10-01

Ukraine has high rates of TB, AIDS and cancer. We estimated the burden of fungal disease from epidemiology papers and specific populations at risk and fungal infection frequencies. HIV/AIDS cases and deaths (2012) and tuberculosis statistics were obtained from the State Service of Ukraine, while chronic obstructive pulmonary disease (COPD) cases were from M. Miravitlles et al., Thorax 64, 863-868 (2009). Annual estimates are 893,579 Ukrainian women get recurrent vaginal thrush (≥4× per year), 50,847 cases of oral candidiasis and 13,727 cases of oesophageal candidiasis in HIV, and 101 (1%) of 10,085 new AIDS cases develop cryptococcal meningitis, 6152 cases of Pneumocystis pneumonia (13.5 cases per 100,000). Of the 29,265 cases of active respiratory TB in 2012, it is estimated that 2881 new cases of chronic pulmonary aspergillosis (CPA) occurred and that the 5-year period prevalence is 7724 cases with a total CPA burden of 10,054 cases. Assuming adult asthma prevalence is ~2.9%, 28,447 patients with allergic bronchopulmonary aspergillosis (ABPA) are likely and 37,491 with severe asthma with fungal sensitisation. We estimate 2278 cases and 376 postsurgical intra-abdominal Candida infections. Invasive aspergillosis in immunocompromised patients is estimated at 303 patients annually; 930 cases in COPD patients. Ninety cases of mucormycosis (2 per 1,000,000) are estimated. In total, ~1,000,000 (2.2%) people in Ukraine develop serious fungal infections annually. © 2015 Blackwell Verlag GmbH.

Host-Induced Gene Silencing of Rice Blast Fungus Magnaporthe oryzae Pathogenicity Genes Mediated by the Brome Mosaic Virus.

PubMed

Zhu, Lin; Zhu, Jian; Liu, Zhixue; Wang, Zhengyi; Zhou, Cheng; Wang, Hong

2017-09-26

Magnaporthe oryzae is a devastating plant pathogen, which has a detrimental impact on rice production worldwide. Despite its agronomical importance, some newly-emerging pathotypes often overcome race-specific disease resistance rapidly. It is thus desirable to develop a novel strategy for the long-lasting resistance of rice plants to ever-changing fungal pathogens. Brome mosaic virus (BMV)-induced RNA interference (RNAi) has emerged as a useful tool to study host-resistance genes for rice blast protection. Planta-generated silencing of targeted genes inside biotrophic pathogens can be achieved by expression of M. oryzae -derived gene fragments in the BMV-mediated gene silencing system, a technique termed host-induced gene silencing (HIGS). In this study, the effectiveness of BMV-mediated HIGS in M. oryzae was examined by targeting three predicted pathogenicity genes, MoABC1, MoMAC1 and MoPMK1 . Systemic generation of fungal gene-specific small interfering RNA (siRNA) molecules induced by inoculation of BMV viral vectors inhibited disease development and reduced the transcription of targeted fungal genes after subsequent M. oryzae inoculation. Combined introduction of fungal gene sequences in sense and antisense orientation mediated by the BMV silencing vectors significantly enhanced the efficiency of this host-generated trans-specific RNAi, implying that these fungal genes played crucial roles in pathogenicity. Collectively, our results indicated that BMV-HIGS system was a great strategy for protecting host plants against the invasion of pathogenic fungi.

Death by Edible Mushroom: First Report of Volvariella volvacea as an Etiologic Agent of Invasive Disease in a Patient following Double Umbilical Cord Blood Transplantation▿

PubMed Central

Salit, R. B.; Shea, Y. R.; Gea-Banacloche, J.; Fahle, G. A.; Abu-Asab, M.; Sugui, J. A.; Carpenter, A. E.; Quezado, M. M.; Bishop, M. R.; Kwon-Chung, K. J.

2010-01-01

We describe a case of invasive fungal infection caused by Volvariella volvacea following double umbilical cord blood transplantation (UCBT). Although infections caused by several mushroom species have been documented, we believe this to be the first published report of invasive infection with Volvariella volvacea, an edible mushroom belonging to Agaricales. PMID:20826647

Release, establishment, and initial spread of the fungal pathogen Entomophaga maimaiga in island populations of Lymantria dispar

Treesearch

Patrick C. Tobin; Ann E. Hajek

2012-01-01

Biological invasions represent a major threat to the function and composition of ecosystems. Although the degree of invasion success of a non-native species and the consequent damage it causes can vary among and within invading species, the absence or presence of natural enemies associated with the invader can also play roles in the invasion dynamics. We used newly...

Histopathologic Diagnosis of Fungal Infections in the 21st Century

PubMed Central

Guarner, Jeannette; Brandt, Mary E.

2011-01-01

Summary: Fungal infections are becoming more frequent because of expansion of at-risk populations and the use of treatment modalities that permit longer survival of these patients. Because histopathologic examination of tissues detects fungal invasion of tissues and vessels as well as the host reaction to the fungus, it is and will remain an important tool to define the diagnostic significance of positive culture isolates or results from PCR testing. However, there are very few instances where the morphological characteristics of fungi are specific. Therefore, histopathologic diagnosis should be primarily descriptive of the fungus and should include the presence or absence of tissue invasion and the host reaction to the infection. The pathology report should also include a comment stating the most frequent fungi associated with that morphology as well as other possible fungi and parasites that should be considered in the differential diagnosis. Alternate techniques have been used to determine the specific agent present in the histopathologic specimen, including immunohistochemistry, in situ hybridization, and PCR. In addition, techniques such as laser microdissection will be useful to detect the now more frequently recognized dual fungal infections and the local environment in which this phenomenon occurs. PMID:21482725

Galactomannan, β-D-Glucan, and Polymerase Chain Reaction-Based Assays for the Diagnosis of Invasive Fungal Disease in Pediatric Cancer and Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis.

PubMed

Lehrnbecher, Thomas; Robinson, Paula D; Fisher, Brian T; Castagnola, Elio; Groll, Andreas H; Steinbach, William J; Zaoutis, Theoklis E; Negeri, Zelalem F; Beyene, Joseph; Phillips, Bob; Sung, Lillian

2016-11-15

We systematically reviewed and analyzed the available data for galactomannan (GM), β-D-glucan (BG), and polymerase chain reaction (PCR)-based assays to detect invasive fungal disease (IFD) in patients with pediatric cancer or undergoing hematopoietic stem cell transplantation when used as screening tools during immunosuppression or as diagnostic tests in patients presenting with symptoms such as fever during neutropenia (FN). Of 1532 studies screened, 25 studies reported on GM (n = 19), BG (n = 3), and PCR (n = 11). All fungal biomarkers demonstrated highly variable sensitivity, specificity, and positive predictive values, and these were generally poor in both clinical settings. GM negative predictive values were high, ranging from 85% to 100% for screening and 70% to 100% in the diagnostic setting, but failure to identify non-Aspergillus molds limits its usefulness. Future work could focus on the usefulness of combinations of fungal biomarkers in pediatric cancer and HSCT. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Allergic Aspergillus Rhinosinusitis.

PubMed

Chakrabarti, Arunaloke; Kaur, Harsimran

2016-12-08

Allergic fungal rhinosinusitis (AFRS) is a unique variety of chronic polypoid rhinosinusitis usually in atopic individuals, characterized by presence of eosinophilic mucin and fungal hyphae in paranasal sinuses without invasion into surrounding mucosa. It has emerged as an important disease involving a large population across the world with geographic variation in incidence and epidemiology. The disease is surrounded by controversies regarding its definition and etiopathogenesis. A working group on "Fungal Sinusitis" under the International Society for Human and Animal Mycology (ISHAM) addressed some of those issues, but many questions remain unanswered. The descriptions of "eosinophilic fungal rhinosinusitis" (EFRS), "eosinophilic mucin rhinosinusitis" (EMRS) and mucosal invasion by hyphae in few patients have increased the problem to delineate the disease. Various hypotheses exist for etiopathogenesis of AFRS with considerable overlap, though recent extensive studies have made certain in depth understanding. The diagnosis of AFRS is a multi-disciplinary approach including the imaging, histopathology, mycology and immunological investigations. Though there is no uniform management protocol for AFRS, surgical clearing of the sinuses with steroid therapy are commonly practiced. The role of antifungal agents, leukotriene antagonists and immunomodulators is still questionable. The present review covers the controversies, recent advances in pathogenesis, diagnosis, and management of AFRS.

The F-box protein Fbp1 functions in the invasive growth and cell wall integrity mitogen-activated protein kinase (MAPK) pathways in Fusarium oxysporum.

PubMed

Miguel-Rojas, Cristina; Hera, Concepcion

2016-01-01

F-box proteins determine substrate specificity of the ubiquitin-proteasome system. Previous work has demonstrated that the F-box protein Fbp1, a component of the SCF(Fbp1) E3 ligase complex, is essential for invasive growth and virulence of the fungal plant pathogen Fusarium oxysporum. Here, we show that, in addition to invasive growth, Fbp1 also contributes to vegetative hyphal fusion and fungal adhesion to tomato roots. All of these functions have been shown previously to require the mitogen-activated protein kinase (MAPK) Fmk1. We found that Fbp1 is required for full phosphorylation of Fmk1, indicating that Fbp1 regulates virulence and invasive growth via the Fmk1 pathway. Moreover, the Δfbp1 mutant is hypersensitive to sodium dodecylsulfate (SDS) and calcofluor white (CFW) and shows reduced phosphorylation levels of the cell wall integrity MAPK Mpk1 after SDS treatment. Collectively, these results suggest that Fbp1 contributes to both the invasive growth and cell wall integrity MAPK pathways of F. oxysporum. © 2015 BSPP AND JOHN WILEY & SONS LTD.

Diagnostic Imaging and Invasive Fungal Diseases in Children.

PubMed

Katragkou, Aspasia; Fisher, Brian T; Groll, Andreas H; Roilides, Emmanuel; Walsh, Thomas J

2017-09-01

Invasive fungal disease (IFD) is a life-threatening condition, especially in immunocompromised children. The role of diagnostic imaging in children at risk for an IFD is multifactorial, including initially detecting it, evaluating for dissemination of infection beyond the primary site of disease, monitoring the response to antifungal therapy, and assessing for potential relapse. The objective of this review was to synthesize the published literature relevant to the use of various imaging modalities for the diagnosis and management of IFD in children. © The Author 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Invasive fungal infection following chemotherapy for acute myeloid leukaemia-Experience from a developing country.

PubMed

Korula, Anu; Abraham, Aby; Abubacker, Fouzia N; Viswabandya, Auro; Lakshmi, Kavitha M; Abraham, O C; Rupali, Priscilla; Varghese, George M; Michael, Joy S; Srivastava, Alok; Mathews, Vikram; George, Biju

2017-10-01

The incidence of invasive fungal infections (IFI) is believed to be higher in patients with acute myeloid leukaemia (AML) undergoing chemotherapy in non-HEPA-filtered rooms. The aim of this study is to review the incidence of IFI in a large cohort of patients with AML treated at a single centre in India. Two hundred and twenty-two patients with AML treated with either induction chemotherapy or salvage chemotherapy between 2008 and 2013 were studied retrospectively. IFI was defined as per the revised EORTC-MSG criteria. Data on type of chemotherapy, prophylactic strategies, engraftment (ANC>500), the presence of IFI and survival were collected. IFI was diagnosed in 86 patients (38.7%) with proven IFI in 12 (5.4%). Use of posaconazole prophylaxis (P=.001) was the only factor associated with reduced incidence of IFI. Survival in patients with proven IFI was lower than those without proven IFI, but not statistically significant (59.4% vs 78.5%; P=.139). There is a high incidence of IFI during induction chemotherapy for acute myeloid leukaemia in developing countries. Posaconazole prophylaxis was associated with a significantly lower incidence of IFI. Optimal yet cost-effective strategies for prevention and early diagnosis of IFI are required to improve survival in patients undergoing chemotherapy for AML. © 2017 Blackwell Verlag GmbH.

Consensus guidelines for implementation of quality processes to prevent invasive fungal disease and enhanced surveillance measures during hospital building works, 2014.

PubMed

Chang, C C; Ananda-Rajah, M; Belcastro, A; McMullan, B; Reid, A; Dempsey, K; Athan, E; Cheng, A C; Slavin, M A

2014-12-01

Healthcare-associated fungal outbreaks impose a substantial economic burden on the health system and typically result in high patient morbidity and mortality, particularly in the immunocompromised host. As the population at risk of invasive fungal infection continues to grow due to the increased burden of cancer and related factors, the need for hospitals to employ preventative measures has become increasingly important. These guidelines outline the standard quality processes hospitals need to accommodate into everyday practice and at times of healthcare-associated outbreak, including the role of antifungal stewardship programmes and best practice environmental sampling. Specific recommendations are also provided to help guide the planning and implementation of quality processes and enhanced surveillance before, during and after high-risk activities, such as hospital building works. Areas in which information is still lacking and further research is required are also highlighted. © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.

Mutant characterization and in vivo conditional repression identify aromatic amino acid biosynthesis to be essential for Aspergillus fumigatus virulence

PubMed Central

Sasse, Anna; Hamer, Stefanie N; Amich, Jorge; Binder, Jasmin; Krappmann, Sven

2016-01-01

Pathogenicity of the saprobe Aspergillus fumigatus strictly depends on nutrient acquisition during infection, as fungal growth determines colonisation and invasion of a susceptible host. Primary metabolism has to be considered as a valid target for antimycotic therapy, based on the fact that several fungal anabolic pathways are not conserved in higher eukaryotes. To test whether fungal proliferation during invasive aspergillosis relies on endogenous biosynthesis of aromatic amino acids, defined auxotrophic mutants of A. fumigatus were generated and assessed for their infectious capacities in neutropenic mice and found to be strongly attenuated in virulence. Moreover, essentiality of the complete biosynthetic pathway could be demonstrated, corroborated by conditional gene expression in infected animals and inhibitor studies. This brief report not only validates the aromatic amino acid biosynthesis pathway of A. fumigatus to be a promising antifungal target but furthermore demonstrates feasibility of conditional gene expression in a murine infection model of aspergillosis. PMID:26605426

[Antifungal therapy for infants, children and adolescents with suspected or documented invasive fungal infection].

PubMed

Odio, C M

2010-04-01

Fungal nosocomial infections have gradually and consistently increased since the 90s.This increasing threat is closely related with the growing number of people with immune system disorders and their survival. It is also related with the destruction of their physical barriers against infection due to the use of cytotoxic drugs or invasive procedures, such is the case of cancer patients and bone marrow and solid organ transplant patients. Increased survival of patients with congenital or acquired immunodeficiency, premature babies and patients with complex congenital malformations, especially in the gastrointestinal tract, also add up to this scenario. The occurrence of yeast and filamentous fungi infections, especially of the Candida species, has been on the rise. Azole agents overuse, especially fluconazole, for the treatment and prophylaxis of fungal infections has put selective pressure on Candida spp. which resulted in an increase of non-albican species such as C. krusei, C. glabrata and C. famata, among others, as well as their growing resistance to these antifungal agents.

Distinct innate immune phagocyte responses to Aspergillus fumigatus conidia and hyphae in zebrafish larvae.

PubMed

Knox, Benjamin P; Deng, Qing; Rood, Mary; Eickhoff, Jens C; Keller, Nancy P; Huttenlocher, Anna

2014-10-01

Aspergillus fumigatus is the most common filamentous fungal pathogen of immunocompromised hosts, resulting in invasive aspergillosis (IA) and high mortality rates. Innate immunity is known to be the predominant host defense against A. fumigatus; however, innate phagocyte responses to A. fumigatus in an intact host and their contributions to host survival remain unclear. Here, we describe a larval zebrafish A. fumigatus infection model amenable to real-time imaging of host-fungal interactions in live animals. Following infection with A. fumigatus, innate phagocyte populations exhibit clear preferences for different fungal morphologies: macrophages rapidly phagocytose conidia and form aggregates around hyphae, while the neutrophil response is dependent upon the presence of hyphae. Depletion of macrophages rendered host larvae susceptible to invasive disease. Moreover, a zebrafish model of human leukocyte adhesion deficiency with impaired neutrophil function also resulted in invasive disease and impaired host survival. In contrast, macrophage-deficient but not neutrophil-deficient larvae exhibited attenuated disease following challenge with a less virulent (ΔlaeA) strain of A. fumigatus, which has defects in secondary metabolite production. Taking these results together, we have established a new vertebrate model for studying innate immune responses to A. fumigatus that reveals distinct roles for neutrophils and macrophages in mediating host defense against IA. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Commonly used oncology drugs decrease antifungal effectiveness against Candida and Aspergillus species.

PubMed

Butts, Arielle; Reitler, Parker; Ge, Wenbo; Fortwendel, Jarrod R; Palmer, Glen E

2018-04-30

The incidence of invasive fungal infections has risen significantly in recent decades as medical interventions have become increasingly aggressive. These infections are extremely difficult to treat due to the extremely limited repertoire of systemic antifungals, the development of drug resistance, and the extent of to which the patient's immune function is compromised. Even when the appropriate antifungal therapies are administered in a timely fashion, treatment failure is common, frequently even in the absence of in vitro microbial resistance. In this study, we screened a small collection of FDA approved oncolytic agents for compounds that impact the efficacy of the two most widely used classes of system antifungals against Candida albicans, Candida glabrata , and Aspergillus fumigatus We have identified several drugs that enhance fungal growth in the presence of the azole antifungals and examine the potential that these drugs directly affect fungal fitness, specifically antifungal susceptibility, and may be contributing to clinical treatment failure. Copyright © 2018 American Society for Microbiology.

Invasive Fungal Infections Acquired from Contaminated Food or Nutritional Supplements: A Review of the Literature

PubMed Central

Benedict, Kaitlin; Chiller, Tom M.; Mody, Rajal K.

2017-01-01

Fungi are an integral part of the natural environment and, therefore, play many roles in relation to food: some fungi are used in food production, some are food sources themselves, and some are agents of food spoilage. Some fungi that contaminate food can also be harmful to human health. The harmful but noninfectious health consequences of mycotoxins have been well-characterized, but the extent to which fungi in food pose a risk for invasive infections is unknown. We conducted a literature review to identify cases of invasive fungal infections (IFIs) believed to have resulted from ingestion or inhalation of food, beverages, or dietary supplements (excluding Saccharomyces infections). We identified 11 publications describing cases or small outbreaks of IFIs related to foods or beverages and three describing IFIs related to dietary supplements. These food-associated IFIs were predominantly mold infections, and the few yeast infections were associated with dairy products. Suspected foodborne IFIs appear to be rare, but are increasingly described in the electronically searchable literature. They are associated with a variety of foods, are due to a variety of fungal pathogens, and primarily occur in persons with immunosuppressive conditions or other predisposing factors. Various guidelines for high-risk patients recommend avoidance of certain food products that may contain high levels of fungi, but further work is needed to evaluate the effectiveness of these restrictive diets in preventing fungal infections. The relationships between food spoilage, food insecurity, and IFI risk are another area that may warrant further exploration. PMID:27074753

An integrated approach to evaluating alternative risk prediction strategies: a case study comparing alternative approaches for preventing invasive fungal disease.

PubMed

Sadique, Z; Grieve, R; Harrison, D A; Jit, M; Allen, E; Rowan, K M

2013-12-01

This article proposes an integrated approach to the development, validation, and evaluation of new risk prediction models illustrated with the Fungal Infection Risk Evaluation study, which developed risk models to identify non-neutropenic, critically ill adult patients at high risk of invasive fungal disease (IFD). Our decision-analytical model compared alternative strategies for preventing IFD at up to three clinical decision time points (critical care admission, after 24 hours, and end of day 3), followed with antifungal prophylaxis for those judged "high" risk versus "no formal risk assessment." We developed prognostic models to predict the risk of IFD before critical care unit discharge, with data from 35,455 admissions to 70 UK adult, critical care units, and validated the models externally. The decision model was populated with positive predictive values and negative predictive values from the best-fitting risk models. We projected lifetime cost-effectiveness and expected value of partial perfect information for groups of parameters. The risk prediction models performed well in internal and external validation. Risk assessment and prophylaxis at the end of day 3 was the most cost-effective strategy at the 2% and 1% risk threshold. Risk assessment at each time point was the most cost-effective strategy at a 0.5% risk threshold. Expected values of partial perfect information were high for positive predictive values or negative predictive values (£11 million-£13 million) and quality-adjusted life-years (£11 million). It is cost-effective to formally assess the risk of IFD for non-neutropenic, critically ill adult patients. This integrated approach to developing and evaluating risk models is useful for informing clinical practice and future research investment. © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Published by International Society for Pharmacoeconomics and Outcomes Research (ISPOR) All rights reserved.

Caspofungin in the treatment of invasive fungal infections.

PubMed

Keady, Simon; Thacker, Meera

2006-02-01

Caspofungin is a member of a new class of antifungals called Echinocandins and is the first to have marketing authorisation in the United Kingdom. This article reviews the clinical efficacy, side effect profile, dosing and administration schedule of caspofungin. The article also discusses the warnings and precautions associated with the use of this drug. Caspofungin is an effective treatment option in the management of fungal infections.

Development and validation of a risk model for identification of non-neutropenic, critically ill adult patients at high risk of invasive Candida infection: the Fungal Infection Risk Evaluation (FIRE) Study.

PubMed

Harrison, D; Muskett, H; Harvey, S; Grieve, R; Shahin, J; Patel, K; Sadique, Z; Allen, E; Dybowski, R; Jit, M; Edgeworth, J; Kibbler, C; Barnes, R; Soni, N; Rowan, K

2013-02-01

There is increasing evidence that invasive fungal disease (IFD) is more likely to occur in non-neutropenic patients in critical care units. A number of randomised controlled trials (RCTs) have evaluated antifungal prophylaxis in non-neutropenic, critically ill patients, demonstrating a reduction in the risk of proven IFD and suggesting a reduction in mortality. It is necessary to establish a method to identify and target antifungal prophylaxis at those patients at highest risk of IFD, who stand to benefit most from any antifungal prophylaxis strategy. To develop and validate risk models to identify non-neutropenic, critically ill adult patients at high risk of invasive Candida infection, who would benefit from antifungal prophylaxis, and to assess the cost-effectiveness of targeting antifungal prophylaxis to high-risk patients based on these models. Systematic review, prospective data collection, statistical modelling, economic decision modelling and value of information analysis. Ninety-six UK adult general critical care units. Consecutive admissions to participating critical care units. None. Invasive fungal disease, defined as a blood culture or sample from a normally sterile site showing yeast/mould cells in a microbiological or histopathological report. For statistical and economic modelling, the primary outcome was invasive Candida infection, defined as IFD-positive for Candida species. Systematic review: Thirteen articles exploring risk factors, risk models or clinical decision rules for IFD in critically ill adult patients were identified. Risk factors reported to be significantly associated with IFD were included in the final data set for the prospective data collection. Data were collected on 60,778 admissions between July 2009 and March 2011. Overall, 383 patients (0.6%) were admitted with or developed IFD. The majority of IFD patients (94%) were positive for Candida species. The most common site of infection was blood (55%). The incidence of IFD identified in unit was 4.7 cases per 1000 admissions, and for unit-acquired IFD was 3.2 cases per 1000 admissions. Statistical modelling: Risk models were developed at admission to the critical care unit, 24 hours and the end of calendar day 3. The risk model at admission had fair discrimination (c-index 0.705). Discrimination improved at 24 hours (c-index 0.823) and this was maintained at the end of calendar day 3 (c-index 0.835). There was a drop in model performance in the validation sample. Economic decision model: Irrespective of risk threshold, incremental quality-adjusted life-years of prophylaxis strategies compared with current practice were positive but small compared with the incremental costs. Incremental net benefits of each prophylaxis strategy compared with current practice were all negative. Cost-effectiveness acceptability curves showed that current practice was the strategy most likely to be cost-effective. Across all parameters in the decision model, results indicated that the value of further research for the whole population of interest might be high relative to the research costs. The results of the Fungal Infection Risk Evaluation (FIRE) Study, derived from a highly representative sample of adult general critical care units across the UK, indicated a low incidence of IFD among non-neutropenic, critically ill adult patients. IFD was associated with substantially higher mortality, more intensive organ support and longer length of stay. Risk modelling produced simple risk models that provided acceptable discrimination for identifying patients at 'high risk' of invasive Candida infection. Results of the economic model suggested that the current most cost-effective treatment strategy for prophylactic use of systemic antifungal agents among non-neutropenic, critically ill adult patients admitted to NHS adult general critical care units is a strategy of no risk assessment and no antifungal prophylaxis. Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.

Activity of a Long-Acting Echinocandin (CD101) and Seven Comparator Antifungal Agents Tested against a Global Collection of Contemporary Invasive Fungal Isolates in the SENTRY 2014 Antifungal Surveillance Program.

PubMed

Pfaller, Michael A; Messer, Shawn A; Rhomberg, Paul R; Castanheira, Mariana

2017-03-01

The activity of CD101 and comparator antifungal agents against 606 invasive fungal isolates collected worldwide during 2014 was evaluated using the Clinical and Laboratory Standards Institute (CLSI) method. All Candida albicans ( n = 251), Candida tropicalis ( n = 51), Candida krusei ( n = 16), and Candida dubliniensis ( n = 11) isolates were inhibited by ≤0.12 μg/ml of CD101 and were susceptible or showed wild-type susceptibility to the other echinocandins tested. Five C. glabrata isolates ( n = 100) displayed CD101 MIC values of 1 to 4 μg/ml, had elevated MICs of caspofungin (2 to >8 μg/ml), anidulafungin (2 to 4 μg/ml), and micafungin (2 to 4 μg/ml), and carried mutations on fks1 and fks2 Candida parapsilosis ( n = 92) and Candida orthopsilosis ( n = 10) displayed higher CD101 MIC values (ranges, 0.5 to 4 μg/ml and 0.12 to 2 μg/ml, respectively), and similar results were observed for the other echinocandins tested. Fluconazole resistance was noted among 11.0% of Candida glabrata isolates, 4.3% of C. parapsilosis isolates, and 2.0% of C. albicans and C. tropicalis isolates. The activity of CD101 against Aspergillus fumigatus ( n = 56) was similar to that of micafungin and 2-fold greater than that of caspofungin but less than that of anidulafungin. These isolates had wild-type susceptibility to itraconazole, voriconazole, and posaconazole. The echinocandins had limited activity against Cryptococcus neoformans ( n = 19). CD101 was as active as the other echinocandins against common fungal organisms recovered from patients with invasive fungal infections. The long half-life profile is very desirable for the prevention and treatment of serious fungal infections, especially in patients who can then be discharged from the hospital to complete antifungal therapy on an outpatient basis. Copyright © 2017 Pfaller et al.

[Mycoviruses and importance in mycology].

PubMed

Keçeli, Sema Aşkın

2017-10-01

Opportunistic fungal infections like invasive candidiasis and aspergillozis have high mortality rate particularly in immunosupressive patients. The rate of therapy success with antifungal agents is usually low. Although immunotherapy methods have been developed to increase the host response against antifungals, there has been a need for new antifungal therapeutic agents in the treatment of invasive aspergillozis and other opportunistic fungal infections. Mycoviruses are the viruses that specifically infect fungi. The use of mycoviruses in the treatment of invasive fungal infections has not been suggested yet. However, as mentioned in this review, the researches about the use of mycoviruses as a therapeutic agent have been still carried on. Mycoviruses have no infectivity as free particules. Many of them have RNA genome. They are classified as: Fungi containing "double stranded (ds) RNA, ds DNA or single stranded RNA". Although most of them are found in plant pathogenic fungi, they are also found in human pathogenic fungi. In most of the mycoviruses identified up to now, dsRNA genome are present. Mycoviruses that can be pathogenic for human and carrying dsRNA genome have been classified as Partitiviridae, Totiviridae, Chrysoviridae, Reoviridae and Hypoviridae. A part of mycoviruses may not cause any sign of infection in fungal host. The other part of mycoviruses causes hypovirulence or lethal effect. When hypovirulence occured in fungi, the observed effects are the decrease in pigmentation, mycelium formation, asexual sporulation, growing rate and the loss of fertility. The transfer of mycovirus to fungi may occur by intracellular or extracellular way. The transfer of genetic content to fungi occurs in two way: transformation and transfection. In both ways, there is a need for a spheroblast that has no cell wall. There are various scenarios about mycoviruses for the their use in the treatment. In the first scenario, the transfer of selective mycovirus is ensured by extracellular way, and then the binding of mycovirus to target fungus by genetic modifications is aimed. The second scenario is about the use of mycovirus as a vector for genetic transformation. In fact, this method is applied by using toxins in fungal diseases of plants. In addition, the production of lethal antibodies or peptides derived from antibodies obtained from toxin-coding cytoplasmic dsRNA mycovirus toxins may be a new therapeutic approach. It has been claimed that these derivatives may be used as parentheral therapeutic agents against human pathogenic fungi including Candida albicans. In this review article, the importance of mycoviruses in mycology has been discussed.

Complex interactions among host pines and fungi vectored by an invasive bark beetle

Treesearch

Min Lu; Michael J. Wingfield; Nancy E. Gillette; Sylvia R. Mori; Jian-Hua Sun

2010-01-01

Recent studies have investigated the relationships between pairs or groups of exotic species to illustrate invasive mechanisms, but most have focused on interactions at a single trophic level.Here, we conducted pathogenicity tests, analyses of host volatiles and fungal growth tests to elucidate an intricate network of interactions between the host...

Antifungal Wound Penetration of Amphotericin and Voriconazole in Combat-related Injuries: Case Report

DTIC Science & Technology

2015-04-15

trauma can have long and challenging recoveries , which may be complicated by infection. Invasive fungal infections are a rare but serious complication...and massive blood transfu- sion [6]. Inoculation of soil-dwelling molds into wounds is proposed to occur at the time of injury, with subsequent growth...microbiological assays in austere field hos- pitals, histopathological confirmation, and positive fungal culture. Thus, the median time from infection

Monitoring of clinical strains and environmental fungal aerocontamination to prevent invasive aspergillosis infections in hospital during large deconstruction work: a protocol study

PubMed Central

Loeffert, Sophie Tiphaine; Melloul, Elise; Dananché, Cédric; Hénaff, Laetitia; Bénet, Thomas; Cassier, Pierre; Dupont, Damien; Guillot, Jacques; Botterel, Françoise; Wallon, Martine; Gustin, Marie-Paule; Vanhems, Philippe

2017-01-01

Introduction Monitoring fungal aerocontamination is an essential measure to prevent severe invasive aspergillosis (IA) infections in hospitals. One central block among 32 blocks of Edouard Herriot Hospital (EHH) was entirely demolished in 2015, while care activities continued in surrounding blocks. The main objective was to undertake broad environmental monitoring and clinical surveillance of IA cases to document fungal dispersion during major deconstruction work and to assess clinical risk. Methods and analysis A daily environmental survey of fungal loads was conducted in eight wards located near the demolition site. Air was collected inside and outside selected wards by agar impact samplers. Daily spore concentrations were monitored continuously by volumetric samplers at a flow rate of 10 L.min-1. Daily temperature, wind direction and speed as well as relative humidity were recorded by the French meteorological station Meteociel. Aspergillus fumigatus strains stored will be genotyped by multiple-locus, variable-number, tandem-repeat analysis. Antifungal susceptibility will be assessed by E-test strips on Roswell Park Memorial Institute medium supplemented with agar. Ascertaining the adequacy of current environmental monitoring techniques in hospital is of growing importance, considering the rising impact of fungal infections and of curative antifungal costs. The present study could improve the daily management of IA risk during major deconstruction work and generate new data to ameliorate and redefine current guidelines. Ethics and dissemination This study was approved by the clinical research and ethics committees of EHH. PMID:29175886

Invasive fungal rhinosinusitis in adult patients: Our experience in diagnosis and management.

PubMed

Pagella, Fabio; De Bernardi, Francesca; Dalla Gasperina, Daniela; Pusateri, Alessandro; Matti, Elina; Avato, Irene; Cavanna, Caterina; Zappasodi, Patrizia; Bignami, Maurizio; Bernardini, Elena; Grossi, Paolo Antonio; Castelnuovo, Paolo

2016-04-01

This paper describes our experience in the management of acute and chronic invasive fungal rhinosinusitis (IFRS) in adults. Medical files of all patients aged >18 years treated in our institutions for IFRS from 2002 to 2013 were retrospectively reviewed. A total of 18 cases (10 acute and 8 chronic) were recorded. In acute form, haematological malignancies represented the principal comorbidity (100%), while in chronic form this was diabetes mellitus (87.5%). All patients received systemic antifungal agents. Endoscopic sinus surgery was performed in 16/18 patients (88.9%). Among patients with an acute IFRS, 4/10 died of fungal infection (40%), on the other side 2/8 patients with chronic IFRS died of the evolution of the mycosis (25%). Acute and chronic IFRS are different entities: in acute form, prognosis is poor, so therapy should be promptly performed, although host immune status and evolution of the haematological disease are key factors for the outcome. In chronic form, a wide surgical excision of the disease is recommended in order to obtain a complete removal of fungal infection. In both forms, early clinical findings are non-specific and ambiguous, so diagnosis depends on a high index of suspicion, taking into account predisposing factors. Copyright © 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Treatment of invasive fungal infections in high-risk haematological patients: what have we learnt in the past 10 years?

PubMed

Vallejo, Carlos; Vázquez, Lourdes; Cabrera Martín, José Rafael; Carreras, Enric; García Rodríguez, Julio; Ruiz Camps, Isabel; Fortún, Jesús; Mensa, Josep; Barberán, José

2013-12-01

Invasive fungal infection (IFI) caused by filamentous fungi remains a very severe infectious complication in patients with onco-haematological diseases. Last advances in the diagnostic and therapeutic fields, today we know that their contributions are limited. Something similar can be said of clinical trials especially in relation to some changes in the characteristics of the host. The development of promising diagnostic techniques and the relative expansion in the number of antifungal agents has been associated with diversification of therapeutic strategies (prophylaxis with extended-spectrum azoles and preemptive antifungal treatment). However, the low sensitivity of AGA testing in some circumstances, and the potential delay in starting treatment due to logistic reasons, has been reflected by a greater mortality in certain type of patients and a significant increase in the days of treatment. All these circumstances has once again focus attention to the empirical approach as a central strategy in high-risk patients. The objective of this article is to review the clinical experience in the treatment of IFI in onco-haematological patients according to data published in the literature in the last decade and to present a set of recommendations.

Update on mucormycosis pathogenesis

PubMed Central

Ibrahim, Ashraf S.; Kontoyiannis, Dimitrios P.

2014-01-01

Purpose of review Mucormycosis is an increasingly common fungal infection with unacceptably high mortality. The recent sequencing genome projects of Mucorales and the development of gene manipulation have enabled significant advances in understanding the pathogenesis of mucormycosis. Therefore, we review the pathogenesis of mucormycosis and highlight potential development of novel diagnostic and therapeutic modalities against this lethal disease. Recent findings Much of the work has been focused on the role of iron uptake in the virulence of Mucorales. Additionally, host receptors and fungal ligands involved in the process of tissue invasion as well as sporangiospore size and sex loci and their contribution to virulence of Mucorales are discussed. Finally, the role of innate and adaptive immunity in protection against Mucorales and new evidence about drug-induced apoptosis in these fungi are discussed. Summary Recent discoveries introduce several potentially novel diagnostic and therapeutic modalities, which are likely to improve management and outcome for mucormycosis. Future preclinical and clinical research is warranted to develop these diagnostic and therapeutic strategies. PMID:24126718

More than a colour change: insect melanism, disease resistance and fecundity.

PubMed

Dubovskiy, I M; Whitten, M M A; Kryukov, V Y; Yaroslavtseva, O N; Grizanova, E V; Greig, C; Mukherjee, K; Vilcinskas, A; Mitkovets, P V; Glupov, V V; Butt, T M

2013-07-22

A 'dark morph' melanic strain of the greater wax moth, Galleria mellonella, was studied for its atypical, heightened resistance to infection with the entomopathogenic fungus, Beauveria bassiana. We show that these insects exhibit multiple intraspecific immunity and physiological traits that distinguish them from a non-melanic, fungus-susceptible morph. The melanic and non-melanic morphs were geographical variants that had evolved different, independent defence strategies. Melanic morphs exhibit a thickened cuticle, higher basal expression of immunity- and stress-management-related genes, higher numbers of circulating haemocytes, upregulated cuticle phenoloxidase (PO) activity concomitant with conidial invasion, and an enhanced capacity to encapsulate fungal particles. These insects prioritize specific augmentations to those frontline defences that are most likely to encounter invading pathogens or to sustain damage. Other immune responses that target late-stage infection, such as haemolymph lysozyme and PO activities, do not contribute to fungal tolerance. The net effect is increased larval survival times, retarded cuticular fungal penetration and a lower propensity to develop haemolymph infections when challenged naturally (topically) and by injection. In the absence of fungal infection, however, the heavy defence investments made by melanic insects result in a lower biomass, decreased longevity and lower fecundity in comparison with their non-melanic counterparts. Although melanism is clearly correlated with increased fungal resistance, the costly mechanisms enabling this protective trait constitute more than just a colour change.

Comparative Analysis of Amphotericin B Lipid Complex and Liposomal Amphotericin B Kinetics of Lung Accumulation and Fungal Clearance in a Murine Model of Acute Invasive Pulmonary Aspergillosis▿

PubMed Central

Lewis, Russell E.; Liao, Guangling; Hou, Jinggou; Chamilos, Georgios; Prince, Randall A.; Kontoyiannis, Dimitrios P.

2007-01-01

The reformulation of amphotericin B (AMB) into a lipid complex (AMB lipid complex [ABLC]) or liposomal carrier (liposomal AMB [L-AMB]) changes the rate and extent of drug distribution to the lung. The importance of pharmacokinetic differences among the various lipid AMB formulations in the treatment of invasive pulmonary aspergillosis (IPA) remains unknown. We compared the kinetics of AMB lung accumulation and fungal clearance of ABLC- and L-AMB-treated mice with acute IPA. BALB/c mice were immunosuppressed with cyclophosphamide and cortisone before intranasal inoculation with 1.5 × 106 Aspergillus fumigatus 293 conidia. ABLC or L-AMB was administered in daily intravenous doses (1, 5, or 10 mg/kg of body weight), starting 12 h after infection and continuing until day 5. At predetermined times (0, 24, 72, and 120 h), mice were euthanized, and lungs were harvested for determinations of lung fungal burdens (quantitative PCR) and total AMB lung tissue concentrations. Both ABLC and L-AMB were effective at reducing lung fungal burdens at doses of ≥5 mg/kg/day. Clearance of A. fumigatus during the first 24 h was associated with AMB tissue concentrations of >4 μg/g. At 5 mg/kg/day, ABLC produced a more rapid fungal clearance than did L-AMB, but at the end of therapy, fungal burden reductions were similar for both formulations and were not improved with higher dosages. These data suggest that ABLC delivers active AMB to the lung more rapidly than does L-AMB, resulting in faster Aspergillus clearance in an experimental model of IPA. However, pharmacodynamic differences between the two formulations were less apparent when mice were dosed at 10 mg/kg/day. PMID:17261624

Fungal Mimicry of a Mammalian Aminopeptidase Disables Innate Immunity and Promotes Pathogenicity.

PubMed

Sterkel, Alana K; Lorenzini, Jenna L; Fites, J Scott; Subramanian Vignesh, Kavitha; Sullivan, Thomas D; Wuthrich, Marcel; Brandhorst, Tristan; Hernandez-Santos, Nydiaris; Deepe, George S; Klein, Bruce S

2016-03-09

Systemic fungal infections trigger marked immune-regulatory disturbances, but the mechanisms are poorly understood. We report that the pathogenic yeast of Blastomyces dermatitidis elaborates dipeptidyl-peptidase IVA (DppIVA), a close mimic of the mammalian ectopeptidase CD26, which modulates critical aspects of hematopoiesis. We show that, like the mammalian enzyme, fungal DppIVA cleaved C-C chemokines and GM-CSF. Yeast producing DppIVA crippled the recruitment and differentiation of monocytes and prevented phagocyte activation and ROS production. Silencing fungal DppIVA gene expression curtailed virulence and restored recruitment of CCR2(+) monocytes, generation of TipDC, and phagocyte killing of yeast. Pharmacological blockade of DppIVA restored leukocyte effector functions and stemmed infection, while addition of recombinant DppIVA to gene-silenced yeast enabled them to evade leukocyte defense. Thus, fungal DppIVA mediates immune-regulatory disturbances that underlie invasive fungal disease. These findings reveal a form of molecular piracy by a broadly conserved aminopeptidase during disease pathogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

INVASIVE FUNGAL INFECTION AMONG FEBRILE PATIENTS WITH CHEMOTHERAPY-INDUCED NEUTROPENIA IN THAILAND.

PubMed

Phikulsod, Ployploen; Suwannawiboon, Bundarika; Chayakulkeeree, Methee

2017-01-01

Invasive fungal infections (IFI) can cause serious morbidity and mortality among febrile patients with chemotherapy-induced neutropenia (CIN). In order to evaluate the incidence, treatment outcome and factors associated with IFI in this patient population in Thailand, we retrospectively reviewed the medical record of patients admitted to Siriraj Hospital from January 2008 to June 2010. Criteria used to diagnosed IFI were those of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases/Mycoses Study Group (EORTC/MSG) consensus 2008 criteria. Three hundred ten episodes of chemotherapy-induced neutropenia occurred in 233 patients. IFI were found in 37 episodes (12%) and occurred only in patients who received chemotherapy for hematological malignancies. The incidence of IFI among patients with hematologic malignancies was 14%. Most commonly occurred in AML patients (17%). Patients who received aggressive induction chemotherapy regimens for AML had the highest incidence of IFI (20.5%). Of the 37 episodes, 12 were candidiasis, 5 were aspergillosis, 1 was zygomycosis, 1 was fusariosis, 10 were probable and 9 were possible IFI. The IFI-related mortality was 35%. The clinical factor associated with IFI was a temperature > 39 °C during febrile neutropenia. A higher mortality rate was seen in patients aged > 40 years and those with a serum albumin level < 3 g/dl.

Role of pathogen-associated molecular patterns (PAMPS) in immune responses to fungal infections.

PubMed

Taghavi, Mehdi; Khosravi, Alireza; Mortaz, Esmaeil; Nikaein, Donya; Athari, Seyyed Shamsadin

2017-08-05

Recent years have seen the rise of invasive fungal infections, which are mostly due to the increase in patients. Three major opportunistic fungal species in human are Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans that pose the biggest concern for these immunocompromised patients' mortality. The growing occurrence of opportunistic fungal infections has sparked the interest to understand defense mechanisms against pathogenic fungi. Toll-like receptors (TLRs), as a part of innate immune system, play an important role for recognizing the invading microorganisms and initiating sufficient immune responses. Recent studies have revealed an integrated role for TLR, signaling inactivating immune defense mechanisms against exact fungi. Among TLRs, TLR2 and TLR4 are the major participants in fungi recognition. The present paper highlights the role of TLR participants in fungal recognition as well as their mechanisms. Copyright © 2016 Elsevier B.V. All rights reserved.

Tissue-Resident Macrophages in Fungal Infections.

PubMed

Xu, Shengjie; Shinohara, Mari L

2017-01-01

Invasive fungal infections result in high morbidity and mortality. Host organs targeted by fungal pathogens vary depending on the route of infection and fungal species encountered. Cryptococcus neoformans infects the respiratory tract and disseminates throughout the central nervous system. Candida albicans infects mucosal tissues and the skin, and systemic Candida infection in rodents has a tropism to the kidney. Aspergillus fumigatus reaches distal areas of the lung once inhaled by the host. Across different tissues in naïve hosts, tissue-resident macrophages (TRMs) are one of the most populous cells of the innate immune system. Although they function to maintain homeostasis in a tissue-specific manner during steady state, TRMs may function as the first line of defense against invading pathogens and may regulate host immune responses. Thus, in any organs, TRMs are uniquely positioned and specifically programmed to function. This article reviews the current understanding of the roles of TRMs during major fungal infections.

Automated in vivo identification of fungal infection on human scalp using optical coherence tomography and machine learning

NASA Astrophysics Data System (ADS)

Dubey, Kavita; Srivastava, Vishal; Singh Mehta, Dalip

2018-04-01

Early identification of fungal infection on the human scalp is crucial for avoiding hair loss. The diagnosis of fungal infection on the human scalp is based on a visual assessment by trained experts or doctors. Optical coherence tomography (OCT) has the ability to capture fungal infection information from the human scalp with a high resolution. In this study, we present a fully automated, non-contact, non-invasive optical method for rapid detection of fungal infections based on the extracted features from A-line and B-scan images of OCT. A multilevel ensemble machine model is designed to perform automated classification, which shows the superiority of our classifier to the best classifier based on the features extracted from OCT images. In this study, 60 samples (30 fungal, 30 normal) were imaged by OCT and eight features were extracted. The classification algorithm had an average sensitivity, specificity and accuracy of 92.30, 90.90 and 91.66%, respectively, for identifying fungal and normal human scalps. This remarkable classifying ability makes the proposed model readily applicable to classifying the human scalp.

Invasive pulmonary aspergillosis: current diagnostic methodologies and a new molecular approach.

PubMed

Moura, S; Cerqueira, L; Almeida, A

2018-05-13

The fungus Aspergillus fumigatus is the main pathogenic agent responsible for invasive pulmonary aspergillosis. Immunocompromised patients are more likely to develop this pathology due to a decrease in the immune system's defense capacity. Despite of the low occurrence of invasive pulmonary aspergillosis, this pathology presents high rates of mortality, mostly due to late and unspecific diagnosis. Currently, the diagnostic methods used to detect this fungal infection are conventional mycological examination (direct microscopic examination, histological examination, and culture), imaging, non-culture-based tests for the detection of galactomannan, β(1,3)-glucan and an extracellular glycoprotein, and molecular tests based on PCR. However, most of these methods do not detect the species A. fumigatus; they only allow the identification of genus Aspergillus. The development of more specific detection methods is of extreme importance. Fluorescent in situ hybridization-based molecular methods can be a good alternative to achieve this purpose. In this review, it is intended to point out that most of the methods used for the diagnosis of invasive pulmonary aspergillosis do not allow to detect the fungus at the species level and that fluorescence in situ hybridization-based molecular method will be a promising approach in the A. fumigatus detection.

Contrasting introduction scenarios among continents in the worldwide invasion of the banana fungal pathogen Mycosphaerella fijiensis.

PubMed

Robert, S; Ravigne, V; Zapater, M-F; Abadie, C; Carlier, J

2012-03-01

Reconstructing and characterizing introduction routes is a key step towards understanding the ecological and evolutionary factors underlying successful invasions and disease emergence. Here, we aimed to decipher scenarios of introduction and stochastic demographic events associated with the global spread of an emerging disease of bananas caused by the destructive fungal pathogen Mycosphaerella fijiensis. We analysed the worldwide population structure of this fungus using 21 microsatellites and 8 sequence-based markers on 735 individuals from 37 countries. Our analyses designated South-East Asia as the source of the global invasion and supported the location of the centre of origin of M. fijiensis within this area. We confirmed the occurrence of bottlenecks upon introduction into other continents followed by widespread founder events within continents. Furthermore, this study suggested contrasting introduction scenarios of the pathogen between the African and American continents. While potential signatures of admixture resulting from multiple introductions were detected in America, all the African samples examined seem to descend from a single successful founder event. In combination with historical information, our study reveals an original and unprecedented global scenario of invasion for this recently emerging disease caused by a wind-dispersed pathogen. © 2012 Blackwell Publishing Ltd.

A multimodal imaging approach enables in vivo assessment of antifungal treatment in a mouse model of invasive pulmonary aspergillosis.

PubMed

Poelmans, Jennifer; Himmelreich, Uwe; Vanherp, Liesbeth; Zhai, Luca; Hillen, Amy; Holvoet, Bryan; Belderbos, Sarah; Brock, Matthias; Maertens, Johan; Velde, Greetje Vande; Lagrou, Katrien

2018-05-14

Aspergillus fumigatus causes life-threatening lung infections in immunocompromised patients. Mouse models are extensively used in research to assess the in vivo efficacy of antifungals. In recent years, there has been an increasing interest in the use of non-invasive imaging techniques to evaluate experimental infections. However, single imaging modalities have limitations concerning the type of information they can provide. In this study, magnetic resonance imaging and bioluminescence imaging were combined to obtain longitudinal information on the extent of developing lesions and fungal load in a leucopenic mouse model of IPA. This multimodal imaging approach was used to assess changes occurring within lungs of infected mice receiving voriconazole treatment starting at different time points after infection. Results showed that IPA development depends on the inoculum size used to infect animals and that disease can be successfully prevented or treated by initiating intervention during early stages of infection. Furthermore, we demonstrated that reduction of the fungal load is not necessarily associated with the disappearance of lesions on anatomical lung images, especially when antifungal treatment coincides with immune recovery. In conclusion, multimodal imaging allows to investigate different aspects of disease progression or recovery by providing complementary information on dynamic processes, which are highly useful for assessing the efficacy of (novel) therapeutic compounds in a time- and labor-efficient manner. Copyright © 2018 American Society for Microbiology.

Active invasion of bacteria into living fungal cells

PubMed Central

Moebius, Nadine; Üzüm, Zerrin; Dijksterhuis, Jan; Lackner, Gerald; Hertweck, Christian

2014-01-01

The rice seedling blight fungus Rhizopus microsporus and its endosymbiont Burkholderia rhizoxinica form an unusual, highly specific alliance to produce the highly potent antimitotic phytotoxin rhizoxin. Yet, it has remained a riddle how bacteria invade the fungal cells. Genome mining for potential symbiosis factors and functional analyses revealed that a type 2 secretion system (T2SS) of the bacterial endosymbiont is required for the formation of the endosymbiosis. Comparative proteome analyses show that the T2SS releases chitinolytic enzymes (chitinase, chitosanase) and chitin-binding proteins. The genes responsible for chitinolytic proteins and T2SS components are highly expressed during infection. Through targeted gene knock-outs, sporulation assays and microscopic investigations we found that chitinase is essential for bacteria to enter hyphae. Unprecedented snapshots of the traceless bacterial intrusion were obtained using cryo-electron microscopy. Beyond unveiling the pivotal role of chitinolytic enzymes in the active invasion of a fungus by bacteria, these findings grant unprecedented insight into the fungal cell wall penetration and symbiosis formation. DOI: http://dx.doi.org/10.7554/eLife.03007.001 PMID:25182414

The Effect of the Acetone Extract of Arctotis arctotoides (Asteraceae) on the Growth and Ultrastructure of Some Opportunistic Fungi Associated with HIV/AIDS

PubMed Central

Otang, Wilfred M.; Grierson, Donald S.; Ndip, Roland N.

2011-01-01

In this study, the effect of the acetone extract of Arctotis arctotoides (L.f.) O. Hoffm. (Asteraceae) on the growth and ultrastructure of some opportunistic fungi associated with HIV/AIDS was analyzed by means of scanning electron microscope (SEM). Remarkable morphological alterations in the fungal mycelia which were attributed to the loss of cell wall strength ranged from loss of turgidity and uniformity, collapse of entire hyphae to evident destruction of the hyphae. The elements responsible for giving the fungi their characteristic virulence were detected and quantified by energy dispersive X-ray microanalysis techniques. X-ray microanalysis showed the specific spectra of sodium, potassium and sulfur as the principal intersection of the four pathogenic fungi studied. Since these ions have the potential of fostering fungal invasion by altering the permeability of hosts’ membranes, their presence was considered inherent to the pathogenicity of the opportunistic fungi. Hence, these findings indicate the potential of the crude extract of A. arctotoides in preventing fungal invasion and subsequent infection of host’s membranes. PMID:22272130

Epidemiology of invasive fungal infections in patients with acquired immunodeficiency syndrome at a reference hospital for infectious diseases in Brazil.

PubMed

de Oliveira, Renata Buccheri; Atobe, Jane Harumi; Souza, Simone Aparecida; de Castro Lima Santos, Daniel Wagner

2014-08-01

Invasive fungal infections (IFIs) represent one of the main causes of morbimortality in immunocompromised patients. Pneumocystosis, cryptococcosis and histoplasmosis are the most frequently occurring IFIs in patients with acquired immunodeficiency syndrome (AIDS). Fungi, such as Candida spp. and Aspergillus spp., may cause severe diseases during the course of an HIV infection. Following the introduction of highly active anti-retroviral therapy, there has been a marked reduction of opportunistic fungal infections, which today is 20-25 % of the number of infections observed in the mid-1990s. This study is an observational and retrospective study aimed at the characterising IFI incidence and describing the epidemiology, clinical diagnostic and therapeutic features and denouement in HIV/AIDS patients. In HIV/AIDS patients, the IFI incidence is 54.3/1,000 hospitalisation/year, with a lethality of 37.7 %. Cryptococcosis represents the main opportunistic IFI in the population, followed by histoplasmosis. Nosocomial pathogenic yeast infections are caused principally by Candida spp., with a higher candidemia incidence at our institution compared to other Brazilian centres.

Mixed Fungal Lung Infection with Aspergillus Fumigatus and Candida Albicans in a Immunocomprimised Patient: Case Report

PubMed Central

Vipparti, Haritha

2014-01-01

The frequency of invasive, opportunistic mycoses has increased significantly over the past 2 decades. In the immune-compromised host, many fungi, including species of fungi typically considered non-pathogenic, have the potential to cause serious morbidity and mortality. Here we report a rare case of mixed fungal infection of the lung with Candida albicans and Aspergillus fumigatus in a patient on prolonged steroid therapy. PMID:24959447

Recognition and Clinical Presentation of Invasive Fungal Disease in Neonates and Children.

PubMed

King, Jill; Pana, Zoi-Dorothea; Lehrnbecher, Thomas; Steinbach, William J; Warris, Adilia

2017-09-01

Invasive fungal diseases (IFDs) are devastating opportunistic infections that result in significant morbidity and death in a broad range of pediatric patients, particularly those with a compromised immune system. Recognizing them can be difficult, because nonspecific clinical signs and symptoms or isolated fever are frequently the only presenting features. Therefore, a high index of clinical suspicion is necessary in patients at increased risk of IFD, which requires knowledge of the pediatric patient population at risk, additional predisposing factors within this population, and the clinical signs and symptoms of IFD. With this review, we aim to summarize current knowledge regarding the recognition and clinical presentation of IFD in neonates and children. © The Author 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.

[Allergic fungal rhinosinusitis caused by Curvularia sp.].

PubMed

Alvarez, Verónica C; Guelfand, Liliana; Pidone, Juan Carlos; Soloaga, Rolando; Ontivero, Paula; Margari, Alejandra; López Daneri, Gabriela

2011-01-01

Allergic fungal rhinosinusitis is a benign and non-invasive sinusal disease related to a hypersensitivity reaction to fungal antigens. This process can cause tissue edema with chronic inflammatory disturbances of the respiratory mucosa. We present the case of a 17 year-old immunocompetent male, with history of seasonal allergic rhinosinusitis, nasal polyps and previous surgery for mucocele of the frontal sinus. Sticky material was removed in the last surgery that revealed pigmented and septed filaments on direct examination, and yielded Curvularia on Sabouraud dextrose agar. After a course of amphotericin B, treatment was switched to itraconazole, with good tolerance and favorable clinical outcome. Copyright © 2011. Published by Elsevier Espana.

Current Perspectives on Ophthalmic Mycoses

PubMed Central

Thomas, Philip A.

2003-01-01

Fungi may infect the cornea, orbit and other ocular structures. Species of Fusarium, Aspergillus, Candida, dematiaceous fungi, and Scedosporium predominate. Diagnosis is aided by recognition of typical clinical features and by direct microscopic detection of fungi in scrapes, biopsy specimens, and other samples. Culture confirms the diagnosis. Histopathological, immunohistochemical, or DNA-based tests may also be needed. Pathogenesis involves agent (invasiveness, toxigenicity) and host factors. Specific antifungal therapy is instituted as soon as the diagnosis is made. Amphotericin B by various routes is the mainstay of treatment for life-threatening and severe ophthalmic mycoses. Topical natamycin is usually the first choice for filamentous fungal keratitis, and topical amphotericin B is the first choice for yeast keratitis. Increasingly, the triazoles itraconazole and fluconazole are being evaluated as therapeutic options in ophthalmic mycoses. Medical therapy alone does not usually suffice for invasive fungal orbital infections, scleritis, and keratitis due to Fusarium spp., Lasiodiplodia theobromae, and Pythium insidiosum. Surgical debridement is essential in orbital infections, while various surgical procedures may be required for other infections not responding to medical therapy. Corticosteroids are contraindicated in most ophthalmic mycoses; therefore, other methods are being sought to control inflammatory tissue damage. Fungal infections following ophthalmic surgical procedures, in patients with AIDS, and due to use of various ocular biomaterials are unique subsets of ophthalmic mycoses. Future research needs to focus on the development of rapid, species-specific diagnostic aids, broad-spectrum fungicidal compounds that are active by various routes, and therapeutic modalities which curtail the harmful effects of fungus- and host tissue-derived factors. PMID:14557297

Estimated burden of fungal infections in Kenya.

PubMed

Guto, John Abuga; Bii, Christine C; Denning, David W

2016-08-31

Kenya is a developing country with a high rate of tuberculosis (TB) and a moderate HIV infection burden. No estimate of the burden of fungal diseases in Kenya is published. We used specific populations at risk and fungal infection frequencies from the literature to estimate national incidence or prevalence of serious fungal infections. Used sources were: 2010 WHO TB statistics, Kenya Acquired Immunodeficiency Syndrome (AIDS) Epidemic Update 2012, Kenya Facts and figures 2012, Kenya Demographic and Health Survey 2008-2009. Of Kenya's population of ~40 million, 43% are under 15 years old and approximately 594,660 Kenyan women get >4 episodes Candida vulvovaginitis annually (2,988/100,000). The HIV/AIDS population at risk of opportunistic infections (OI) is 480,000 and the OI estimates include 306,000 patients with oral thrush (768/100,000), 114,000 with oesophageal candidiasis (286/100,000), 11,900 with cryptococcal meningitis (29/100,000) and 17,000 patients with Pneumocystis pneumonia (42/100,000). Chronic pulmonary aspergillosis following TB has a prevalence of 10,848 cases (32/100,000). The adult asthma prevalence is 3.1% and assuming 2.5% have allergic bronchopulmonary aspergillosis then 17,696 (44/100,000) are affected.  Invasive aspergillosis, candidaemia and Candida peritonitis are probably uncommon. Tinea capitis infects 9.6% of children in Kenya, while fungal keratitis and otomycoses are difficult to estimate. At any one time, about 7% of the Kenyan population suffers from a significant fungal infection, with recurrent vaginitis and tinea capitis accounting for 82% of the infections. These estimates require further epidemiological studies for validation.

Early diagnosis of candidemia in intensive care unit patients with sepsis: a prospective comparison of (1→3)-β-D-glucan assay, Candida score, and colonization index

PubMed Central

2011-01-01

Introduction The culture-independent serum (1→3)-β-D-glucan (BG) detection test may allow early diagnosis of invasive fungal disease, but its clinical usefulness needs to be firmly established. A prospective single-center observational study was conducted to compare the diagnostic value of BG assay, Candida score (CS), and colonization index in intensive care unit (ICU) patients at risk for Candida sepsis. Methods Of 377 patients, consecutively admitted to ICU for sepsis, 95 patients having an ICU stay of more than five days were studied. Blood specimens for fungal culture and BG measurement were obtained at the onset of clinical sepsis. For CS and colonization index calculations, surveillance cultures for Candida growth, and/or clinical data were recorded. Results Sixteen (16.8%) patients were diagnosed with proven invasive fungal infection, 14 with candidiasis (13 candidemia and 1 mediastinitis) and 2 with pulmonary aspergillosis or fusariosis. Of 14 invasive Candida-infection patients, 13 had a serum sample positive for BG, 10 had a CS value ≥3, and 7 a colonization index ≥0.5. In the 12 candidemic patients, a positive BG result was obtained 24 to 72 hrs before a culture-documented diagnosis of invasive candidiasis. The positive and negative predictive values for the BG assay were higher than those of CS and colonization index (72.2% versus 57.1% and 27.3%; and 98.7% versus 97.2% and 91.7%, respectively). Conclusions A single-point BG assay based on a blood sample drawn at the sepsis onset, alone or in combination withCS, may guide the decision to start antifungal therapy early in patients at risk for Candida infection. PMID:22018278

Aspergillus fumigatus Invasion Increases with Progressive Airway Ischemia

PubMed Central

Hsu, Joe L.; Khan, Mohammad A.; Sobel, Raymond A.; Jiang, Xinguo; Clemons, Karl V.; Nguyen, Tom T.; Stevens, David A.; Martinez, Marife; Nicolls, Mark R.

2013-01-01

Despite the prevalence of Aspergillus-related disease in immune suppressed lung transplant patients, little is known of the host-pathogen interaction. Because of the mould’s angiotropic nature and because of its capacity to thrive in hypoxic conditions, we hypothesized that the degree of Aspergillus invasion would increase with progressive rejection-mediated ischemia of the allograft. To study this relationship, we utilized a novel orthotopic tracheal transplant model of Aspergillus infection, in which it was possible to assess the effects of tissue hypoxia and ischemia on airway infectivity. Laser Doppler flowmetry and FITC-lectin were used to determine blood perfusion, and a fiber optic microsensor was used to measure airway tissue oxygen tension. Fungal burden and depth of invasion were graded using histopathology. We demonstrated a high efficacy (80%) for producing a localized fungal tracheal infection with the majority of infection occurring at the donor-recipient anastomosis; Aspergillus was more invasive in allogeneic compared to syngeneic groups. During the study period, the overall kinetics of both non-infected and infected allografts was similar, demonstrating a progressive loss of perfusion and oxygenation, which reached a nadir by days 10-12 post-transplantation. The extent of Aspergillus invasion directly correlated with the degree of graft hypoxia and ischemia. Compared to the midtrachea, the donor-recipient anastomotic site exhibited lower perfusion and more invasive disease; a finding consistent with clinical experience. For the first time, we identify ischemia as a putative risk factor for Aspergillus invasion. Therapeutic approaches focused on preserving vascular health may play an important role in limiting Aspergillus infections. PMID:24155924

Methods of Controlling Invasive Fungal Infections Using CD8+ T Cells.

PubMed

Kumaresan, Pappanaicken R; da Silva, Thiago Aparecido; Kontoyiannis, Dimitrios P

2017-01-01

Invasive fungal infections (IFIs) cause high rates of morbidity and mortality in immunocompromised patients. Pattern-recognition receptors present on the surfaces of innate immune cells recognize fungal pathogens and activate the first line of defense against fungal infection. The second line of defense is the adaptive immune system which involves mainly CD4 + T cells, while CD8 + T cells also play a role. CD8 + T cell-based vaccines designed to prevent IFIs are currently being investigated in clinical trials, their use could play an especially important role in acquired immune deficiency syndrome patients. So far, none of the vaccines used to treat IFI have been approved by the FDA. Here, we review current and future antifungal immunotherapy strategies involving CD8 + T cells. We highlight recent advances in the use of T cells engineered using a Sleeping Beauty vector to treat IFIs. Recent clinical trials using chimeric antigen receptor (CAR) T-cell therapy to treat patients with leukemia have shown very promising results. We hypothesized that CAR T cells could also be used to control IFI. Therefore, we designed a CAR that targets β-glucan, a sugar molecule found in most of the fungal cell walls, using the extracellular domain of Dectin-1, which binds to β-glucan. Mice treated with D-CAR + T cells displayed reductions in hyphal growth of Aspergillus compared to the untreated group. Patients suffering from IFIs due to primary immunodeficiency, secondary immunodeficiency (e.g., HIV), or hematopoietic transplant patients may benefit from bioengineered CAR T cell therapy.

Methods of Controlling Invasive Fungal Infections Using CD8+ T Cells

PubMed Central

Kumaresan, Pappanaicken R.; da Silva, Thiago Aparecido; Kontoyiannis, Dimitrios P.

2018-01-01

Invasive fungal infections (IFIs) cause high rates of morbidity and mortality in immunocompromised patients. Pattern-recognition receptors present on the surfaces of innate immune cells recognize fungal pathogens and activate the first line of defense against fungal infection. The second line of defense is the adaptive immune system which involves mainly CD4+ T cells, while CD8+ T cells also play a role. CD8+ T cell-based vaccines designed to prevent IFIs are currently being investigated in clinical trials, their use could play an especially important role in acquired immune deficiency syndrome patients. So far, none of the vaccines used to treat IFI have been approved by the FDA. Here, we review current and future antifungal immunotherapy strategies involving CD8+ T cells. We highlight recent advances in the use of T cells engineered using a Sleeping Beauty vector to treat IFIs. Recent clinical trials using chimeric antigen receptor (CAR) T-cell therapy to treat patients with leukemia have shown very promising results. We hypothesized that CAR T cells could also be used to control IFI. Therefore, we designed a CAR that targets β-glucan, a sugar molecule found in most of the fungal cell walls, using the extracellular domain of Dectin-1, which binds to β-glucan. Mice treated with D-CAR+ T cells displayed reductions in hyphal growth of Aspergillus compared to the untreated group. Patients suffering from IFIs due to primary immunodeficiency, secondary immunodeficiency (e.g., HIV), or hematopoietic transplant patients may benefit from bioengineered CAR T cell therapy. PMID:29358941

Distinct CD4+-T-cell responses to live and heat-inactivated Aspergillus fumigatus conidia.

PubMed

Rivera, Amariliz; Van Epps, Heather L; Hohl, Tobias M; Rizzuto, Gabrielle; Pamer, Eric G

2005-11-01

Aspergillus fumigatus is an important fungal pathogen that causes invasive pulmonary disease in immunocompromised hosts. Respiratory exposure to A. fumigatus spores also causes allergic bronchopulmonary aspergillosis, a Th2 CD4+-T-cell-mediated disease that accompanies asthma. The microbial factors that influence the differentiation of A. fumigatus-specific CD4+ T lymphocytes into Th1 versus Th2 cells remain incompletely defined. We therefore examined CD4+-T-cell responses of immunologically intact mice to intratracheal challenge with live or heat-inactivated A. fumigatus spores. Live but not heat-inactivated fungal spores resulted in recruitment of gamma interferon (IFN-gamma)-producing, fungus-specific CD4+ T cells to lung airways, achieving A. fumigatus-specific frequencies exceeding 5% of total CD4+ T cells. While heat-inactivated spores did not induce detectable levels of IFN-gamma-producing, A. fumigatus-specific CD4+ T cells in the airways, they did prime CD4+ T-cell responses in draining lymph nodes that produced greater amounts of interleukin 4 (IL-4) and IL-13 than T cells responding to live conidia. While immunization with live fungal spores induced antibody responses, we found a marked decrease in isotype-switched, A. fumigatus-specific antibodies in sera of mice following immunization with heat-inactivated spores. Our studies demonstrate that robust Th1 T-cell and humoral responses are restricted to challenge with fungal spores that have the potential to germinate and cause invasive infection. How the adaptive immune system distinguishes between metabolically active and inactive fungal spores remains an important question.

Mucormycosis pulmonary abscess, containment in a patient with uncontrolled diabetes mellitus.

PubMed

Jaffer, Faraz; Beatty, Norman; Ahmad, Kareem

2017-01-18

A 56-year-old Hispanic male with solo risk factor of uncontrolled diabetes mellitus presented with recurrent haemoptysis. Initial concern was for malignancy with postobstructive pneumonia; however, invasive testing and biopsy confirmed infectious mass of fungal aetiology requiring surgical resection followed by a prolonged course of anti-fungal therapy. Discussion centred on approach to, progression of and course of action in the management of pulmonary abscess due to mucormycosis. 2017 BMJ Publishing Group Ltd.

Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation

PubMed Central

Carter, Shelly L.; Walsh, Thomas J.; Kurtzberg, Joanne; Small, Trudy N.; Baden, Lindsey R.; Gersten, Iris D.; Mendizabal, Adam M.; Leather, Helen L.; Confer, Dennis L.; Maziarz, Richard T.; Stadtmauer, Edward A.; Bolaños-Meade, Javier; Brown, Janice; DiPersio, John F.; Boeckh, Michael; Marr, Kieren A.

2010-01-01

Invasive fungal infection (IFI) is a serious threat after allogeneic hematopoietic cell transplant (HCT). This multicenter, randomized, double-blind trial compared fluconazole (N = 295) versus voriconazole (N = 305) for the prevention of IFI in the context of a structured fungal screening program. Patients undergoing myeloablative allogeneic HCT were randomized before HCT to receive study drugs for 100 days, or for 180 days in higher-risk patients. Serum galactomannan was assayed twice weekly for 60 days, then at least weekly until day 100. Positive galactomannan or suggestive signs triggered mandatory evaluation for IFI. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days. Despite trends to fewer IFIs (7.3% vs 11.2%; P = .12), Aspergillus infections (9 vs 17; P = .09), and less frequent empiric antifungal therapy (24.1% vs 30.2%, P = .11) with voriconazole, FFS rates (75% vs 78%; P = .49) at 180 days were similar with fluconazole and voriconazole, respectively. Relapse-free and overall survival and the incidence of severe adverse events were also similar. This study demonstrates that in the context of intensive monitoring and structured empiric antifungal therapy, 6-month FFS and overall survival did not differ in allogeneic HCT recipients given prophylactic fluconazole or voriconazole. This trial was registered at www.clinicaltrials.gov as NCT00075803. PMID:20826719

Molecular detection of fungal pathogens in clinical specimens by 18S rDNA high-throughput screening in comparison to ITS PCR and culture.

PubMed

Wagner, K; Springer, B; Pires, V P; Keller, P M

2018-05-03

The rising incidence of invasive fungal infections and the expanding spectrum of fungal pathogens makes early and accurate identification of the causative pathogen a daunting task. Diagnostics using molecular markers enable rapid identification of fungi, offer new insights into infectious disease dynamics, and open new possibilities for infectious disease control and prevention. We performed a retrospective study using clinical specimens (N = 233) from patients with suspected fungal infection previously subjected to culture and/or internal transcribed spacer (ITS) PCR. We used these specimens to evaluate a high-throughput screening method for fungal detection using automated DNA extraction (QIASymphony), fungal ribosomal small subunit (18S) rDNA RT-PCR and amplicon sequencing. Fungal sequences were compared with sequences from the curated, commercially available SmartGene IDNS database for pathogen identification. Concordance between 18S rDNA RT-PCR and culture results was 91%, and congruence between 18S rDNA RT-PCR and ITS PCR results was 94%. In addition, 18S rDNA RT-PCR and Sanger sequencing detected fungal pathogens in culture negative (N = 13) and ITS PCR negative specimens (N = 12) from patients with a clinically confirmed fungal infection. Our results support the use of the 18S rDNA RT-PCR diagnostic workflow for rapid and accurate identification of fungal pathogens in clinical specimens.

The use of gas-sensor arrays in the detection of bole and root decays in living trees: development of a new non-invasive method of sampling and analysis

Treesearch

Manuela Baietto; Sofia Aquaro; Dan Wilson; Letizia Pozzi; Danieli Bassi

2015-01-01

Wood rot is a serious fungal disease of trees. Wood decay fungi penetrate and gain entry into trees through pruning cuts or open wounds using extracellular digestive enzymes to attack all components of the cell wall, leading to the destruction of sapwood which compromises wood strength and stability. On living trees, it is often difficult to diagnose wood rot disease,...

Echinocandin Resistance in Candida Species: a Review of Recent Developments.

PubMed

Wiederhold, Nathan P

2016-12-01

The echinocandins are important agents for the treatment of invasive fungal infections, especially those caused by Candida species. However, as with other antimicrobial agents, microbiologic resistance to this class of antifungal agents has emerged and can result in clinical failure. Several studies have recently reported an increase in echinocandin resistance in Candida glabrata isolates at various medical centers in different geographic regions of the USA. Recent studies have also reported that many of these isolates may also be fluconazole resistant, leaving few treatment options available for clinicians to use in patients with invasive candidiasis caused by this species. Our understanding of the clinical relevance of specific point mutations within the FKS genes that cause echinocandin resistance and risk factors for the development of microbiologic resistance and clinical failure have also increased. The purpose of this review is to discuss echinocandin resistance in Candida species and recent reports that have increased our understanding of this growing clinical problem.

Efficacy, safety and feasibility of antifungal prophylaxis with posaconazole tablet in paediatric patients after haematopoietic stem cell transplantation.

PubMed

Döring, Michaela; Cabanillas Stanchi, Karin Melanie; Queudeville, Manon; Feucht, Judith; Blaeschke, Franziska; Schlegel, Patrick; Feuchtinger, Tobias; Lang, Peter; Müller, Ingo; Handgretinger, Rupert; Heinz, Werner J

2017-07-01

Paediatric recipients of haematopoietic stem cell transplantation (HSCT) have a high risk for invasive fungal infections. Posaconazole oral suspension has proven to be effective in antifungal prophylaxis in adult and paediatric patients. A new posaconazole tablet formulation with absorption independent of the gastric conditions was approved by the FDA in 2013. This is the first report on the use of posaconazole tablets in paediatric patients. This single-centre study included 63 paediatric patients with haemato-oncological malignancies who received posaconazole for antifungal prophylaxis after HSCT. They were analysed for efficacy, feasibility and the safety of posaconazole. Out of 63 patients, 31 received posaconazole oral suspension and 32 received posaconazole tablets up to 200 days after transplantation. Analyses of the posaconazole trough levels were determined. No possible, probable or proven invasive fungal infection was observed in either group. Posaconazole trough levels were significantly higher in the tablet group than in the suspension group at all analysed time points. Drug-related adverse events were similarly low in both groups. Posaconazole tablets are effective in preventing invasive fungal infections in paediatric patients. As early as day 3 after starting posaconazole tablets, over 50% of the posaconazole trough levels were >500 ng/mL, while this was observed on day 14 after start with posaconazole suspension. The administration of posaconazole tablets was safe, effective and feasible as antifungal prophylaxis in paediatric patients after HSCT.

Dermatophyte-host relationship of a murine model of experimental invasive dermatophytosis.

PubMed

Venturini, James; Alvares, Anuska Marcelino; Camargo, Marcela Rodrigues de; Marchetti, Camila Martins; Fraga-Silva, Thais Fernanda de Campos; Luchini, Ana Carolina; Arruda, Maria Sueli Parreira de

2012-11-01

Recognizing the invasive potential of the dermatophytes and understanding the mechanisms involved in this process will help with disease diagnosis and with developing an appropriate treatment plan. In this report, we present the histopathological, microbiological and immunological features of a model of invasive dermatophytosis that is induced by subcutaneous infection of Trichophyton mentagrophytes in healthy adult Swiss mice. Using this model, we observed that the fungus rapidly spreads to the popliteal lymph nodes, spleen, liver and kidneys. Similar to the human disease, the lymph nodes were the most severely affected sites. The fungal infection evoked acute inflammation followed by a granulomatous reaction in the mice, which is similar to what is observed in patients. The mice were able to mount a Th1-polarized immune response and displayed IL-10-mediated immune regulation. We believe that the model described here will provide valuable information regarding the dermatophyte-host relationship and will yield new perspective for a better understanding of the immunological and pathological aspects of invasive dermatophytosis. Copyright © 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Prediction of invasion from the early stage of an epidemic

PubMed Central

Pérez-Reche, Francisco J.; Neri, Franco M.; Taraskin, Sergei N.; Gilligan, Christopher A.

2012-01-01

Predictability of undesired events is a question of great interest in many scientific disciplines including seismology, economy and epidemiology. Here, we focus on the predictability of invasion of a broad class of epidemics caused by diseases that lead to permanent immunity of infected hosts after recovery or death. We approach the problem from the perspective of the science of complexity by proposing and testing several strategies for the estimation of important characteristics of epidemics, such as the probability of invasion. Our results suggest that parsimonious approximate methodologies may lead to the most reliable and robust predictions. The proposed methodologies are first applied to analysis of experimentally observed epidemics: invasion of the fungal plant pathogen Rhizoctonia solani in replicated host microcosms. We then consider numerical experiments of the susceptible–infected–removed model to investigate the performance of the proposed methods in further detail. The suggested framework can be used as a valuable tool for quick assessment of epidemic threat at the stage when epidemics only start developing. Moreover, our work amplifies the significance of the small-scale and finite-time microcosm realizations of epidemics revealing their predictive power. PMID:22513723

A hematology consensus agreement on antifungal strategies for neutropenic patients with hematological malignancies and stem cell transplant recipients. Gruppo Italiano Malattie Ematologiche dell'Adulto, Gruppo Italiano Trapianto di Midollo Osseo, Associazione Italiana Ematologia ed Oncologia Pediatrica, Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer and Sorveglianza Epidemiologica delle Infezioni Fungine nelle Emopatie Maligne.

PubMed

Girmenia, Corrado; Aversa, Franco; Busca, Alessandro; Candoni, Anna; Cesaro, Simone; Luppi, Mario; Pagano, Livio; Rossi, Giuseppe; Venditti, Adriano; Nosari, Anna Maria

2013-09-01

In the attempt to establish key therapy definitions and provide shared approaches to invasive fungal diseases in neutropenic patients, trials of empiric, preeemptive and targeted antifungal therapy (EAT, PAT and TAT) were reviewed, and a Consensus Development Conference Project was convened. The Expert-Panel concurred that all antifungal treatments, including EAT, should always follow an adequate diagnostic strategy and that the standard definition of PAT may be misleading: being PAT guided by the results of a diagnostic work-up, it should better be termed diagnostic-driven antifungal therapy (DDAT). The Expert-Panel agreed that radiological findings alone are insufficient for the choice of a TAT and that the identification of the etiologic pathogen is needed. The Consensus Agreement proceeded identifying which clinical and microbiological findings were sufficient to start a DDAT and which were not. Finally, an algorithm to rationalize the choice of antifungal drugs on the basis of clinical manifestations, antifungal prophylaxis, instrumental and laboratory findings was drawn up. Copyright © 2012 John Wiley & Sons, Ltd.

Human Skin Fungal Diversity

PubMed Central

Findley, Keisha; Oh, Julia; Yang, Joy; Conlan, Sean; Deming, Clayton; Meyer, Jennifer A.; Schoenfeld, Deborah; Nomicos, Effie; Park, Morgan; Kong, Heidi H.; Segre, Julia A.

2013-01-01

Traditional culture-based methods have incompletely defined the etiology of common recalcitrant human fungal skin diseases including athlete’s foot and toenail infections. Skin protects humans from invasion by pathogenic microorganisms, while providing a home for diverse commensal microbiota1. Bacterial genomic sequence data have generated novel hypotheses about species and community structures underlying human disorders2,3,4. However, microbial diversity is not limited to bacteria; microorganisms such as fungi also play major roles in microbial community stability, human health and disease5. Genomic methodologies to identify fungal species and communities have been limited compared with tools available for bacteria6. Fungal evolution can be reconstructed with phylogenetic markers, including ribosomal RNA gene regions and other highly conserved genes7. Here, we sequenced and analyzed fungal communities of 14 skin sites in 10 healthy adults. Eleven core body and arm sites were dominated by Malassezia fungi, with species-level classifications revealing greater topographical resolution between sites. By contrast, three foot sites, plantar heel, toenail, and toeweb, exhibited tremendous fungal diversity. Concurrent analysis of bacterial and fungal communities demonstrated that skin physiologic attributes and topography differentially shape these two microbial communities. These results provide a framework for future investigation of interactions between pathogenic and commensal fungal and bacterial communities in maintaining human health and contributing to disease pathogenesis. PMID:23698366

Fungal endophytes which invade insect galls: insect pathogens, benign saprophytes, or fungal inquilines?

PubMed

Wilson, Dennis

1995-08-01

Fungi are frequently found within insect galls. However, the origin of these fungi, whether they are acting as pathogens, saprophytes invading already dead galls, or fungal inquilines which invade the gall but kill the gall maker by indirect means, is rarely investigated. A pathogenic role for these fungi is usually inferred but never tested. I chose the following leaf-galling-insect/host-plant pairs (1) a cynipid which forms two-chambered galls on the veins of Oregon white oak, (2) a cynipid which forms single-chambered galls on California coast live oak, and (3) an aphid which forms galls on narrowleaf cottonwood leaves. All pairs were reported to have fungi associated with dead insects inside the gall. These fungi were cultured and identified. For the two cynipids, all fungi found inside the galls were also present in the leaves as fungal endophytes. The cottonwood leaves examined did not harbor fungal endophytes. For the cynipid on Oregon white oak, the fungal endophyte grows from the leaf into the gall and infects all gall tissue but does not directly kill the gall maker. The insect dies as a result of the gall tissue dying from fungal infection. Therefore, the fungus acts as an inquiline. Approximately 12.5% of these galls die as a result of invasion by the fungal endophyte.

[Quantitative assessment of fungal risk in the case of construction works in healthcare establishments: Proposed indicators for the determination of the impact of management precautions on the risk of fungal infection].

PubMed

Gangneux, J-P; Adjidé, C-C; Bernard, L; Botterel, F; Carel, A; Castel, O; Derouin, F; Hoarau, G; Labussière, H; Lafaurie, M; Millon, L; Pottecher, B; Thiebaut, A; Turco, M; Baron, R

2012-03-01

Construction works in healthcare establishments produce airborne fungal spores and considerably increase the risk of exposure of immunosuppressed patients. It is necessary to reinforce protective measures, or even to implement specific precautions, during this critical phase. The aim of these precautions is to protect both those areas, which are susceptible to dust, and patients at risk of a fungal infection particularly invasive aspergillosis. When construction works are planned in healthcare establishments, the first step consists in the characterisation of the environmental fungal risk and the second one in proposing risk management methods. It is then essential to establish impact indicators in order to evaluate the risk management precautions applied. The working group promoted by the French societies of medical mycology and hospital hygiene (SFMM & SF2H) details here both environmental and epidemiological impact indicators that can be used. Copyright © 2012. Published by Elsevier SAS.

Prevention and diagnosis of invasive fungal disease in high-risk patients within an integrative care pathway.

PubMed

Barnes, Rosemary A; Stocking, Kate; Bowden, Sarah; Poynton, Matthew H; White, P Lewis

2013-09-01

The aim of this study was to assess the clinical utility of enhanced diagnostics on the management of invasive fungal disease in high risk patients within an integrated care pathway and to audit compliance and efficacy of antifungal prophylaxis. A cohort of 549 high risk haematology and stem-cell transplant recipients was followed over a 5 year period. The routine standard of care involved the use of antimould prophylaxis and a neutropenic care pathway utilizing twice weekly antigen and PCR testing. Prophylaxis with itraconazole was poorly tolerated and therapeutic levels could not be maintained. Antigen testing and PCR showed good clinical utility in the management of invasive aspergilosis with high sensitivity (98%) and negative predictive value (99.6%) when both tests were used together, allowing a diagnosis IA to be excluded and obviating the need for empirical antifungal agents. When used serially, multiple positive PCR and antigen test results enabled accurate diagnosis of IA with a specificity of 95% and a positive likelihood ratio of 11. Biomarkers preceded clinical signs in 85% of proven and probable invasive disease. The combination of both tests showed optimum clinical utility for the diagnosis and management of IA in this high risk group. Copyright © 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Extrasinonasal infiltrative process associated with a sinonasal fungus ball: does it mean invasive fungal sinusitis?

PubMed Central

Kim, Yi-Kyung; Kim, Hyung-Jin; Kim, Hyo Yeol; Cha, Jihoon; Lee, Ji Young; Chung, Seung-Kyu; Dhong, Hun-Jong; Song, Mina; Kim, Sung Tae

2016-01-01

PURPOSE Invasive fungal sinusitis (IFS) has rarely been reported to develop from non-IFS. The purpose of this study was to disclose the nature of the extrasinonasal infiltrative process in the presence of a sinonasal fungus ball (FB). METHODS We retrospectively reviewed the medical records, computed tomography, magnetic resonance images of 13 patients with sinonasal FB and the extrasinonasal infiltrative process. Based on histology and clinical course, we divided the extrasinonasal infiltrative process into IFS and the nonfungal inflammatory/infectious process (NFIP). The images were analyzed with particular attention to the presence of cervicofacial tissue infarction (CFTI). RESULTS Of the 13 patients, IFS was confirmed in only one, while the remaining 12 were diagnosed to have presumed NFIP. One patient with IFS died shortly after diagnosis. In contrast, all 12 patients with presumed NFIP, except one, survived during a mean follow-up of 17 months. FB was located in the maxillary sinus (n=4), sphenoid sinus (n=8), and both sinuses (n=1). Bone defect was found in five patients, of whom four had a defect in the sphenoid sinus. Various sites were involved in the extrasinonasal infiltrative process, including the orbit (n=10), intracranial cavity (n=9), and soft tissues of the face and neck (n=7). CFTI was recognized only in one patient with IFS. CONCLUSION In most cases, the extrasinonasal infiltrative process in the presence of sinonasal FB did not seem to be caused by IFS but probably by NFIP. In our study, there were more cases of invasive changes with the sphenoid than with the maxillary FB. PMID:27283592

Extrasinonasal infiltrative process associated with a sinonasal fungus ball: does it mean invasive fungal sinusitis?

PubMed

Kim, Yi Kyung; Kim, Hyung Jin; Kim, Hyo Yeol; Cha, Jihoon; Lee, Ji Young; Chung, Seung Kyu; Dhong, Hun Jong; Song, Mina; Kim, Sung Tae

2016-01-01

Invasive fungal sinusitis (IFS) has rarely been reported to develop from non-IFS. The purpose of this study was to disclose the nature of the extrasinonasal infiltrative process in the presence of a sinonasal fungus ball (FB). We retrospectively reviewed the medical records, computed tomography, magnetic resonance images of 13 patients with sinonasal FB and the extrasinonasal infiltrative process. Based on histology and clinical course, we divided the extrasinonasal infiltrative process into IFS and the nonfungal inflammatory/infectious process (NFIP). The images were analyzed with particular attention to the presence of cervicofacial tissue infarction (CFTI). Of the 13 patients, IFS was confirmed in only one, while the remaining 12 were diagnosed to have presumed NFIP. One patient with IFS died shortly after diagnosis. In contrast, all 12 patients with presumed NFIP, except one, survived during a mean follow-up of 17 months. FB was located in the maxillary sinus (n=4), sphenoid sinus (n=8), and both sinuses (n=1). Bone defect was found in five patients, of whom four had a defect in the sphenoid sinus. Various sites were involved in the extrasinonasal infiltrative process, including the orbit (n=10), intracranial cavity (n=9), and soft tissues of the face and neck (n=7). CFTI was recognized only in one patient with IFS. In most cases, the extrasinonasal infiltrative process in the presence of sinonasal FB did not seem to be caused by IFS but probably by NFIP. In our study, there were more cases of invasive changes with the sphenoid than with the maxillary FB.

Serious fungal infections in Pakistan.

PubMed

Jabeen, K; Farooqi, J; Mirza, S; Denning, D; Zafar, A

2017-06-01

The true burden of fungal infection in Pakistan is unknown. High-risk populations for fungal infections [tuberculosis (TB), diabetes, chronic respiratory diseases, asthma, cancer, transplant and human immunodeficiency virus (HIV) infection] are numerous. Here, we estimate the burden of fungal infections to highlight their public health significance. Whole and at-risk population estimates were obtained from the WHO (TB), BREATHE study (COPD), UNAIDS (HIV), GLOBOCAN (cancer) and Heartfile (diabetes). Published data from Pakistan reporting fungal infections rates in general and specific populations were reviewed and used when applicable. Estimates were made for the whole population or specific populations at risk, as previously described in the LIFE methodology. Of the 184,500,000 people in Pakistan, an estimated 3,280,549 (1.78%) are affected by a serious fungal infection, omitting all cutaneous infection, oral candidiasis and allergic fungal sinusitis, which we could not estimate. Compared with other countries, the rates of candidaemia (21/100,000) and mucormycosis (14/100,000) are estimated to be very high, and are based on data from India. Chronic pulmonary aspergillosis rates are estimated to be high (39/100,000) because of the high TB burden. Invasive aspergillosis was estimated to be around 5.9/100,000. Fungal keratitis is also problematic in Pakistan, with an estimated rate of 44/100,000. Pakistan probably has a high rate of certain life- or sight-threatening fungal infections.

[Invasive yeast infections in neutropenic patients].

PubMed

Ruiz Camps, Isabel; Jarque, Isidro

2016-01-01

Invasive fungal diseases caused by yeasts still play an important role in the morbidity and mortality in neutropenic patients with haematological malignancies. Although the overall incidence of invasive candidiasis has decreased due to widespread use of antifungal prophylaxis, the incidence of non-Candida albicans Candida species is increasing compared with that of C.albicans, and mortality of invasive candidiasis continues to be high. In addition, there has been an increase in invasive infections caused by an array of uncommon yeasts, including species of the genus Malassezia, Rhodotorula, Trichosporon and Saprochaete, characterised by their resistance to echinocandins and poor prognosis. Copyright © 2016 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

Emerging Drugs and Vaccines for Candidemia

PubMed Central

Moriyama, Brad; Gordon, Lori A.; McCarthy, Matthew; Henning, Stacey A.; Walsh, Thomas J.; Penzak, Scott R.

2014-01-01

Summary Candidemia and other forms of invasive candidiasis are important causes of morbidity and mortality. The evolving challenge of antimicrobial resistance among fungal pathogens continues to highlight the need for potent, new antifungal agents. MEDLINE, EMBASE, Scopus, and Web of Science searches (up to January 2014) of the English-language literature were performed with the keywords “Candida” or “Candidemia” or “Candidiasis” and terms describing investigational drugs with activity against Candida spp. Conference abstracts and the bibliographies of pertinent articles were also reviewed for relevant reports. ClinicalTrials.gov was searched for relevant clinical trials. Currently available antifungal agents for the treatment of candidemia are summarized. Investigational antifungal agents with potential activity against Candida bloodstream infections and other forms of invasive candidiasis and vaccines for prevention of Candida infections are also reviewed as are selected antifungal agents no longer in development. Antifungal agents currently in clinical trials include isavuconazole, albaconazole, SCY-078, VT-1161, and T-2307. Further data are needed to determine the role of these compounds in the treatment of candidemia and other forms of invasive candidiasis. The progressive reduction in antimicrobial drug development may result in a decline in antifungal drug discovery. Still there remains a critical need for new antifungal agents to treat and prevent invasive candidiasis and other life-threatening mycoses. PMID:25294098

Immunoproteomics of Aspergillus for the development of biomarkers and immunotherapies.

PubMed

Kniemeyer, Olaf; Ebel, Frank; Krüger, Thomas; Bacher, Petra; Scheffold, Alexander; Luo, Ting; Strassburger, Maria; Brakhage, Axel A

2016-10-01

Filamentous fungi of the genus Aspergillus play significant roles as pathogens causing superficial and invasive infections as well as allergic reactions in humans. Particularly invasive mycoses caused by Aspergillus species are characterized by high mortality rates due to difficult diagnosis and insufficient antifungal therapy. The application of immunoproteomic approaches has a great potential to identify new targets for the diagnosis, therapy, and vaccine development of diseases caused by Aspergillus species. Serological proteome analyses (SERPA) that combine 2D electrophoresis with Western blotting are still one of the most popular techniques for the identification of antigenic proteins. However, recently a growing number of approaches have been developed to identify proteins, which either provoke an antibody response or which represent targets of T-cell immunity in patients with allergy or fungal infections. Here, we review advances in the studies of immune responses against pathogenic Aspergilli as well as the current status of diagnosis and immunotherapy of Aspergillus infections. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Genetic susceptibility to Candida infections

PubMed Central

Smeekens, Sanne P; van de Veerdonk, Frank L; Kullberg, Bart Jan; Netea, Mihai G

2013-01-01

Candida spp. are medically important fungi causing severe mucosal and life-threatening invasive infections, especially in immunocompromised hosts. However, not all individuals at risk develop Candida infections, and it is believed that genetic variation plays an important role in host susceptibility. On the one hand, severe fungal infections are associated with monogenic primary immunodeficiencies such as defects in STAT1, STAT3 or CARD9, recently discovered as novel clinical entities. On the other hand, more common polymorphisms in genes of the immune system have also been associated with fungal infections such as recurrent vulvovaginal candidiasis and candidemia. The discovery of the genetic susceptibility to Candida infections can lead to a better understanding of the pathogenesis of the disease, as well as to the design of novel immunotherapeutic strategies. This review is part of the review series on host-pathogen interactions. See more reviews from this series. PMID:23629947

In vitro and in vivo photosensitized inactivation of dermatophyte fungi by heterotricyclic dyes.

PubMed Central

Propst, C; Lubin, L

1978-01-01

The ability of three heterotricyclic dyes to photosensitize dermatophyte fungi was studied with Trichophyton mentagrophytes and Microsporum gypseum. In vitro studies showed that methylene blue, neutral red, and proflavine were capable of killing these fungi when used in conjunction with broad-spectrum light. Proflavine, however, killed both fungi most rapidly and was used for further studies. Fungal killing by proflavine plus light was dependent on dye concentration, pH, light wavelength, and light intensity. Based on the in vitro studies, a treatment regimen was developed for in vivo use on experimentally infected animals. When treatment of guinea pigs inoculated with T. mentagrophytes was begun during fungal invasion, lesion formation at inoculated sites was either prevented or substantially reduced. When treatment was begun after lesion formation, however, light-plus-dyed treated sites showed only slightly faster curing than untreated sites. PMID:669788

Antifungal effect and action mechanism of antimicrobial peptide polybia-CP.

PubMed

Wang, Kairong; Jia, Fengjing; Dang, Wen; Zhao, Yanyan; Zhu, Ranran; Sun, Mengyang; Qiu, Shuai; An, Xiaoping; Ma, Zelin; Zhu, Yuanyuan; Yan, Jiexi; Kong, Ziqing; Yan, Wenjin; Wang, Rui

2016-01-01

The incidence of life-threatening invasive fungal infections increased significantly in recent years. However, the antifungal therapeutic options are very limited. Antimicrobial peptides are a class of potential lead chemical for the development of novel antifungal agents. Antimicrobial peptide polybia-CP was purified from the venom of the social wasp Polybia paulista. In this study, we synthesized polybia-CP and determined its antifungal effects against a series of Candidian species. Our results showed that polybia-CP has potent antifungal activity and fungicidal activity against the tested fungal cells with a proposed membrane-active action mode. In addition, polybia-CP could induce the increase of cellular reactive oxygen species production, which would attribute to its antifungal activity. In conclusion, the present study suggests that polybia-CP has potential as an antifungal agent or may offer a new strategy for antifungal therapeutic option. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

Concepts and Principles of Photodynamic Therapy as an Alternative Antifungal Discovery Platform

PubMed Central

Dai, Tianhong; Fuchs, Beth B.; Coleman, Jeffrey J.; Prates, Renato A.; Astrakas, Christos; St. Denis, Tyler G.; Ribeiro, Martha S.; Mylonakis, Eleftherios; Hamblin, Michael R.; Tegos, George P.

2012-01-01

Opportunistic fungal pathogens may cause superficial or serious invasive infections, especially in immunocompromised and debilitated patients. Invasive mycoses represent an exponentially growing threat for human health due to a combination of slow diagnosis and the existence of relatively few classes of available and effective antifungal drugs. Therefore systemic fungal infections result in high attributable mortality. There is an urgent need to pursue and deploy novel and effective alternative antifungal countermeasures. Photodynamic therapy (PDT) was established as a successful modality for malignancies and age-related macular degeneration but photodynamic inactivation has only recently been intensively investigated as an alternative antimicrobial discovery and development platform. The concept of photodynamic inactivation requires microbial exposure to either exogenous or endogenous photosensitizer molecules, followed by visible light energy, typically wavelengths in the red/near infrared region that cause the excitation of the photosensitizers resulting in the production of singlet oxygen and other reactive oxygen species that react with intracellular components, and consequently produce cell inactivation and death. Antifungal PDT is an area of increasing interest, as research is advancing (i) to identify the photochemical and photophysical mechanisms involved in photoinactivation; (ii) to develop potent and clinically compatible photosensitizers; (iii) to understand how photoinactivation is affected by key microbial phenotypic elements multidrug resistance and efflux, virulence and pathogenesis determinants, and formation of biofilms; (iv) to explore novel photosensitizer delivery platforms; and (v) to identify photoinactivation applications beyond the clinical setting such as environmental disinfectants. PMID:22514547

A Novel Extraction Method Combining Plasma with a Whole-Blood Fraction Shows Excellent Sensitivity and Reproducibility for Patients at High Risk for Invasive Aspergillosis

PubMed Central

Springer, Jan; Schloßnagel, Hannes; Heinz, Werner; Doedt, Thomas; Soeller, Rainer; Einsele, Hermann

2012-01-01

Diagnosis of invasive aspergillosis (IA) is still a major problem in routine clinical practice. Early diagnosis is essential for a good patient prognosis. PCR is a highly sensitive method for the detection of nucleic acids and could play an important role in improving the diagnosis of fungal infections. Therefore, a novel DNA extraction method, ultraclean production (UCP), was developed allowing purification of both cellular and cell-free circulating fungal DNA. In this prospective study we evaluated the commercially available UCP extraction system and compared it to an in-house system. Sixty-three patients at high risk for IA were screened twice weekly, and DNA extracted by both methods was cross-analyzed, in triplicate, by two different real-time PCR assays. The negative predictive values were high for all methods (94.3 to 100%), qualifying them as screening methods, but the sensitivity and diagnostic odds ratios were higher using the UCP extraction method. Sensitivity ranged from 33.3 to 66.7% using the in-house extracts to 100% using the UCP extraction method. Most of the unclassified patients showed no positive PCR results; however, single-positive PCR replicates were observed in some cases. These can bear clinical relevance but should be interpreted with additional clinical and laboratory data. The PCR assays from the UCP extracts showed greater reproducibility than the in-house method for probable IA patients. The standardized UCP extraction method yielded superior results, with regard to sensitivity and reproducibility, than the in-house method. This was independent of the PCR assay used to detect fungal DNA in the sample extracts. PMID:22593600

Plant Invasions Associated with Change in Root-Zone Microbial Community Structure and Diversity.

PubMed

Rodrigues, Richard R; Pineda, Rosana P; Barney, Jacob N; Nilsen, Erik T; Barrett, John E; Williams, Mark A

2015-01-01

The importance of plant-microbe associations for the invasion of plant species have not been often tested under field conditions. The research sought to determine patterns of change in microbial communities associated with the establishment of invasive plants with different taxonomic and phenetic traits. Three independent locations in Virginia, USA were selected. One site was invaded by a grass (Microstegium vimineum), another by a shrub (Rhamnus davurica), and the third by a tree (Ailanthus altissima). The native vegetation from these sites was used as reference. 16S rRNA and ITS regions were sequenced to study root-zone bacterial and fungal communities, respectively, in invaded and non-invaded samples and analyzed using Quantitative Insights Into Microbial Ecology (QIIME). Though root-zone microbial community structure initially differed across locations, plant invasion shifted communities in similar ways. Indicator species analysis revealed that Operational Taxonomic Units (OTUs) closely related to Proteobacteria, Acidobacteria, Actinobacteria, and Ascomycota increased in abundance due to plant invasions. The Hyphomonadaceae family in the Rhodobacterales order and ammonia-oxidizing Nitrospirae phylum showed greater relative abundance in the invaded root-zone soils. Hyphomicrobiaceae, another bacterial family within the phyla Proteobacteria increased as a result of plant invasion, but the effect associated most strongly with root-zones of M. vimineum and R. davurica. Functional analysis using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) showed bacteria responsible for nitrogen cycling in soil increased in relative abundance in association with plant invasion. In agreement with phylogenetic and functional analyses, greater turnover of ammonium and nitrate was associated with plant invasion. Overall, bacterial and fungal communities changed congruently across plant invaders, and support the hypothesis that nitrogen cycling bacteria and functions are important factors in plant invasions. Whether the changes in microbial communities are driven by direct plant microbial interactions or a result of plant-driven changes in soil properties remains to be determined.

Plant Invasions Associated with Change in Root-Zone Microbial Community Structure and Diversity

PubMed Central

Rodrigues, Richard R.; Pineda, Rosana P.; Barney, Jacob N.; Nilsen, Erik T.; Barrett, John E.; Williams, Mark A.

2015-01-01

The importance of plant-microbe associations for the invasion of plant species have not been often tested under field conditions. The research sought to determine patterns of change in microbial communities associated with the establishment of invasive plants with different taxonomic and phenetic traits. Three independent locations in Virginia, USA were selected. One site was invaded by a grass (Microstegium vimineum), another by a shrub (Rhamnus davurica), and the third by a tree (Ailanthus altissima). The native vegetation from these sites was used as reference. 16S rRNA and ITS regions were sequenced to study root-zone bacterial and fungal communities, respectively, in invaded and non-invaded samples and analyzed using Quantitative Insights Into Microbial Ecology (QIIME). Though root-zone microbial community structure initially differed across locations, plant invasion shifted communities in similar ways. Indicator species analysis revealed that Operational Taxonomic Units (OTUs) closely related to Proteobacteria, Acidobacteria, Actinobacteria, and Ascomycota increased in abundance due to plant invasions. The Hyphomonadaceae family in the Rhodobacterales order and ammonia-oxidizing Nitrospirae phylum showed greater relative abundance in the invaded root-zone soils. Hyphomicrobiaceae, another bacterial family within the phyla Proteobacteria increased as a result of plant invasion, but the effect associated most strongly with root-zones of M. vimineum and R. davurica. Functional analysis using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) showed bacteria responsible for nitrogen cycling in soil increased in relative abundance in association with plant invasion. In agreement with phylogenetic and functional analyses, greater turnover of ammonium and nitrate was associated with plant invasion. Overall, bacterial and fungal communities changed congruently across plant invaders, and support the hypothesis that nitrogen cycling bacteria and functions are important factors in plant invasions. Whether the changes in microbial communities are driven by direct plant microbial interactions or a result of plant-driven changes in soil properties remains to be determined. PMID:26505627

Fungal infections in adult patients on extracorporeal life support.

PubMed

Cavayas, Yiorgos Alexandros; Yusuff, Hakeem; Porter, Richard

2018-04-17

Patients on extracorporeal membrane oxygenation (ECMO) are often among the most severely ill in the intensive care unit. They are often receiving broad-spectrum antibiotics; they have multiple entry points for pathogens; and their immune system is impaired by blood circuit interaction. These factors are thought to predispose them to fungal infections. We thus aimed to evaluate the prevalence, risk factors, and prognosis of fungal infections in adults on ECMO. We conducted a retrospective cohort study using the Extracorporeal Life Support Organization registry, which compiles data on ECMO use from hundreds of international centers. We included all adult patients from 2006 to 2016 on any mode of ECMO with either a diagnosis of fungal infection or a positive fungal culture. Our study comprised 2129 adult patients (10.8%) with fungal colonization or infection. Aspergillus involvement (colonization or infection) was present in 272 patients (1.4%), of whom 35.7% survived to hospital discharge. There were 245 patients (1.2%) with Candida invasive bloodstream infection, with 35.9% survival. Risk factors for Aspergillus involvement included solid organ transplant (OR 1.83; p = 0.008), respiratory support (OR 2.75; p < 0.001), and influenza infection (OR 2.48; p < 0.001). Risk factors for candidemia included sepsis (OR 1.60; p = 0.005) and renal replacement therapy (OR 1.55; p = 0.007). In multivariable analysis, Aspergillus involvement (OR 0.40; p < 0.001) and candidemia (OR 0.47; p < 0.001) were both independently associated with decreased survival. The prevalence of Aspergillus involvement and Candida invasive bloodstream infection were not higher in patients on ECMO than what has been reported in the general intensive care population. Both were independently associated with a reduced survival. Aspergillus involvement was strongly associated with ECMO for respiratory support and influenza.

Deep Invasive Fungal Infection of the Hand in a Child Mimicking a Local Gigantism.

PubMed

Chatterjee, Anirban; Chatterjee, Shamita

2018-04-01

Subcutaneous and deep fungal infections in the hand are rare among children. These are usually found in immunocompromised adults or in persons engaged in soil handling activities, due to direct exposure, especially in the tropics. Delay in diagnosis is usual because pyogenic and other granulomatous infections are considered first. The authors present the case of a healthy, immunocompetent 2½-year-old child who presented with progressive swelling of the right hand mimicking a localized gigantism of the entire hand. Multiple operative drainage procedures done previously had failed to resolve the condition. A biopsy established the presence of fungal hyphae, thus confirming the diagnosis of deep fungal infection of the hand and guided proper therapeutic intervention. A strong index of suspicion needs to be maintained in cases not responding to conventional antibacterial therapy, and both microbiologic and histopathologic samples need to be obtained to establish the diagnosis.

Jávea consensus guidelines for the treatment of Candida peritonitis and other intra-abdominal fungal infections in non-neutropenic critically ill adult patients.

PubMed

Pemán, Javier; Aguilar, Gerardo; Valía, Juan Carlos; Salavert, Miguel; Navarro, David; Zaragoza, Rafael

Although the management of the invasive candidiasis has improved in the last decade, controversial issues yet remain, especially in the diagnostic and therapeutic approaches to Candida peritonitis and other forms of intra-abdominal fungal infections. We sought to identify core clinical knowledge about intra-abdominal fungal infections and to achieve high-agreement recommendations required to care for critically ill adult patients with Candida peritonitis and other forms of intra-abdominal fungal infection. A biregional Spanish survey, to elucidate the consensus about the already mentioned fungal infections by means of the Delphi technique, was conducted anonymously by e-mail with 29 multidisciplinary experts in invasive fungal infections from 14 hospitals in the Valencia and Murcia communities during 2014. Respondents included intensivists, anesthesiologists, microbiologists, pharmacologists, and infectious disease specialists, who answered 31 questions prepared by a coordination group after a strict review of the literature from the 5 previous years. The educational objectives spanned 6 categories: epidemiology, microbiological diagnosis, clinical diagnosis, antifungal treatment, de-escalation therapy, and special situations. The agreement required among the panelists for each item to be selected had to be higher than 70%. After extracting the recommendations from the selected items, a meeting at which the experts were asked to validate the previously selected recommendations in a second round of scoring took place. After the second round, 36 recommendations were validated according to the following distribution: epidemiology (5), microbiological diagnosis (4), clinical diagnosis (4), antifungal treatment (3), de-escalation therapy (4), and special situations (16). Treatment of Candida peritonitis and other forms of intra-abdominal fungal infections in ICU patients requires a broad range of knowledge application and skills that our recommendations address. Based on the DELPHI methodology, these recommendations might help to optimize the therapeutic management of these patients in special situations and in various scenarios to improve their outcome. Copyright © 2017 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

Chapter 8: Invasive fungal rhinosinusitis.

PubMed

Duggal, Praveen; Wise, Sarah K

2013-01-01

Invasive fungal rhinosinusitis (IFRS) is a disease of the paranasal sinuses and nasal cavity that typically affects immunocompromised patients in the acute fulminant form. Early symptoms can often mimic rhinosinusitis, while late symptoms can cause significant morbidity and mortality. Swelling and mucosal thickening can quickly progress to pale or necrotic tissue in the nasal cavity and sinuses, and the disease can rapidly spread and invade the palate, orbit, cavernous sinus, cranial nerves, skull base, carotid artery, and brain. IFRS can be life threatening if left undiagnosed or untreated. While the acute fulminant form of IFRS is the most rapidly progressive and destructive, granulomatous and chronic forms also exist. Diagnosis of IFRS often mandates imaging studies in conjunction with clinical, endoscopic, and histopathological examination. Treatment of IFRS consists of reversing the underlying immunosuppression, antifungal therapy, and aggressive surgical debridement. With early diagnosis and treatment, IFRS can be treated and increase patient survival.

Chapter 8: Invasive fungal rhinosinusitis.

PubMed

Duggal, Praveen; Wise, Sarah K

2013-05-01

Invasive fungal rhinosinusitis (IFRS) is a disease of the paranasal sinuses and nasal cavity that typically affects immunocompromised patients in the acute fulminant form. Early symptoms can often mimic rhinosinusitis, while late symptoms can cause significant morbidity and mortality. Swelling and mucosal thickening can quickly progress to pale or necrotic tissue in the nasal cavity and sinuses, and the disease can rapidly spread and invade the palate, orbit, cavernous sinus, cranial nerves, skull base, carotid artery, and brain. IFRS can be life threatening if left undiagnosed or untreated. While the acute fulminant form of IFRS is the most rapidly progressive and destructive, granulomatous and chronic forms also exist. Diagnosis of IFRS often mandates imaging studies in conjunction with clinical, endoscopic, and histopathological examination. Treatment of IFRS consists of reversing the underlying immunosuppression, antifungal therapy, and aggressive surgical debridement. With early diagnosis and treatment, IFRS can be treated and increase patient survival.

Nebulised amphotericin B-polymethacrylic acid nanoparticle prophylaxis prevents invasive aspergillosis

PubMed Central

Shirkhani, Khojasteh; Teo, Ian; Armstrong-James, Darius; Shaunak, Sunil

2015-01-01

Aspergillus species are the major life threatening fungal pathogens in transplant patients. Germination of inhaled fungal spores initiates infection, causes severe pneumonia, and has a mortality of > 50%. This is leading to the consideration of pre-exposure prophylaxis to prevent infection. We made a very low MWt amphotericin B-polymethacrylic acid nanoparticle. It was not toxic to lung epithelial cells or monocyte-derived-macrophages in-vitro, or in an in-vivo transplant immuno-suppression mouse model of life threatening invasive aspergillosis. Three days of nebuliser based prophylaxis delivered the nanoparticle effectively to lung and prevented both fungal growth and lung inflammation. Protection from disease was associated with > 99% killing of the Aspergillus and a 90% reduction in lung TNF-α; the primary driver of tissue destructive immuno-pathology. This study provides in-vivo proof-of-principle that very small and cost-effective nanoparticles can be made simply, and delivered safely and effectively to lung by the aerosol route to prevent fungal infections. From the Clinical Editor Aspergillus is an opportunistic pathogen, which affects immunocompromised patients. One novel way to help fight against this infection is pre-exposure prophylaxis. The authors here made PMA based anionic hydrogels carrying amphotericin B, with mucoadhesive behavior. They showed that aerosol route of the drug was very effective in protecting against the disease in an in-vivo model and should provide a stepping-stone towards clinical trials in the future. PMID:25791815

Nebulised amphotericin B-polymethacrylic acid nanoparticle prophylaxis prevents invasive aspergillosis.

PubMed

Shirkhani, Khojasteh; Teo, Ian; Armstrong-James, Darius; Shaunak, Sunil

2015-07-01

Aspergillus species are the major life threatening fungal pathogens in transplant patients. Germination of inhaled fungal spores initiates infection, causes severe pneumonia, and has a mortality of >50%. This is leading to the consideration of pre-exposure prophylaxis to prevent infection. We made a very low MWt amphotericin B-polymethacrylic acid nanoparticle. It was not toxic to lung epithelial cells or monocyte-derived-macrophages in-vitro, or in an in-vivo transplant immuno-suppression mouse model of life threatening invasive aspergillosis. Three days of nebuliser based prophylaxis delivered the nanoparticle effectively to lung and prevented both fungal growth and lung inflammation. Protection from disease was associated with >99% killing of the Aspergillus and a 90% reduction in lung TNF-α; the primary driver of tissue destructive immuno-pathology. This study provides in-vivo proof-of-principle that very small and cost-effective nanoparticles can be made simply, and delivered safely and effectively to lung by the aerosol route to prevent fungal infections. Aspergillus is an opportunistic pathogen, which affects immunocompromised patients. One novel way to help fight against this infection is pre-exposure prophylaxis. The authors here made PMA based anionic hydrogels carrying amphotericin B, with mucoadhesive behavior. They showed that aerosol route of the drug was very effective in protecting against the disease in an in-vivo model and should provide a stepping-stone towards clinical trials in the future. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis.

PubMed

Wring, Stephen A; Randolph, Ryan; Park, SeongHee; Abruzzo, George; Chen, Qing; Flattery, Amy; Garrett, Graig; Peel, Michael; Outcalt, Russell; Powell, Kendall; Trucksis, Michelle; Angulo, David; Borroto-Esoda, Katyna

2017-04-01

SCY-078 (MK-3118) is a novel, semisynthetic derivative of enfumafungin and represents the first compound of the triterpene class of antifungals. SCY-078 exhibits potent inhibition of β-(1,3)-d-glucan synthesis, an essential cell wall component of many pathogenic fungi, including Candida spp. and Aspergillus spp. SCY-078 is currently in phase 2 clinical development for the treatment of invasive fungal diseases. In vitro disposition studies to assess solubility, intestinal permeability, and metabolic stability were predictive of good oral bioavailability. Preclinical pharmacokinetic studies were consistent with once-daily administration to humans. After intravenous delivery, plasma clearance in rodents and dogs was low, representing <15% and <25% of hepatic blood flow, respectively. The terminal elimination-phase half-life was 5.5 to 8.7 h in rodents, and it was ∼9.3 h in dogs. The volume of distribution at steady-state was high (4.7 to 5.3 liters/kg), a finding suggestive of extensive tissue distribution. Exposure of SCY-078 in kidney tissue, a target organ for invasive fungal disease such as candidiasis, exceeded plasma by 20- to 25-fold for the area under the concentration-time curve from 0 h to infinity (AUC 0-∞ ) and C max SCY-078 achieved efficacy endpoints following oral delivery across multiple murine models of disseminated candidiasis. The pharmacokinetic/pharmacodynamic indices C max /MIC and AUC/MIC correlated with outcome. Target therapeutic exposure, expressed as the plasma AUC 0-24 , was comparable across models, with an upper value of 11.2 μg·h/ml (15.4 μM·h); the corresponding mean value for free drug AUC/MIC was ∼0.75. Overall, these results demonstrate that SCY-078 has the oral and intravenous (i.v.) pharmacokinetic properties and potency in murine infection models of disseminated candidiasis to support further investigation as a novel i.v. and oral treatment for invasive fungal diseases. Copyright © 2017 Wring et al.

Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis

PubMed Central

Randolph, Ryan; Park, SeongHee; Abruzzo, George; Chen, Qing; Flattery, Amy; Garrett, Graig; Peel, Michael; Outcalt, Russell; Powell, Kendall; Trucksis, Michelle; Angulo, David; Borroto-Esoda, Katyna

2017-01-01

ABSTRACT SCY-078 (MK-3118) is a novel, semisynthetic derivative of enfumafungin and represents the first compound of the triterpene class of antifungals. SCY-078 exhibits potent inhibition of β-(1,3)-d-glucan synthesis, an essential cell wall component of many pathogenic fungi, including Candida spp. and Aspergillus spp. SCY-078 is currently in phase 2 clinical development for the treatment of invasive fungal diseases. In vitro disposition studies to assess solubility, intestinal permeability, and metabolic stability were predictive of good oral bioavailability. Preclinical pharmacokinetic studies were consistent with once-daily administration to humans. After intravenous delivery, plasma clearance in rodents and dogs was low, representing <15% and <25% of hepatic blood flow, respectively. The terminal elimination-phase half-life was 5.5 to 8.7 h in rodents, and it was ∼9.3 h in dogs. The volume of distribution at steady-state was high (4.7 to 5.3 liters/kg), a finding suggestive of extensive tissue distribution. Exposure of SCY-078 in kidney tissue, a target organ for invasive fungal disease such as candidiasis, exceeded plasma by 20- to 25-fold for the area under the concentration-time curve from 0 h to infinity (AUC0–∞) and Cmax. SCY-078 achieved efficacy endpoints following oral delivery across multiple murine models of disseminated candidiasis. The pharmacokinetic/pharmacodynamic indices Cmax/MIC and AUC/MIC correlated with outcome. Target therapeutic exposure, expressed as the plasma AUC0–24, was comparable across models, with an upper value of 11.2 μg·h/ml (15.4 μM·h); the corresponding mean value for free drug AUC/MIC was ∼0.75. Overall, these results demonstrate that SCY-078 has the oral and intravenous (i.v.) pharmacokinetic properties and potency in murine infection models of disseminated candidiasis to support further investigation as a novel i.v. and oral treatment for invasive fungal diseases. PMID:28137806

Voriconazole Exposure and Risk of Cutaneous Squamous Cell Carcinoma, Aspergillus Colonization, Invasive Aspergillosis and Death in Lung Transplant Recipients

PubMed Central

Mansh, M.; Binstock, M.; Williams, K.; Hafeez, F.; Kim, J.; Glidden, D.; Boettger, R.; Hays, S.; Kukreja, J.; Golden, J.; Asgari, M.M.; Chin-Hong, P.; Singer, J.P.; Arron, S.

2015-01-01

Voriconazole is a triazole antifungal used to prevent and treat invasive fungal infections after lung transplantation, but has been associated with an increased risk for developing cutaneous squamous cell carcinoma (SCC). Despite widespread use, there are no clear guidelines for optimal prophylactic regimens that balance its competing risks and benefits. We conducted a retrospective cohort study of all lung transplant recipients at the University of California, San Francisco transplanted between October 1991 and December 2012 (n=455) to investigate whether voriconazole exposure impacted development of SCC, Aspergillus colonization, invasive aspergillosis, and all-cause mortality. Voriconazole exposure was associated with a 73% increased risk for developing SCC (HR=1.73; 95% CI: 1.04–2.88; p=0.03), with each additional 30-day exposure at the standard dose increasing the risk by 3.0% (HR=1.03; 95% CI: 1.02–1.04; p<0.001). Voriconazole exposure reduced risk of Aspergillus colonization by 50% (HR=0.50; 95% CI: 0.34–0.72; p<0.001), but we were underpowered to detect risk reduction for invasive aspergillosis. Voriconazole exposure significantly reduced all-cause mortality among subjects who developed Aspergillus colonization (HR=0.34; 95% CI: 0.13–0.91; p=0.03), but had no significant impact on those without colonization. Physicians should consider patient-specific factors that modify the potential risks and benefits of voriconazole in the care of lung transplant recipients. PMID:26372838

Differential susceptibility of Dectin-1 isoforms to functional inactivation by neutrophil and fungal proteases.

PubMed

Griffiths, James S; Thompson, Aiysha; Stott, Matthew; Benny, Ankita; Lewis, Natalie A; Taylor, Philip R; Forton, Julian; Herrick, Sarah; Orr, Selinda J; McGreal, Eamon P

2018-06-01

Patients with cystic fibrosis (CF) experience chronic or recurrent bacterial and fungal lung infections. Many patients with CF cannot effectively clear Aspergillus from their lungs. This may result in IgE sensitization and the development of allergic bronchopulmonary aspergillosis, or invasive infections, such as Aspergillus bronchitis. Lung disease in patients with CF is associated with neutrophil-dominated inflammation and elevated levels of the serine protease, neutrophil elastase (NE). Various C-type lectin-like receptors (CLRs), including Dectin-1 and Dectin-2, are involved in the immune response to Aspergillus. Here, we show that purified NE cleaves Dectin-1 in an isoform-specific manner. Bronchoalveolar lavage fluid from patients with CF, which contains high NE activity, induces Dectin-1 cleavage. Similarly, filtrate from a protease-producing strain of Aspergillus fumigatus induces isoform-specific cleavage of Dectin-1. Dectin-1 knockout (KO) cells and NE-treated cells demonstrated reduced phagocytosis of zymosan, a fungal cell wall preparation. In addition, NE cleaves 2 other CLRs, Dectin-2 and Mincle, and fungal-induced cytokine production was reduced in Dectin-1 KO cells, Dectin-2 KO cells, and NE-treated cells. Thus, Dectin-1 and Dectin-2 cleavage by NE and/or A. fumigatus-derived proteases results in an aberrant antifungal immune response that likely contributes to disease pathology in patients with CF.-Griffiths, J. S., Thompson, A., Stott, M., Benny, A., Lewis, N. A., Taylor, P. R., Forton, J., Herrick, S., Orr, S. J., McGreal, E. P. Differential susceptibility of Dectin-1 isoforms to functional inactivation by neutrophil and fungal proteases.

Onychomycosis: Pathogenesis, Diagnosis, and Management

PubMed Central

Elewski, Boni E.

1998-01-01

Although not life-threatening, onychomycosis (a fungal infection of the nail, usually caused by a dermatophyte) constitutes an important public health problem because of its high prevalence (about 10% of the U.S. population) and associated morbidity. The disease can have certain negative consequences for patients, such as pain, and can potentially undermine work and social lives. This review discusses the etiology, classification, diagnosis, and treatment of onychomycosis. Four types of onychomycosis are recognized based on the site and pattern of fungal invasion. Dermatophyte fungi are the predominant pathogens, but yeasts (especially Candida albicans) and nondermatophyte molds may also be implicated. Accurate diagnosis requires direct microscopy and fungal culture. The differential diagnosis includes psoriasis, lichen planus, onychogryphosis, and nail trauma. Onychomycosis is more difficult to treat than most dermatophytoses because of the inherent slow growth of the nail. Older antifungal agents (ketoconazole and griseofulvin) are unsuitable for onychomycosis because of their relatively poor efficacy and potential adverse effects. Three recently developed antimycotic agents (fluconazole, itraconazole, and terbinafine) offer high cure rates and good safety profiles. In addition, the short treatment times (<3 months) and intermittent dosing schedules are likely to enhance compliance and reduce the costs of therapy. PMID:9665975

Probing the effect of tip pressure on fungal growth: Application to Aspergillus nidulans

NASA Astrophysics Data System (ADS)

González-Bermúdez, Blanca; Li, Qingxuan; Guinea, Gustavo V.; Peñalva, Miguel A.; Plaza, Gustavo R.

2017-08-01

The study of fungal cells is of great interest due to their importance as pathogens and as fermenting fungi and for their appropriateness as model organisms. The differential pressure between the hyphal cytoplasm and the bordering medium is essential for the growth process, because the pressure is correlated with the growth rate. Notably, during the invasion of tissues, the external pressure at the tip of the hypha may be different from the pressure in the surrounding medium. We report the use of a method, based on the micropipette-aspiration technique, to study the influence of this external pressure at the hyphal tip. Moreover, this technique makes it possible to study hyphal growth mechanics in the case of very thin hyphae, not accessible to turgor pressure probes. We found a correlation between the local pressure at the tip and the growth rate for the species Arpergillus nidulans. Importantly, the proposed method allows one to measure the pressure at the tip required to arrest the hyphal growth. Determining that pressure could be useful to develop new medical treatments for fungal infections. Finally, we provide a mechanical model for these experiments, taking into account the cytoplasm flow and the wall deformation.

Is there a need for autopsies in the management of fungal disease?

PubMed

Knoke, Manfred; Bernhardt, Hannelore; Schwesinger, Günther

2008-07-01

The autopsy rates in Germany became low like in other European, American and Asian countries. Main reasons for this development are the lack of acceptance of autopsy in the society as well as in the medical profession, the introduction of a requirement for consent, unclear legal position, the public health system, pressure of costs and a change in the field of activity in pathology with much more diagnostics of surgical and biopsy material. The autopsy is missing with respect to the reliability of causes of death and morbidity statistics and other epidemiological studies. Published data indicate that up to 20-30% of patients who die in hospitals have important diseases/lesions that remain undetected before death but that are found at autopsy. For infectious diseases, the data are similar. Therefore, a higher incidence of invasive fungal infections was found. Some rare fungal disorders are diagnosed by autopsy. Only exact death statistics makes specific health care possible and is cost saving in a public health system in the long term. Autopsy remains an important tool for quality control in medical diagnostic and therapeutic activity. It is also essential for fundamental medical education and further training.

Intranasal tissue necrosis associated with opioid abuse: Case report and systematic review.

PubMed

Morrison, Danielle A; Wise, Sarah K; DelGaudio, John M; Chowdhury, Naweed I; Levy, Joshua M

2017-12-27

Opioid abuse is a common disorder affecting over 2 million Americans. Intranasal tissue necrosis is a previously described sequela of nasal opioid inhalation, with a similar presentation to invasive fungal rhinosinusitis (IFRS). The goal of this case report and systematic review is to evaluate the evidence supporting this uncommon disease, with qualitative analysis of the presentation, management and treatment outcomes. MEDLINE, EMBASE, Google Scholar, Scopus, and Web of Science. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were utilized to identify English-language studies reporting intranasal mucosal injury associated with prescription opioid abuse. Primary outcomes included clinical presentation, treatment strategies, and outcomes. Systematic review identified 61 patients for qualitative analysis. Common clinical features include facial pain without a history of chronic sinusitis or known immunodeficiency. Diagnostic nasal endoscopy revealed superficial debris with underlying tissue necrosis, consistent with a preliminary diagnosis of IFRS. Characteristic pathologic findings include mucosal ulceration with an overlying acellular substrate, often with polarizable material. Fungal colonization is often reported, with several accounts of angiocentric invasion in immunocompetent patients. Complete symptom resolution is expected following surgical debridement with cessation of intranasal opioid inhalation, with 89% of identified patients experiencing a complete resolution of disease. Intranasal opioid abuse is a prevalent condition associated with chronic pain and tissue necrosis that is clinically concerning for invasive fungal disease. Whereas IFRS must be excluded, even in patients without known immunodeficiency, complete resolution of symptoms can be expected following surgical debridement with cessation of opioid abuse. Laryngoscope, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

Impact of routine fluconazole prophylaxis for premature infants with birth weights of less than 1250 grams in a developing country.

PubMed

Rueda, Kathia; Moreno, Maria Teresa; Espinosa, Manuel; Sáez-Llorens, Xavier

2010-11-01

Systemic fungal infections are associated with substantial case-morbidity and fatality rates in premature infants. Considerable evidence indicates that prophylaxis with fluconazole given to premature infants reduces the risk of invasive fungal infection. There is scant information from developing countries. A comparative study of 2 years, one with fluconazole prophylaxis and the other without was conducted in all premature babies weighing less than 1250 g at birth. Fluconazole was administered in 3 mg/kg doses, given every 48 hours, starting on day 3 of life, for a period of 6 weeks. Documented systemic Candida infection was the primary outcome. A total of 271 and 252 patients, respectively, were evaluated during the year before (control group) and after (treatment group) routine fluconazole prophylaxis. The control group developed 21 Candida infections (7.7%) while the treatment group had only 3 Candida infections (1.1%). This difference was statistically significant (P = 0.007; odds ratio, 0.13; 95% confidence interval, 0.03-0.47). The number needed to treat to prevent one case was 7. Although case-fatality rates for documented Candida infection were similar in both periods (76% vs. 67%), fewer deaths attributed to the fungal infection were noted in the prophylaxis year (6% vs. 1%, P = 0.003). Routine fluconazole prophylaxis given to premature infants of less than 1250 g at birth is associated with a significant impact on frequency of documented systemic Candida infections.

Biological Invasion Influences the Outcome of Plant-Soil Feedback in the Invasive Plant Species from the Brazilian Semi-arid.

PubMed

de Souza, Tancredo Augusto Feitosa; de Andrade, Leonaldo Alves; Freitas, Helena; da Silva Sandim, Aline

2017-05-30

Plant-soil feedback is recognized as the mutual interaction between plants and soil microorganisms, but its role on the biological invasion of the Brazilian tropical seasonal dry forest by invasive plants still remains unclear. Here, we analyzed and compared the arbuscular mycorrhizal fungi (AMF) communities and soil characteristics from the root zone of invasive and native plants, and tested how these AMF communities affect the development of four invasive plant species (Cryptostegia madagascariensis, Parkinsonia aculeata, Prosopis juliflora, and Sesbania virgata). Our field sampling revealed that AMF diversity and frequency of the Order Diversisporales were positively correlated with the root zone of the native plants, whereas AMF dominance and frequency of the Order Glomerales were positively correlated with the root zone of invasive plants. We grew the invasive plants in soil inoculated with AMF species from the root zone of invasive (I changed ) and native (I unaltered ) plant species. We also performed a third treatment with sterilized soil inoculum (control). We examined the effects of these three AMF inoculums on plant dry biomass, root colonization, plant phosphorous concentration, and plant responsiveness to mycorrhizas. We found that I unaltered and I changed promoted the growth of all invasive plants and led to a higher plant dry biomass, mycorrhizal colonization, and P uptake than control, but I changed showed better results on these variables than I unaltered . For plant responsiveness to mycorrhizas and fungal inoculum effect on plant P concentration, we found positive feedback between changed-AMF community (I changed ) and three of the studied invasive plants: C. madagascariensis, P. aculeata, and S. virgata.

A polymerase chain reaction enzyme immunoassay for diagnosing infection caused by Aspergillus fumigatus.

PubMed Central

Golbang, N; Burnie, J P; Matthews, R C

1999-01-01

AIM: To develop a polymerase chain reaction enzyme immunoassay (PCR-EIA) to measure levels of circulating aspergillus DNA in invasive aspergillosis caused by Aspergillus fumigatus. METHODS: The PCR reaction was based on primers from the 18s rRNA gene. Binding of the product to a streptavidin coated microtitration plate was mediated by a biotinylated capture probe. The product was digoxigenylated during PCR and this was the tag to which antibody was bound in the subsequent EIA. RESULTS: The optical density (OD) endpoint was < 0.1 in 10 sera from neutropenic patients with no evidence of invasive aspergillosis, and in 10 sera from nonneutropenic patients with bacterial pneumonia (group 1). The OD from five of 12 patients with allergic bronchopulmonary aspergillosis (ABPA) (group 2), three with an aspergilloma (group 3), and five with possible invasive aspergillosis (group 4) was > or = 0.1. In 63 sera from 33 cases of proven invasive aspergillosis (group 5) an OD > or = 0.1 was achieved in 48 sera from 30 patients. The maximum OD was 0.510. The level fell in survivors and gradually rose in fatal cases. CONCLUSIONS: This assay validated the concept of diagnosing invasive aspergillosis by measuring levels of circulating fungal DNA in serum. PMID:10562808

Phylogenetics of a Fungal Invasion: Origins and Widespread Dispersal of White-Nose Syndrome.

PubMed

Drees, Kevin P; Lorch, Jeffrey M; Puechmaille, Sebastien J; Parise, Katy L; Wibbelt, Gudrun; Hoyt, Joseph R; Sun, Keping; Jargalsaikhan, Ariunbold; Dalannast, Munkhnast; Palmer, Jonathan M; Lindner, Daniel L; Marm Kilpatrick, A; Pearson, Talima; Keim, Paul S; Blehert, David S; Foster, Jeffrey T

2017-12-12

Globalization has facilitated the worldwide movement and introduction of pathogens, but epizoological reconstructions of these invasions are often hindered by limited sampling and insufficient genetic resolution among isolates. Pseudogymnoascus destructans , a fungal pathogen causing the epizootic of white-nose syndrome in North American bats, has exhibited few genetic polymorphisms in previous studies, presenting challenges for both epizoological tracking of the spread of this fungus and for determining its evolutionary history. We used single nucleotide polymorphisms (SNPs) from whole-genome sequencing and microsatellites to construct high-resolution phylogenies of P. destructans Shallow genetic diversity and the lack of geographic structuring among North American isolates support a recent introduction followed by expansion via clonal reproduction across the epizootic zone. Moreover, the genetic relationships of isolates within North America suggest widespread mixing and long-distance movement of the fungus. Genetic diversity among isolates of P. destructans from Europe was substantially higher than in those from North America. However, genetic distance between the North American isolates and any given European isolate was similar to the distance between the individual European isolates. In contrast, the isolates we examined from Asia were highly divergent from both European and North American isolates. Although the definitive source for introduction of the North American population has not been conclusively identified, our data support the origin of the North American invasion by P. destructans from Europe rather than Asia. IMPORTANCE This phylogenetic study of the bat white-nose syndrome agent, P. destructans , uses genomics to elucidate evolutionary relationships among populations of the fungal pathogen to understand the epizoology of this biological invasion. We analyze hypervariable and abundant genetic characters (microsatellites and genomic SNPs, respectively) to reveal previously uncharacterized diversity among populations of the pathogen from North America and Eurasia. We present new evidence supporting recent introduction of the fungus to North America from a diverse Eurasian population, with limited increase in genetic variation in North America since that introduction. Copyright © 2017 Drees et al.

Clinical utility of Aspergillus galactomannan and PCR in bronchoalveolar lavage fluid for the diagnosis of invasive pulmonary aspergillosis in patients with haematological malignancies.

PubMed

Heng, Siow-Chin; Chen, Sharon C-A; Morrissey, C Orla; Thursky, Karin; Manser, Renee L; De Silva, Harini D; Halliday, Catriona L; Seymour, John F; Nation, Roger L; Kong, David C M; Slavin, Monica A

2014-07-01

Interpretation of Aspergillus galactomannan (GM) and PCR results in bronchoalveolar lavage (BAL) fluid for the diagnosis of invasive pulmonary aspergillosis (IPA) in patients with haematological malignancies requires clarification. A total of 116 patients underwent BAL for investigation of new lung infiltrates: 40% were neutropenic, 68% and 36% were receiving mould-active antifungal agents and β-lactam antibiotics. The diagnosis of proven IPA (n = 3), probable IPA (n = 15), and possible invasive fungal disease (IFD, n = 50) was made without inclusion of GM results. BAL GM (at cut-off of 0.8) had lower diagnostic sensitivity for IPA than PCR (61% versus 78%) but higher specificity (93% versus 79%). Both tests had excellent negative predictive values (85-90%), supporting their utility in excluding IPA. The use of BAL GM and PCR results increased the certainty of Aspergillus aetiology in 7 probable IPA cases where fungal hyphae were detected in respiratory samples by microscopy, and upgraded 24 patients from possible IFD to probable IPA. Use of BAL GM and PCR improves the diagnosis of IPA. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

A new diagnostic technique for tinea incognito: in vivo reflectance confocal microscopy. Report of five cases.

PubMed

Turan, Enver; Erdemir, Asli Turgut; Gurel, Mehmet Salih; Yurt, Nurdan

2013-02-01

In vivo confocal laser scanning microscopy (CLSM) is a modern non-invasive method for investigation of the skin that allows real-time visualization of individual cells and subcellular structures with the highest resolution imaging comparable to the routine histopathology. Our aim was to demonstrate the potential of CLSM for non-invasive diagnosis of difficult tinea incognito cases. Clinically atypical lesions in five cases of tinea incognito due to dermatophyte spp. were demonstrated using reflectance confocal laser scanning microscopy (RCM), parallel to KOH preparation and fungal culture of skin scrapings performed in the same patients. The morphological features characteristic for tinea incognito, namely linear branched hyphae in the intercellular area of the stratum corneum, were readily detectable by means of CLSM. In vivo tissue imaging were performed at three different wavelengths (785, 658, 445 nm) and the best images of fungal elements were obtained at 445 nm. All of our five cases had similar reflectance confocal microscopical findings. Our findings suggest the potential of CLSM as a non-invasive tool for the diagnosis of tinea incognito having atypical clinical appearance. Although at present the reflectance confocal microscopy cannot replace the current diagnostic standards for tinea incognito, it may be successfully used as in vivo non-invasive screening tool to facilitate the diagnosis and point to the need for further investigation of the patient. © 2012 John Wiley & Sons A/S.

Detection of a Serum Siderophore by LC-MS/MS as a Potential Biomarker of Invasive Aspergillosis

PubMed Central

Carroll, Cassandra S.; Amankwa, Lawrence N.; Pinto, Linda J.; Fuller, Jeffrey D.; Moore, Margo M.

2016-01-01

Invasive aspergillosis (IA) is a life-threatening systemic mycosis caused primarily by Aspergillus fumigatus. Early diagnosis of IA is based, in part, on an immunoassay for circulating fungal cell wall carbohydrate, galactomannan (GM). However, a wide range of sensitivity and specificity rates have been reported for the GM test across various patient populations. To obtain iron in vivo, A. fumigatus secretes the siderophore, N,N',N"-triacetylfusarinine C (TAFC) and we hypothesize that TAFC may represent a possible biomarker for early detection of IA. We developed an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for TAFC analysis from serum, and measured TAFC in serum samples collected from patients at risk for IA. The method showed lower and upper limits of quantitation (LOQ) of 5 ng/ml and 750 ng/ml, respectively, and complete TAFC recovery from spiked serum. As proof of concept, we evaluated 76 serum samples from 58 patients with suspected IA that were investigated for the presence of GM. Fourteen serum samples obtained from 11 patients diagnosed with probable or proven IA were also analyzed for the presence of TAFC. Control sera (n = 16) were analyzed to establish a TAFC cut-off value (≥6 ng/ml). Of the 36 GM-positive samples (≥0.5 GM index) from suspected IA patients, TAFC was considered positive in 25 (69%). TAFC was also found in 28 additional GM-negative samples. TAFC was detected in 4 of the 14 samples (28%) from patients with proven/probable aspergillosis. Log-transformed TAFC and GM values from patients with proven/probable IA, healthy individuals and SLE patients showed a significant correlation with a Pearson r value of 0.77. In summary, we have developed a method for the detection of TAFC in serum that revealed this fungal product in the sera of patients at risk for invasive aspergillosis. A prospective study is warranted to determine whether this method provides improved early detection of IA. PMID:26974544

Fungal diversity and Aspergillus species in hospital environments.

PubMed

Martínez-Herrera, Erick Obed; Frías De-León, María Guadalupe; Duarte-Escalante, Esperanza; Calderón-Ezquerro, María Del Carmen; Jiménez-Martínez, María Del Carme; Acosta-Altamirano, Gustavo; Rivera-Becerril, Facundo; Toriello, Conchita; Reyes Montes, María Del Rocío

2016-06-02

Nosocomial invasive fungal infections, particularly aspergillosis, are an increasing problem in immunocompromised patients. The presented study evaluates fungal diversity and the presence of Aspergillus in air samples from two hospitals. Over the course of one year (rainy and dry seasons), the air was sampled from three areas in two hospitals (1 and 2) using a single-stage Andersen viable particle sampler (Thermo Scientific, Waltham, MA, USA). The fungi were identified by macro- and micromorphology, and the number of colony forming units (CFU)/m(3) air and their richness, abundance, and diversity were determined. Isolates Aspergillus genus were characterized by their thermotolerance. The CFU/m(3) air was similar at both hospitals during the two seasons, but different between the sampled areas. Results showed 10 fungal genera for hospital 1, and 8 for hospital 2. The most abundant were Penicillium, Cladosporium and Aspergillus. The thermotolerance test confirmed the identification of A. fumigatus section Fumigati. The highest growth rate was found in Aspergillus section Nigri. Determining the fungal diversity in the two hospitals was important because all the species have the potential to be pathogenic, especially the section Fumigati.

Different strategies to kill the host presented by Metarhizium anisopliae and Beauveria bassiana.

PubMed

Rustiguel, Cynthia Barbosa; Fernández-Bravo, María; Guimarães, Luis Henrique Souza; Quesada-Moraga, Enrique

2018-03-01

Studies conducted over the last decades have shown the potential of entomopathogenic fungi for the biocontrol of some insect pests. Entomopathogenic fungi infect their host through the cuticle, so they do not need to be ingested to be effective. These fungi also secrete secondary metabolites and proteins that are toxic to insect pests. In this context, we analyzed the pathogenicity of Metarhizium anisopliae (Metschn.) strains IBCB 384 and IBCB 425 and Beauveria bassiana (Bals.-Criv.) Vuill. strains E 1764 and E 3158 against Galleria mellonella (Linn.) larvae, during pre-invasion and post-invasion phases. The results showed M. anisopliae, especially strain IBCB 384, was most virulent in the pre-invasion phase against G. mellonella, whereas B. bassiana, especially strain E 1764, was most virulent in the post-invasion phase. During in vivo development and in the production of toxic serum, B. bassiana E 3158 was the most virulent. Different fungal growth (or toxin) strategies were observed for studied strains. Metarhizium anisopliae IBCB 425 prioritizes the growth strategy, whereas strain IBCB 384 and B. bassiana strains E 1764 and E 3158 have a toxic strategy. All strains have pathogenicity against G. mellonella, indicating their possible use for biocontrol.

Specific and Novel microRNAs Are Regulated as Response to Fungal Infection in Human Dendritic Cells.

PubMed

Dix, Andreas; Czakai, Kristin; Leonhardt, Ines; Schäferhoff, Karin; Bonin, Michael; Guthke, Reinhard; Einsele, Hermann; Kurzai, Oliver; Löffler, Jürgen; Linde, Jörg

2017-01-01

Within the last two decades, the incidence of invasive fungal infections has been significantly increased. They are characterized by high mortality rates and are often caused by Candida albicans and Aspergillus fumigatus . The increasing number of infections underlines the necessity for additional anti-fungal therapies, which require extended knowledge of gene regulations during fungal infection. MicroRNAs are regulators of important cellular processes, including the immune response. By analyzing their regulation and impact on target genes, novel therapeutic and diagnostic approaches may be developed. Here, we examine the role of microRNAs in human dendritic cells during fungal infection. Dendritic cells represent the bridge between the innate and the adaptive immune systems. Therefore, analysis of gene regulation of dendritic cells is of particular significance. By applying next-generation sequencing of small RNAs, we quantify microRNA expression in monocyte-derived dendritic cells after 6 and 12 h of infection with C. albicans and A. fumigatus as well as treatment with lipopolysaccharides (LPS). We identified 26 microRNAs that are differentially regulated after infection by the fungi or LPS. Three and five of them are specific for fungal infections after 6 and 12 h, respectively. We further validated interactions of miR-132-5p and miR-212-5p with immunological relevant target genes, such as FKBP1B, KLF4 , and SPN , on both RNA and protein level. Our results indicate that these microRNAs fine-tune the expression of immune-related target genes during fungal infection. Beyond that, we identified previously undiscovered microRNAs. We validated three novel microRNAs via qRT-PCR. A comparison with known microRNAs revealed possible relations with the miR-378 family and miR-1260a/b for two of them, while the third one features a unique sequence with no resemblance to known microRNAs. In summary, this study analyzes the effect of known microRNAs in dendritic cells during fungal infections and proposes novel microRNAs that could be experimentally verified.

Trehalose pathway as an antifungal target.

PubMed

Perfect, John R; Tenor, Jennifer L; Miao, Yi; Brennan, Richard G

2017-02-17

With an increasing immunocompromised population which is linked to invasive fungal infections, it is clear that our present 3 classes of antifungal agents may not be sufficient to provide optimal management to these fragile patients. Furthermore, with widespread use of antifungal agents, drug-resistant fungal infections are on the rise. Therefore, there is some urgency to develop the antifungal pipeline with the goal of new antifungal agent discovery. In this review, a simple metabolic pathway, which forms the disaccharide, trehalose, will be characterized and its potential as a focus for antifungal target(s) explained. It possesses several important features for development of antifungal agents. First, it appears to have fungicidal characteristics and second, it is broad spectrum with importance across both ascomycete and basidiomycete species. Finally, this pathway is not found in mammals so theoretically specific inhibitors of the trehalose pathway and its enzymes in fungi should be relatively non-toxic for mammals. The trehalose pathway and its critical enzymes are now in a position to have directed antifungal discovery initiated in order to find a new class of antifungal drugs.

Neutrophil Interactions Stimulate Evasive Hyphal Branching by Aspergillus fumigatus

PubMed Central

Jorgensen, Julianne; Frydman, Galit H.; Jones, Caroline N.

2017-01-01

Invasive aspergillosis (IA), primarily caused by Aspergillus fumigatus, is an opportunistic fungal infection predominantly affecting immunocompromised and neutropenic patients that is difficult to treat and results in high mortality. Investigations of neutrophil-hypha interaction in vitro and in animal models of IA are limited by lack of temporal and spatial control over interactions. This study presents a new approach for studying neutrophil-hypha interaction at single cell resolution over time, which revealed an evasive fungal behavior triggered by interaction with neutrophils: Interacting hyphae performed de novo tip formation to generate new hyphal branches, allowing the fungi to avoid the interaction point and continue invasive growth. Induction of this mechanism was independent of neutrophil NADPH oxidase activity and neutrophil extracellular trap (NET) formation, but could be phenocopied by iron chelation and mechanical or physiological stalling of hyphal tip extension. The consequence of branch induction upon interaction outcome depends on the number and activity of neutrophils available: In the presence of sufficient neutrophils branching makes hyphae more vulnerable to destruction, while in the presence of limited neutrophils the interaction increases the number of hyphal tips, potentially making the infection more aggressive. This has direct implications for infections in neutrophil-deficient patients and opens new avenues for treatments targeting fungal branching. PMID:28076396

Phagocytosis-dependent activation of a TLR9–BTK–calcineurin–NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus

PubMed Central

Herbst, Susanne; Shah, Anand; Mazon Moya, Maria; Marzola, Vanessa; Jensen, Barbara; Reed, Anna; Birrell, Mark A; Saijo, Shinobu; Mostowy, Serge; Shaunak, Sunil; Armstrong-James, Darius

2015-01-01

Transplant recipients on calcineurin inhibitors are at high risk of invasive fungal infection. Understanding how calcineurin inhibitors impair fungal immunity is a key priority for defining risk of infection. Here, we show that the calcineurin inhibitor tacrolimus impairs clearance of the major mould pathogen Aspergillus fumigatus from the airway, by inhibiting macrophage inflammatory responses. This leads to defective early neutrophil recruitment and fungal clearance. We confirm these findings in zebrafish, showing an evolutionarily conserved role for calcineurin signalling in neutrophil recruitment during inflammation. We find that calcineurin–NFAT activation is phagocytosis dependent and collaborates with NF-κB for TNF-α production. For yeast zymosan particles, activation of macrophage calcineurin–NFAT occurs via the phagocytic Dectin-1–spleen tyrosine kinase pathway, but for A. fumigatus, activation occurs via a phagosomal TLR9-dependent and Bruton's tyrosine kinase-dependent signalling pathway that is independent of MyD88. We confirm the collaboration between NFAT and NF-κB for TNF-α production in primary alveolar macrophages. These observations identify inhibition of a newly discovered macrophage TLR9–BTK–calcineurin–NFAT signalling pathway as a key immune defect that leads to organ transplant-related invasive aspergillosis. PMID:25637383

Serious fungal infections in Egypt.

PubMed

Zaki, S M; Denning, D W

2017-06-01

We aimed to estimate the burden of serious fungal infections in Egypt, currently unknown, based on the size of the populations at risk and available epidemiological data. Data were obtained from the World Health Organization (WHO), the Joint United Nations Programme on HIV/AIDS (UNAIDS), and published reports with clearcut denominators. When no data existed, risk populations were used to estimate frequencies of fungal infections, using previously described methodology. The population of Egypt in 2011 was ∼82,500,000; 31% children, and 8% women >60 years of age. Amongst about 21.8 million women aged 15-50 years, recurrent vulvovaginal candidiasis (≥4 episodes/year) is estimated to occur in 1.3 million (3,169/100,000 females). Using a low international average rate of 5/100,000, we estimate 4,127 cases of candidaemia, and 619 patients with intra-abdominal candidiasis. Amongst the survivors of pulmonary tuberculosis (TB) in Egypt in 2012, 319 new cases of chronic pulmonary aspergillosis (CPA) are likely, a prevalence of 1,005 post-TB and a total prevalence estimate of 3,015 CPA patients in all. Asthma is common in Egypt, affecting 9.4% of adults, 5.35 million, and so ABPA and SAFS were estimated in around 162/100,000 and 214/100,000 respectively. Invasive aspergillosis is estimated to affect 495 patients following leukaemia therapy, there are an estimated 37 cases in renal and liver transplant recipients, and an estimated 132 patients develop IA in the context of lung cancer. Amongst 641,000 COPD admissions to hospital each year, 8,337 patients develop IA. The total HIV-infected population is small, with an estimated 6,500 patients, 2,500 not on antiretroviral therapy. Amongst HIV-infected patients, 38 (0.6%) cases of cryptococcal meningitis and 125 (1.9%) cases of Pneumocystis pneumonia are estimated each year. Fungal keratitis is common, with 28-55% (mean 40%) of corneal infections being fungal, an estimated total of 11,550 cases. The present study indicates that 2% of the Egyptian population is affected by fungal infections. The estimates are certainly incomplete, and need further epidemiological and diagnostic studies.

Early Complications and Outcomes in Combat Injury Related Invasive Fungal Wound Infections: A Case-Control Analysis

PubMed Central

Lewandowski, Louis R.; Weintrob, Amy C.; Tribble, David R.; Rodriguez, Carlos J.; Petfield, Joseph; Lloyd, Bradley A.; Murray, Clinton K.; Stinner, Daniel; Aggarwal, Deepak; Shaikh, Faraz; Potter, Benjamin K.

2015-01-01

Objective Clinicians have anecdotally noted that combat-related invasive fungal wound infections (IFIs) lead to residual limb shortening, additional days and operative procedures prior to initial wound closure, and high early complication rates. We evaluated the validity of these observations and identified risk factors that may impact time to initial wound closure. Design Retrospective review and case-control analysis. Setting Military hospitals. Patients/Participants United States military personnel injured during combat operations (2009–2011). The IFI cases were identified based upon the presence of recurrent, necrotic extremity wounds with mold growth in culture and/or histopathologic fungal evidence. Non-IFI controls were matched on injury pattern and severity. In a supplemental matching analysis, non-IFI controls were also matched by blood volume transfused within 24 hours of injury. Intervention None. Main Outcome Measurements Amputation revision rate and loss of functional levels. Results Seventy-one IFI cases (112 fungal-infected extremity wounds) were identified and matched to 160 control patients (315 non-IFI extremity wounds). The IFI wounds resulted in significantly more changes in amputation level (p<0.001). Additionally, significantly (p<0.001) higher number of operative procedures and longer duration to initial wound closure was associated with IFI. A shorter duration to initial wound closure was significantly associated with wounds lacking IFIs (Hazard ratio: 1.53; 95% CI: 1.17, 2.01). The supplemental matching analysis found similar results. Conclusions Our analysis indicates that IFIs adversely impact wound healing and patient recovery, requiring more frequent proximal amputation revisions and leading to higher early complication rates. PMID:26360542

Bacterial and fungal keratitis in Upper Egypt: In vitro screening of enzymes, toxins and antifungal activity

PubMed Central

Gharamah, Abdullah A; Moharram, Ahmed M; Ismail, Mady A; AL-Hussaini, Ashraf K

2014-01-01

Purpose: This work was conducted to study the ability of bacterial and fungal isolates from keratitis cases in Upper Egypt to produce enzymes, toxins, and to test the isolated fungal species sensitivity to some therapeutic agents. Materials and Methods: One hundred and fifteen patients clinically diagnosed to have microbial keratitis were investigated. From these cases, 37 bacterial isolates and 25 fungal isolates were screened for their ability to produce extra-cellular enzymes in solid media. In addition, the ability of fungal isolates to produce mycotoxins and their sensitivity to 4 antifungal agents were tested. Results: Protease, lipase, hemolysins, urease, phosphatase, and catalase were detected respectively in 48.65%, 37.84%, 59.46%, 43.24%, 67.57%, and 100% out of 37 bacterial isolates tested. Out of 25 fungal isolates tested during the present study, 80% were positive for protease, 84% for lipase and urease, 28% for blood hemolysis, and 100% for phosphatase and catalase enzymes. Thirteen fungal isolates were able to produce detectable amounts of 7 mycotoxins in culture medium (aflatoxins (B1, B2, G1, and G2), sterigmatocystin, fumagillin, diacetoxyscirpenol, zearalenone, T-2 toxin, and trichodermin). Among the antifungal agents tested in this study, terbinafine showed the highest effect against most isolates in vitro. Conclusion: In conclusion, the ability of bacterial and fungal isolates to produce extracellular enzymes and toxins may be aid in the invasion and destruction of eye tissues, which, in turn, lead to vision loss. PMID:24008795

Estimated burden of fungal infections in Germany.

PubMed

Ruhnke, Markus; Groll, Andreas H; Mayser, Peter; Ullmann, Andrew J; Mendling, Werner; Hof, Herbert; Denning, David W

2015-10-01

In the late 1980's, the incidence of invasive fungal diseases (IFDs) in Germany was estimated with 36.000 IFDs per year. The current number of fungal infections (FI) occurring each year in Germany is still not known. In the actual analysis, data on incidence of fungal infections in various patients groups at risk for FI were calculated and mostly estimated from various (mostly national) resources. According to the very heterogenous data resources robust data or statistics could not be obtained but preliminary estimations could be made and compared with data from other areas in the world using a deterministic model that has consistently been applied in many countries by the LIFE program ( www.LIFE-worldwide.org). In 2012, of the 80.52 million population (adults 64.47 million; 41.14 million female, 39.38 million male), 20% are children (0-14 years) and 16% of population are ≥65 years old. Using local data and literature estimates of the incidence or prevalence of fungal infections, about 9.6 million (12%) people in Germany suffer from a fungal infection each year. These figures are dominated (95%) by fungal skin disease and recurrent vulvo-vaginal candidosis. In general, considerable uncertainty surrounds the total numbers because IFDs do not belong to the list of reportable infectious diseases in Germany and most patients were not hospitalised because of the IFD but a distinct underlying disease. © 2015 Blackwell Verlag GmbH.

Estimation of the Burden of Serious Human Fungal Infections in Malaysia

PubMed Central

Velayuthan, Rukumani Devi; Samudi, Chandramathi; Lakhbeer Singh, Harvinder Kaur; Ng, Kee Peng

2018-01-01

Fungal infections (mycoses) are likely to occur more frequently as ever-increasingly sophisticated healthcare systems create greater risk factors. There is a paucity of systematic data on the incidence and prevalence of human fungal infections in Malaysia. We conducted a comprehensive study to estimate the burden of serious fungal infections in Malaysia. Our study showed that recurrent vaginal candidiasis (>4 episodes/year) was the most common of all cases with a diagnosis of candidiasis (n = 501,138). Oesophageal candidiasis (n = 5850) was most predominant among individuals with HIV infection. Candidemia incidence (n = 1533) was estimated in hospitalized individuals, some receiving treatment for cancer (n = 1073), and was detected also in individuals admitted to intensive care units (ICU) (n = 460). In adults with asthma, allergic bronchopulmonary aspergillosis (ABPA) was the second most common respiratory mycoses noticed (n = 30,062) along with severe asthma with fungal sensitization (n = 39,628). Invasive aspergillosis was estimated in 184 cases undergoing anti-cancer treatment and 834 ICU cases. Cryptococcal meningitis was diagnosed in 700 subjects with HIV/AIDS and Pneumocystis jirovecii pneumonitis (PCP) in 1286 subjects with underlying HIV disease. The present study indicates that at least 590,214 of the Malaysian population (1.93%) is affected by a serious fungal infection annually. This problem is serious enough to warrant the further epidemiological studies to estimate the burden of human fungal infections in Malaysia. PMID:29562712

Reintroduction of locally extinct vertebrates impacts arid soil fungal communities.

PubMed

Clarke, Laurence J; Weyrich, Laura S; Cooper, Alan

2015-06-01

Introduced species have contributed to extinction of native vertebrates in many parts of the world. Changes to vertebrate assemblages are also likely to alter microbial communities through coextinction of some taxa and the introduction of others. Many attempts to restore degraded habitats involve removal of exotic vertebrates (livestock and feral animals) and reintroduction of locally extinct species, but the impact of such reintroductions on microbial communities is largely unknown. We used high-throughput DNA sequencing of the fungal internal transcribed spacer I (ITS1) region to examine whether replacing exotic vertebrates with reintroduced native vertebrates led to changes in soil fungal communities at a reserve in arid central Australia. Soil fungal diversity was significantly different between dune and swale (interdune) habitats. Fungal communities also differed significantly between sites with exotic or reintroduced native vertebrates after controlling for the effect of habitat. Several fungal operational taxonomic units (OTUs) found exclusively inside the reserve were present in scats from reintroduced native vertebrates, providing a direct link between the vertebrate assemblage and soil microbial communities. Our results show that changes to vertebrate assemblages through local extinctions and the invasion of exotic species can alter soil fungal communities. If local extinction of one or several species results in the coextinction of microbial taxa, the full complement of ecological interactions may never be restored. © 2015 John Wiley & Sons Ltd.

Novel disease susceptibility factors for fungal necrotrophic pathogens in Arabidopsis.

PubMed

Dobón, Albor; Canet, Juan Vicente; García-Andrade, Javier; Angulo, Carlos; Neumetzler, Lutz; Persson, Staffan; Vera, Pablo

2015-04-01

Host cells use an intricate signaling system to respond to invasions by pathogenic microorganisms. Although several signaling components of disease resistance against necrotrophic fungal pathogens have been identified, our understanding for how molecular components and host processes contribute to plant disease susceptibility is rather sparse. Here, we identified four transcription factors (TFs) from Arabidopsis that limit pathogen spread. Arabidopsis mutants defective in any of these TFs displayed increased disease susceptibility to Botrytis cinerea and Plectosphaerella cucumerina, and a general activation of non-immune host processes that contribute to plant disease susceptibility. Transcriptome analyses revealed that the mutants share a common transcriptional signature of 77 up-regulated genes. We characterized several of the up-regulated genes that encode peptides with a secretion signal, which we named PROVIR (for provirulence) factors. Forward and reverse genetic analyses revealed that many of the PROVIRs are important for disease susceptibility of the host to fungal necrotrophs. The TFs and PROVIRs identified in our work thus represent novel genetic determinants for plant disease susceptibility to necrotrophic fungal pathogens.

White-nose syndrome without borders: Pseudogymnoascus destructans infection tolerated in Europe and Palearctic Asia but not in North America.

PubMed

Zukal, Jan; Bandouchova, Hana; Brichta, Jiri; Cmokova, Adela; Jaron, Kamil S; Kolarik, Miroslav; Kovacova, Veronika; Kubátová, Alena; Nováková, Alena; Orlov, Oleg; Pikula, Jiri; Presetnik, Primož; Šuba, Jurģis; Zahradníková, Alexandra; Martínková, Natália

2016-01-29

A striking feature of white-nose syndrome, a fungal infection of hibernating bats, is the difference in infection outcome between North America and Europe. Here we show high WNS prevalence both in Europe and on the West Siberian Plain in Asia. Palearctic bat communities tolerate similar fungal loads of Pseudogymnoascus destructans infection as their Nearctic counterparts and histopathology indicates equal focal skin tissue invasiveness pathognomonic for WNS lesions. Fungal load positively correlates with disease intensity and it reaches highest values at intermediate latitudes. Prevalence and fungal load dynamics in Palearctic bats remained persistent and high between 2012 and 2014. Dominant haplotypes of five genes are widespread in North America, Europe and Asia, expanding the source region of white-nose syndrome to non-European hibernacula. Our data provides evidence for both endemicity and tolerance to this persistent virulent fungus in the Palearctic, suggesting that host-pathogen interaction equilibrium has been established.

White-nose syndrome without borders: Pseudogymnoascus destructans infection tolerated in Europe and Palearctic Asia but not in North America

PubMed Central

Zukal, Jan; Bandouchova, Hana; Brichta, Jiri; Cmokova, Adela; Jaron, Kamil S.; Kolarik, Miroslav; Kovacova, Veronika; Kubátová, Alena; Nováková, Alena; Orlov, Oleg; Pikula, Jiri; Presetnik, Primož; Šuba, Jurģis; Zahradníková Jr., Alexandra; Martínková, Natália

2016-01-01

A striking feature of white-nose syndrome, a fungal infection of hibernating bats, is the difference in infection outcome between North America and Europe. Here we show high WNS prevalence both in Europe and on the West Siberian Plain in Asia. Palearctic bat communities tolerate similar fungal loads of Pseudogymnoascus destructans infection as their Nearctic counterparts and histopathology indicates equal focal skin tissue invasiveness pathognomonic for WNS lesions. Fungal load positively correlates with disease intensity and it reaches highest values at intermediate latitudes. Prevalence and fungal load dynamics in Palearctic bats remained persistent and high between 2012 and 2014. Dominant haplotypes of five genes are widespread in North America, Europe and Asia, expanding the source region of white-nose syndrome to non-European hibernacula. Our data provides evidence for both endemicity and tolerance to this persistent virulent fungus in the Palearctic, suggesting that host-pathogen interaction equilibrium has been established. PMID:26821755

Crossover fungal pathogens: the biology and pathogenesis of fungi capable of crossing kingdoms to infect plants and humans.

PubMed

Gauthier, Gregory M; Keller, Nancy P

2013-12-01

The outbreak of fungal meningitis associated with contaminated methylprednisolone acetate has thrust the importance of fungal infections into the public consciousness. The predominant pathogen isolated from clinical specimens, Exserohilum rostratum (teleomorph: Setosphaeria rostrata), is a dematiaceous fungus that infects grasses and rarely humans. This outbreak highlights the potential for fungal pathogens to infect both plants and humans. Most crossover or trans-kingdom pathogens are soil saprophytes and include fungi in Ascomycota and Mucormycotina phyla. To establish infection, crossover fungi must overcome disparate, host-specific barriers, including protective surfaces (e.g. cuticle, skin), elevated temperature, and immune defenses. This review illuminates the underlying mechanisms used by crossover fungi to cause infection in plants and mammals, and highlights critical events that lead to human infection by these pathogens. Several genes including veA, laeA, and hapX are important in regulating biological processes in fungi important for both invasive plant and animal infections. Copyright © 2013 Elsevier Inc. All rights reserved.

Mucorales-Specific T Cells in Patients with Hematologic Malignancies.

PubMed

Potenza, Leonardo; Vallerini, Daniela; Barozzi, Patrizia; Riva, Giovanni; Gilioli, Andrea; Forghieri, Fabio; Candoni, Anna; Cesaro, Simone; Quadrelli, Chiara; Maertens, Johan; Rossi, Giulio; Morselli, Monica; Codeluppi, Mauro; Mussini, Cristina; Colaci, Elisabetta; Messerotti, Andrea; Paolini, Ambra; Maccaferri, Monica; Fantuzzi, Valeria; Del Giovane, Cinzia; Stefani, Alessandro; Morandi, Uliano; Maffei, Rossana; Marasca, Roberto; Narni, Franco; Fanin, Renato; Comoli, Patrizia; Romani, Luigina; Beauvais, Anne; Viale, Pier Luigi; Latgè, Jean Paul; Lewis, Russell E; Luppi, Mario

2016-01-01

Invasive mucormycosis (IM) is an emerging life-threatening fungal infection. It is difficult to obtain a definite diagnosis and to initiate timely intervention. Mucorales-specific T cells occur during the course of IM and are involved in the clearance of the infection. We have evaluated the feasibility of detecting Mucorales-specific T cells in hematological patients at risk for IM, and have correlated the detection of such cells with the clinical conditions of the patients. By using an enzyme linked immunospot assay, the presence of Mucorales-specific T cells in peripheral blood (PB) samples has been investigated at three time points during high-dose chemotherapy for hematologic malignancies. Mucorales-specific T cells producing interferon-γ, interleukin-10 and interleukin-4 were analysed in order to detect a correlation between the immune response and the clinical picture. Twenty-one (10.3%) of 204 patients, accounting for 32 (5.3%) of 598 PB samples, tested positive for Mucorales-specific T cells. Two groups could be identified. Group 1, including 15 patients without signs or symptoms of invasive fungal diseases (IFD), showed a predominance of Mucorales-specific T cells producing interferon-gamma. Group 2 included 6 patients with a clinical picture consistent with invasive fungal disease (IFD): 2 cases of proven IM and 4 cases of possible IFD. The proven patients had significantly higher number of Mucorales-specific T cells producing interleukin-10 and interleukin-4 and higher rates of positive samples by using derived diagnostic cut-offs when compared with the 15 patients without IFD. Mucorales-specific T cells can be detected and monitored in patients with hematologic malignancies at risk for IM. Mucorales-specific T cells polarized to the production of T helper type 2 cytokines are associated with proven IM and may be evaluated as a surrogate diagnostic marker for IM.

Acute invasive fungal rhinosinusitis: our experience with 18 cases.

PubMed

Bakhshaee, Mehdi; Bojdi, Amin; Allahyari, Abolghasem; Majidi, Mohammad Reza; Tavakol, Sherwin; Najafzadeh, Mohammad Javad; Asghari, Masoud

2016-12-01

Acute invasive fungal rhinosinusitis (AIFRS) is a rapidly progressive life threatening infection that is seen most commonly among immunocompromised patients. We present a case series of 18 patients clinically and histopathologically diagnosed with AIFRS with a mean follow-up of 9.11 ± 2.51 months (range 6-17). Demographic data, apparent symptoms and signs, underlying disorders, and outcomes are discussed. The mean age was 39.56 ± 20.66 years (range 2-75). The most common underlying diseases were diabetes mellitus (50 %) and leukemia (44.44 %). Mucosal biopsy confirmed fungal invasion of the nasal mucosa in all cases. The main fungi were Rhizopus oryzae (55.56 %), Absidia mucor (16.67 %), and Aspergillus fumigatus (27.78 %). Headache and facial pain (77.8 %), facial paresthesia (55.6 %), and ophthalmoplegia (33.3 %) were the most common symptoms and signs. Computed tomography and endoscopic findings showed various stages of sinonasal (100 %), pterygopalatine fossa (55.56 %), orbital (44.45 %), and cerebral (5.56 %) involvement. All patients underwent serial surgical debridement (3.78 ± 1.80 times; range 2-8) simultaneously with systemic antifungal therapy and proper management of the underlying disease. The most extreme case with brain involvement survived and recovered with no evidence of recurrent disease following treatment. All patients were considered cured after two endoscopic negative histopathologic evaluations. Three patients (16.67 %) died, one from uncontrolled leukemia and two due to renal failure. AIFRS is a potentially fatal condition, however, early diagnosis and management of the underlying disease accompanied with systemic antifungal and aggressive serial surgical intervention appears to be effective in reducing mortality in most patients.

Ultraviolet-C Light for Treatment of Candida albicans Burn Infection in Mice

PubMed Central

Dai, Tianhong; Kharkwal, Gitika B; Zhao, Jie; St. Denis, Tyler G; Wu, Qiuhe; Xia, Yumin; Huang, Liyi; Sharma, Sulbha K; d’Enfert, Christophe; Hamblin, Michael R

2011-01-01

Burn patients are at high risk of invasive fungal infections, which are a leading cause of morbidity, mortality, and related expense exacerbated by the emergence of drug resistant fungal strains. In this study, we investigated the use of UVC light (254-nm) for the treatment of Candida albicans infection in mouse third degree burns. In-vitro studies demonstrated that UVC could selectively kill the pathogenic yeast C. albicans compared to a normal keratinocyte cell line in a light exposure dependent manner. A mouse model of chronic C. albicans infection in non-lethal 3rd degree burns was developed. The C. albicans strain was stably transformed with a version of the Gaussia princeps luciferase gene that allowed real-time bioluminescence imaging of the progression of C. albicans infection. UVC treatment with a single exposure carried out on day 0 (30 minutes post-infection) gave an average 2.16-log10-unit (99.2%) loss of fungal luminescence when 2.92 J/cm2 UVC had been delivered, while UVC 24-hours post-infection gave 1.94-log10-unit (95.8%) reduction of fungal luminescence after 6.48 J/cm2. Statistical analysis demonstrated that UVC treatment carried out both on both day 0 and day 1 significantly reduced the fungal bioburden of infected burns. UVC was found to be superior to a topical antifungal drug, nystatin cream. UVC was tested on normal mouse skin and no gross damage was observed 24 hours after 6.48 J/cm2. DNA lesions (cyclobutane pyrimidine dimers) were observed by immunofluorescence in normal mouse skin immediately after a 6.48 J/cm2 UVC exposure, but the lesions were extensively repaired at 24-hours after UVC exposure. PMID:21208209

Aspergillus in chronic lung disease: Modeling what goes on in the airways.

PubMed

Takazono, Takahiro; Sheppard, Donald C

2017-01-01

Aspergillus species cause a range of respiratory diseases in humans. While immunocompromised patients are at risk for the development of invasive infection with these opportunistic molds, patients with underlying pulmonary disease can develop chronic airway infection with Aspergillus species. These conditions span a range of inflammatory and allergic diseases including Aspergillus bronchitis, allergic bronchopulmonary aspergillosis, and severe asthma with fungal sensitization. Animal models are invaluable tools for the study of the molecular mechanism underlying the colonization of airways by Aspergillus and the host response to these non-invasive infections. In this review we summarize the state-of-the-art with respect to the available animal models of noninvasive and allergic Aspergillus airway disease; the key findings of host-pathogen interaction studies using these models; and the limitations and future directions that should guide the development and use of models for the study of these important pulmonary conditions. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Transplant tourism and invasive fungal infection.

PubMed

Al Salmi, I; Metry, A M; Al Ismaili, F; Hola, A; Al Riyami, M; Khamis, F; Al-Abri, S

2018-04-01

Deceased and live-related renal transplants (RTXs) are approved procedures that are performed widely throughout the world. In certain regions, commercial RTX has become popular, driven by financial greed. This retrospective, descriptive study was performed at the Royal Hospital from 2013 to 2015. Data were collected from the national kidney transplant registry of Oman. All transplant cases retrieved were divided into two groups: live-related RTX performed in Oman and commercial-unrelated RTX performed abroad. These groups were then divided again into those with and without evidence of fungal infection, either in the wound or renal graft. A total of 198 RTX patients were identified, of whom 162 (81.8%) had undergone a commercial RTX that was done abroad. Invasive fungal infections (IFIs) were diagnosed in 8% of patients who had undergone a commercial RTX; of these patients, 76.9% underwent a nephrectomy and 23.1% continued with a functioning graft. None of the patients with RTXs performed at the Royal Hospital contracted an IFI. The most common fungal isolates were Aspergillus species (including Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, and Aspergillus nigricans), followed by Zygomycetes. However, there was no evidence of fungal infection including Aspergillus outside the graft site. Computed tomography (CT) findings showed infarction of the graft, renal artery thrombosis, aneurysmal dilatation of the external iliac artery, fungal ball, or just the presence of a perigraft collection. Of the total patients with IFIs, 23.1% died due to septic shock and 53.8% were alive and on hemodialysis. The remaining 23.1% who did not undergo nephrectomy demonstrated acceptable graft function. This is the largest single-center study on commercial RTX reporting the highest number of patients with IFI acquired over a relatively short period of time. Aspergillus spp were the main culprit fungi, with no Candida spp being isolated. A high index of suspicion might be the most reasonable means to reduce the possible very poor outcomes. Improving legal transplant programs and strengthening the associated laws could prevent commercial transplant tourism. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Computational approaches for discovery of common immunomodulators in fungal infections: towards broad-spectrum immunotherapeutic interventions.

PubMed

Kidane, Yared H; Lawrence, Christopher; Murali, T M

2013-10-07

Fungi are the second most abundant type of human pathogens. Invasive fungal pathogens are leading causes of life-threatening infections in clinical settings. Toxicity to the host and drug-resistance are two major deleterious issues associated with existing antifungal agents. Increasing a host's tolerance and/or immunity to fungal pathogens has potential to alleviate these problems. A host's tolerance may be improved by modulating the immune system such that it responds more rapidly and robustly in all facets, ranging from the recognition of pathogens to their clearance from the host. An understanding of biological processes and genes that are perturbed during attempted fungal exposure, colonization, and/or invasion will help guide the identification of endogenous immunomodulators and/or small molecules that activate host-immune responses such as specialized adjuvants. In this study, we present computational techniques and approaches using publicly available transcriptional data sets, to predict immunomodulators that may act against multiple fungal pathogens. Our study analyzed data sets derived from host cells exposed to five fungal pathogens, namely, Alternaria alternata, Aspergillus fumigatus, Candida albicans, Pneumocystis jirovecii, and Stachybotrys chartarum. We observed statistically significant associations between host responses to A. fumigatus and C. albicans. Our analysis identified biological processes that were consistently perturbed by these two pathogens. These processes contained both immune response-inducing genes such as MALT1, SERPINE1, ICAM1, and IL8, and immune response-repressing genes such as DUSP8, DUSP6, and SPRED2. We hypothesize that these genes belong to a pool of common immunomodulators that can potentially be activated or suppressed (agonized or antagonized) in order to render the host more tolerant to infections caused by A. fumigatus and C. albicans. Our computational approaches and methodologies described here can now be applied to newly generated or expanded data sets for further elucidation of additional drug targets. Moreover, identified immunomodulators may be used to generate experimentally testable hypotheses that could help in the discovery of broad-spectrum immunotherapeutic interventions. All of our results are available at the following supplementary website: http://bioinformatics.cs.vt.edu/~murali/supplements/2013-kidane-bmc.

Computational approaches for discovery of common immunomodulators in fungal infections: towards broad-spectrum immunotherapeutic interventions

PubMed Central

2013-01-01

Background Fungi are the second most abundant type of human pathogens. Invasive fungal pathogens are leading causes of life-threatening infections in clinical settings. Toxicity to the host and drug-resistance are two major deleterious issues associated with existing antifungal agents. Increasing a host’s tolerance and/or immunity to fungal pathogens has potential to alleviate these problems. A host’s tolerance may be improved by modulating the immune system such that it responds more rapidly and robustly in all facets, ranging from the recognition of pathogens to their clearance from the host. An understanding of biological processes and genes that are perturbed during attempted fungal exposure, colonization, and/or invasion will help guide the identification of endogenous immunomodulators and/or small molecules that activate host-immune responses such as specialized adjuvants. Results In this study, we present computational techniques and approaches using publicly available transcriptional data sets, to predict immunomodulators that may act against multiple fungal pathogens. Our study analyzed data sets derived from host cells exposed to five fungal pathogens, namely, Alternaria alternata, Aspergillus fumigatus, Candida albicans, Pneumocystis jirovecii, and Stachybotrys chartarum. We observed statistically significant associations between host responses to A. fumigatus and C. albicans. Our analysis identified biological processes that were consistently perturbed by these two pathogens. These processes contained both immune response-inducing genes such as MALT1, SERPINE1, ICAM1, and IL8, and immune response-repressing genes such as DUSP8, DUSP6, and SPRED2. We hypothesize that these genes belong to a pool of common immunomodulators that can potentially be activated or suppressed (agonized or antagonized) in order to render the host more tolerant to infections caused by A. fumigatus and C. albicans. Conclusions Our computational approaches and methodologies described here can now be applied to newly generated or expanded data sets for further elucidation of additional drug targets. Moreover, identified immunomodulators may be used to generate experimentally testable hypotheses that could help in the discovery of broad-spectrum immunotherapeutic interventions. All of our results are available at the following supplementary website: http://bioinformatics.cs.vt.edu/~murali/supplements/2013-kidane-bmc PMID:24099000

Burden of fungal infections in Algeria.

PubMed

Chekiri-Talbi, M; Denning, D W

2017-06-01

We report for the first time in Algeria and provide burden estimates. We searched for existing data and estimated the incidence and prevalence of fungal diseases based on the population at risk and available epidemiological data. Demographic data were derived from the National Office of Statistics (Office National des Statistiques: ONS), World Health Organization (WHO), The Joint Nations Programme on HIV/AIDS (UNAIDS) and national published reports. When no data existed, risk populations were used to estimate frequencies of fungal infections, using previously described methodology. Algeria has 40.4 million inhabitants, and probably at least 568,900 (1.41%) of Algerians have a serious fungal infection each year. Recurrent vulvovaginal candidiasis (485,000) and fungal asthma (72,000) are probably the commonest problems, as there are over 1 million adult asthmatics. Candidaemia is estimated in 2,020 people, invasive aspergillosis in 2,865 people, and intra-abdominal candidiasis in 303 people; these are the most common life-threatening problems. AIDS is uncommon, but cancer is not (45,000 new cases of cancer including 1,500 in children), nor is COPD (an estimated 317,762 patients, of whom 20.3% are admitted to hospital each year). A focus on improving the diagnosis and epidemiological data related to fungal infection is necessary in Algeria.

Bacteria in oral secretions of an endophytic insect inhibit antagonistic fungi

Treesearch

Yasmin J. Cardoza; Kier D. Klepzig; Kenneth F. Raffa

2006-01-01

1. Colonisation of host trees by an endophytic herbivore, the spruce beetle, Dendroctonus rufipennis , is accompanied by invasion of its galleries by a number of fungal species. Four of these associated species were identified as Leptographium abietinum , Aspergillus fumigatus , Aspergillus nomius , and ...

Innovations in Wound Infection Prevention and Management and Antimicrobial Countermeasures

DTIC Science & Technology

2011-01-24

2010  Fungal pathogens causing invasive infections  WRAMC - 2002-2008  0.4 cases/1,000 admissions (n=6)  Moulds - Aspergillus (4), Bipolaris (2...clinical wound management decisions.  Expected Outcomes: – Discovery & characterization of host immune response biomarkers associated with

Invasive fungal infections and antifungal therapies in solid organ transplant recipients.

PubMed

Gabardi, Steven; Kubiak, David W; Chandraker, Anil K; Tullius, Stefan G

2007-12-01

This manuscript will review the risk factors, prevalence, clinical presentation, and management of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients. Primary literature was obtained via MEDLINE (1966-April 2007) and EMBASE. Abstracts were obtained from scientific meetings or pharmaceutical manufacturers and included in the analysis. All studies and abstracts evaluating IFIs and/or antifungal therapies, with a primary focus on solid organ transplantation, were considered for inclusion. English-language literature was selected for inclusion, but was limited to those consisting of human subjects. Infectious complications following SOT are common. IFIs are associated with high morbidity and mortality rates in this patient population. Determining the best course of therapy is difficult due to the limited availability of data in SOT recipients. Well-designed clinical studies are infrequent and much of the available information is often based on case-reports or retrospective analyses. Transplant practitioners must remain aware of their therapeutic options and the advantages and disadvantages associated with the available treatment alternatives.

Current status and future perspectives on molecular and serological methods in diagnostic mycology.

PubMed

Lau, Anna; Chen, Sharon; Sleiman, Sue; Sorrell, Tania

2009-11-01

Invasive fungal infections are an important cause of infectious morbidity. Nonculture-based methods are increasingly used for rapid, accurate diagnosis to improve patient outcomes. New and existing DNA amplification platforms have high sensitivity and specificity for direct detection and identification of fungi in clinical specimens. Since laboratories are increasingly reliant on DNA sequencing for fungal identification, measures to improve sequence interpretation should support validation of reference isolates and quality control in public gene repositories. Novel technologies (e.g., isothermal and PNA FISH methods), platforms enabling high-throughput analyses (e.g., DNA microarrays and Luminex xMAP) and/or commercial PCR assays warrant further evaluation for routine diagnostic use. Notwithstanding the advantages of molecular tests, serological assays remain clinically useful for patient management. The serum Aspergillus galactomannan test has been incorporated into diagnostic algorithms of invasive aspergillosis. Both the galactomannan and the serum beta-D-glucan test have value for diagnosing infection and monitoring therapeutic response.

British Society for Medical Mycology proposed standards of care for patients with invasive fungal infections.

PubMed

Denning, David W; Kibbler, Christopher C; Barnes, Rosemary A

2003-04-01

Outcomes for invasive fungal infections have greatly improved in the past decade, and several new antifungal drugs have been or will be licensed in the next few years. Early accurate diagnosis and appropriate treatment have major impact on survival. In a 1995 survey of laboratory practice in the UK for mycology, major disparities were seen, with many laboratories not undertaking even simple diagnostic procedures. Delays in processing and inadequate procedures for handling samples, incomplete or delayed reporting of results, or a combination of these, compromise the care of patients. In randomised trials of antifungal chemotherapy, optimum treatments and good alternatives for others have been defined for some infections. High-quality care requires a multidisciplinary approach to diagnosis and management. In this review, we propose microbiology, histopathology, radiology, and clinical auditing standards, with the evidence base for each reviewed. The standards are absolutes, and, therefore, provide a straightforward basis for improving services to patients if they are all implemented.

Diagnosis and management of fungal urinary tract infection.

PubMed

Kauffman, Carol A

2014-03-01

When the terms funguria or fungal urinary tract infection are used, most physicians are referring to candiduria and urinary tract infections due to Candida species. Other fungi, including yeasts and molds can involve the kidney during the course of disseminated infection, but rarely cause symptoms referable to the urinary tract. Candida species appear to be unique in their ability to both colonize and cause invasive disease in the urinary tract. This overview focuses only on candiduria and Candida urinary tract infection because they are common and many times present perplexing management issues. Published by Elsevier Inc.

Oral exfoliative cytology for the diagnosis of paracoccidoidomycosis in a patient with human immunodeficiency virus: a case report.

PubMed

Cabral, Luiz Antonio Guimarães; Lima, Celina Faig; Coutinho de Oliveira, Maria Lucia; Brandão, Adriana Aigotti Haberbeck; Almeida, Janete Dias

2010-01-01

Paracoccidioidomycosis is not the most common fungal disease in patients infected with human immunodeficiency virus (HIV), except for endemic regions in Latin America countries. A 33-year-old man with HIV presented with mulberry-like lesions on the palate. The diagnosis was made by exfoliative cytology and Papanicolaou staining. Microscopic analysis revealed fungal structures with birefringent walls and exosporulation conferring an airplane radial motor appearance, or even bowel-like or goblet-like forms compatible with Paracoccidioides brasiliensis. This process spares the immunosuppressed patient from undergoing invasive biopsy procedures.

Nitric Oxide in the Offensive Strategy of Fungal and Oomycete Plant Pathogens

PubMed Central

Arasimowicz-Jelonek, Magdalena; Floryszak-Wieczorek, Jolanta

2016-01-01

In the course of evolutionary changes pathogens have developed many invasion strategies, to which the host organisms responded with a broad range of defense reactions involving endogenous signaling molecules, such as nitric oxide (NO). There is evidence that pathogenic microorganisms, including two most important groups of eukaryotic plant pathogens, also acquired the ability to synthesize NO via non-unequivocally defined oxidative and/or reductive routes. Although the both kingdoms Chromista and Fungi are remarkably diverse, the experimental data clearly indicate that pathogen-derived NO is an important regulatory molecule controlling not only developmental processes, but also pathogen virulence and its survival in the host. An active control of mitigation or aggravation of nitrosative stress within host cells seems to be a key determinant for the successful invasion of plant pathogens representing different lifestyles and an effective mode of dispersion in various environmental niches. PMID:26973690

Multiple Phosphatases Regulate Carbon Source-Dependent Germination and Primary Metabolism in Aspergillus nidulans

PubMed Central

de Assis, Leandro José; Ries, Laure Nicolas Annick; Savoldi, Marcela; Dinamarco, Taisa Magnani; Goldman, Gustavo Henrique; Brown, Neil Andrew

2015-01-01

Aspergillus nidulans is an important mold and a model system for the study of fungal cell biology. In addition, invasive A. nidulans pulmonary infections are common in humans with chronic granulomatous disease. The morphological and biochemical transition from dormant conidia into active, growing, filamentous hyphae requires the coordination of numerous biosynthetic, developmental, and metabolic processes. The present study exhibited the diversity of roles performed by seven phosphatases in regulating cell cycle, development, and metabolism in response to glucose and alternative carbon sources. The identified phosphatases highlighted the importance of several signaling pathways regulating filamentous growth, the action of the pyruvate dehydrogenase complex as a metabolic switch controlling carbon usage, and the identification of the key function performed by the α-ketoglutarate dehydrogenase during germination. These novel insights into the fundamental roles of numerous phosphatases in germination and carbon sensing have provided new avenues of research into the identification of inhibitors of fungal germination, with implications for the food, feed, and pharmaceutical industries. PMID:25762568

Oral Bacterial and Fungal Microbiome Impacts Colorectal Carcinogenesis.

PubMed

Klimesova, Klara; Jiraskova Zakostelska, Zuzana; Tlaskalova-Hogenova, Helena

2018-01-01

Host's physiology is significantly influenced by microbiota colonizing the epithelial surfaces. Complex microbial communities contribute to proper mucosal barrier function, immune response, and prevention of pathogen invasion and have many other crucial functions. The oral cavity and large intestine are distant parts of the digestive tract, both heavily colonized by commensal microbiota. Nevertheless, they feature different proportions of major bacterial and fungal phyla, mostly due to distinct epithelial layers organization and different oxygen levels. A few obligate anaerobic strains inhabiting the oral cavity are involved in the pathogenesis of oral diseases. Interestingly, these microbiota components are also enriched in gut inflammatory and tumor tissue. An altered microbiota composition - dysbiosis - and formation of polymicrobial biofilms seem to play important roles in the development of oral diseases and colorectal cancer. In this review, we describe the differences in composition of commensal microbiota in the oral cavity and large intestine and the mechanisms by which microbiota affect the inflammatory and carcinogenic response of the host.

From genes to genomes: a new paradigm for studying fungal pathogenesis in Magnaporthe oryzae.

PubMed

Xu, Jin-Rong; Zhao, Xinhua; Dean, Ralph A

2007-01-01

Magnaporthe oryzae is the most destructive fungal pathogen of rice worldwide and because of its amenability to classical and molecular genetic manipulation, availability of a genome sequence, and other resources it has emerged as a leading model system to study host-pathogen interactions. This chapter reviews recent progress toward elucidation of the molecular basis of infection-related morphogenesis, host penetration, invasive growth, and host-pathogen interactions. Related information on genome analysis and genomic studies of plant infection processes is summarized under specific topics where appropriate. Particular emphasis is placed on the role of MAP kinase and cAMP signal transduction pathways and unique features in the genome such as repetitive sequences and expanded gene families. Emerging developments in functional genome analysis through large-scale insertional mutagenesis and gene expression profiling are detailed. The chapter concludes with new prospects in the area of systems biology, such as protein expression profiling, and highlighting remaining crucial information needed to fully appreciate host-pathogen interactions.

Candida esophagitis in an immunocompetent pregnant woman.

PubMed

Greenspoon, J S; Kivnick, S

1993-01-01

Nausea and vomiting are common during the first half of pregnancy and usually require only supportive measures. When symptoms are progressive and weight loss occurs, treatable causes should be sought by means of upper gastrointestinal endoscopy. We report a case of an immunocompetent gravida with invasive Candida albicans esophagitis. The immunocompetent primigravida developed progressive nausea, vomiting, epigastric pain, and a 4.1 kg weight loss during the second trimester of pregnancy. Treatment with metoclopramide and cimetidine for presumed gastroesophageal reflux was not effective. The patient had normal T-cell CD4 and CD8 subsets and was human immunodeficiency virus (HIV) antibody negative. Upper gastrointestinal endoscopy revealed C. albicans esophagitis which was treated with oral nystatin. The esophagitis had resolved completely when reassessed postpartum. The use of histamine(2) blockers is associated with an increased risk for fungal esophagitis and may have been a contributing cause in this case. Pregnant patients with persistent nausea, vomiting, and weight loss should be evaluated by endoscopy for fungal esophagitis.

Production of conidia by entomopathogenic fungi: from inoculants to final quality tests.

PubMed

Muñiz-Paredes, Facundo; Miranda-Hernández, Francisco; Loera, Octavio

2017-03-01

Demand for biopesticides is growing due to the increase of areas under integrated pest management worldwide. Conidia from entomopathogenic fungi play a major role as infective units in the current market of biopesticides. Success in a massive production of fungal conidia include the use of proper long-term conservation microbial methods, aimed at preserving the phenotypic traits of the strains. The development of suitable inoculants should also be considered since that favours a rapid germination and invasiveness of the substrate in solid state cultures (SSC). After the selection of a suitable fungal strain, proven optimization approaches for SSC mainly include the combination of substrates, moisture, texturizers, aeration and moderate stress to induce conidiation. Nonetheless, during storage and upon application in open fields, conidia either as free propagules or imbibed in formulations are subjected to stress due to abiotic factors, then quality should be preserved to resist such harsh conditions. All of these topics are analysed in this report.

Emerging infections due to filamentous fungi in humans and animals: only the tip of the iceberg?

PubMed

Debourgogne, Anne; Dorin, Joséphine; Machouart, Marie

2016-06-01

Over the last few decades, the number of patients susceptible to invasive filamentous fungal infections has steadily increased, especially in populations suffering from hematological diseases. The pathogens responsible for such mycoses are now quite well characterized, such as Aspergillus spp. - the most commonly isolated mold -, Mucorales, Fusarium spp., Scedosporium spp. or melanized fungi. An increase in the incidence of this category of 'emerging' fungi has been recently highlighted, evoking a shift in fungal ecology. Starting from these medical findings, taking a step back and adopt a wider perspective offers possible explanations of this phenomenon on an even larger scale than previously reported. In this review, we illustrate the link between emerging fungi in medicine and changes in ecology or human behaviours, and we encourage integrative approaches to apprehend the adverse effects of progress and develop preventive measures in vast domains, such as agriculture or medicine. © 2016 Society for Applied Microbiology and John Wiley & Sons Ltd.

Genetic polymorphisms in the cytokine and chemokine system: their possible importance in allogeneic stem cell transplantation.

PubMed

Loeffler, Juergen; Ok, Michael; Morton, Oliver C; Mezger, Markus; Einsele, Hermann

2010-01-01

Chemokines represent central players of the innate and adaptive immunity and are involved in the regulation of inflammatory events occurring during infectious complications or during graft vs. host disease (GvHD). Patients after allogeneic stem cell transplantation (alloSCT) are at a high risk for the development of acute GvHD or to suffer from fungal infections. Susceptibility to fungal infections and the course of GvHD can be genetically influenced by single nucleotide polymorphisms (SNPs), which regulate expression or biological activity of chemokines, and therefore have an impact on the outcome of invasive aspergillosis and GvHD. High lightened studies of abetting factors for GvHD revealed SNPs in TNFA, IL-6, IL-10, INF-γ, CCL2, CCL5 (RANTES), IL-1Ra, IL-23R, IL-7Ralpha, IL-10RB, and CCR9 genes as prevalent considerable. Furthermore, additional SNPs were described to be significantly associated with fungal infections (Aspergillus fumigatus, Candida albicans), including markers in CCL3, CCL4, CCL20, CXCL2, CXCL8, CXCL10, CCR1, and CCR2. This review summarizes the current knowledge about the growing number of genetic markers in chemokine genes and their relevance for patients after alloSCT.

Infective endocarditis and meningitis due to Scedosporium prolificans in a renal transplant recipient.

PubMed

Uno, Kenji; Kasahara, Kei; Kutsuna, Satoshi; Katanami, Yuichi; Yamamoto, Yoshifumi; Maeda, Koichi; Konishi, Mitsuru; Ogawa, Taku; Yoneda, Tatsuo; Yoshida, Katsunori; Kimura, Hiroshi; Mikasa, Keiichi

2014-02-01

Scedosporium prolificans is a ubiquitous filamentous fungi that may cause disseminated diseases in neutropenic patients with hematological malignancies. We report a fatal case of renal transplant recipient who developed both infective endocarditis and meningitis due to S. prolificans during treatment with micafungin and itraconazole for chronic necrotizing aspergillosis. Breakthrough Scedosporium infection should be considered among differential diagnosis of invasive fungal diseases in patients with renal transplant recipients receiving antifungal agents. Copyright © 2013 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Successful Treatment of Combined Aspergillus and Cytomegalovirus Abscess in Brain and Lung After Liver Transplant for Toxic Fulminant Hepatitis.

PubMed

Kim, Tae-Seok; Ahn, Keun Soo; Kim, Yong Hoon; Kim, Hyoung Tae; Jang, Byoung Kuk; Hwang, Jae Seok; Kim, Il-Man; Kang, Yu Na; Kang, Koo Jeong

2017-02-01

Invasive aspergillosis is one of the most important and fatal complications after liver transplant, especially in patients with involvement of the central nervous system. We present a case of a patient who developed cerebral and pulmonary aspergillosis, coinfected with cytomegalovirus, after liver transplant for toxic fulminant hepatitis. The patient was treated successfully with neurosurgical intervention and voriconazole. Voriconazole is considered more effective in cerebral aspergillosis than other anti-fungal agents due to the greater penetration into central nervous system and higher cerebrospinal fluid and brain tissue levels.

Decreased invasive fungal disease but no impact on overall survival by posaconazole compared to fluconazole prophylaxis: a retrospective cohort study in patients receiving induction therapy for acute myeloid leukaemia/myelodysplastic syndromes.

PubMed

Dahlén, Torsten; Kalin, Mats; Cederlund, Kerstin; Nordlander, Anna; Björkholm, Magnus; Ljungman, Per; Blennow, Ola

2016-02-01

Posaconazole prophylaxis during induction chemotherapy for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) has been shown to significantly decrease the incidence of invasive fungal disease (IFD) and increase overall survival in a trial setting, but only small real-life studies have been published. This was a retrospective cohort study including consecutive patients with AML/MDS treated with intensive induction chemotherapy; 176 patients received fluconazole prophylaxis 2008-2011 and 107 patients received posaconazole prophylaxis 2011-2013. Only proven and probable IFD according to the revised EORTC/MSG criteria were included in the analysis. The two cohorts were well matched without significant differences in patient characteristics. At day 100, patients receiving posaconazole had a significantly lower incidence of total IFD (0.9% vs. 10.8%, P < 0.01), invasive aspergillosis (0% vs. 5.7%, P = 0.02) and invasive candidiasis (0% vs. 4.0%, P < 0.05). There was no significant difference in overall survival, neither at day 100 (87% in the posaconazole group vs. 85% in the fluconazole group) nor at end of follow-up (78% vs. 77%). Posaconazole prophylaxis decreased the incidence of IFD but did not improve short-term overall survival. Improved treatment efficacy of manifest IFD is likely to explain the lack of survival benefit. © 2015 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.

Spinal aspergillus abscess in a patient with bronchocentric granulomatosis.

PubMed

Collier, J; Wolfe, R; Lerner, R; Nathan, S; Mohsenifar, Z

1995-01-01

Aspergillus fumigatus hyphae is often found in the lung tissue of patients with bronchocentric granulomatosis (BCG). This organism is believed to be one agent responsible for inciting the hypersensitivity response and subsequent development of the characteristic pathology that defines BCG. The definitive etiology of this disease, however, remains conjectural. Corticosteroids represent the mainstay of therapy. The fungi recovered from patients with BCG are considered noninvasive; thus, the risk of fungal invasion secondary to steroid-induced immunosuppression is believed to be negligible. However, we report a case of spinal aspergillus abscess that developed in a patient with BCG subsequent to steroid therapy. This case also highlights the necessity for aggressive medical and neurosurgical intervention to avert the development of neurological sequelae.

Macrophage–Microbe Interactions: Lessons from the Zebrafish Model

PubMed Central

Yoshida, Nagisa; Frickel, Eva-Maria; Mostowy, Serge

2017-01-01

Macrophages provide front line defense against infections. The study of macrophage–microbe interplay is thus crucial for understanding pathogenesis and infection control. Zebrafish (Danio rerio) larvae provide a unique platform to study macrophage–microbe interactions in vivo, from the level of the single cell to the whole organism. Studies using zebrafish allow non-invasive, real-time visualization of macrophage recruitment and phagocytosis. Furthermore, the chemical and genetic tractability of zebrafish has been central to decipher the complex role of macrophages during infection. Here, we discuss the latest developments using zebrafish models of bacterial and fungal infection. We also review novel aspects of macrophage biology revealed by zebrafish, which can potentiate development of new therapeutic strategies for humans. PMID:29250076

Invasive mold infections: virulence and pathogenesis of mucorales.

PubMed

Morace, Giulia; Borghi, Elisa

2012-01-01

Mucorales have been increasingly reported as cause of invasive fungal infections in immunocompromised subjects, particularly in patients with haematological malignancies or uncontrolled diabetes mellitus and in those under deferoxamine treatment or undergoing dialysis. The disease often leads to a fatal outcome, but the pathogenesis of the infection is still poorly understood as well as the role of specific virulence determinants and the interaction with the host immune system. Members of the order Mucorales are responsible of almost all cases of invasive mucormycoses, the majority of the etiological agents belonging to the Mucoraceae family. Mucorales are able to produce various proteins and metabolic products toxic to animals and humans, but the pathogenic role of these potential virulence factors is unknown. The availability of free iron in plasma and tissues is believed to be crucial for the pathogenesis of these mycoses. Vascular invasion and neurotropism are considered common pathogenic features of invasive mucormycoses.

A Common Fungal Associate of the Spruce Bark Beetle Metabolizes the Stilbene Defenses of Norway Spruce1[C][W][OA

PubMed Central

Hammerbacher, Almuth; Schmidt, Axel; Wadke, Namita; Wright, Louwrance P.; Schneider, Bernd; Bohlmann, Joerg; Brand, Willi A.; Fenning, Trevor M.; Gershenzon, Jonathan; Paetz, Christian

2013-01-01

Norway spruce (Picea abies) forests suffer periodic fatal attacks by the bark beetle Ips typographus and its fungal associate, Ceratocystis polonica. Norway spruce protects itself against fungal and bark beetle invasion by the production of terpenoid resins, but it is unclear whether resins or other defenses are effective against the fungus. We investigated stilbenes, a group of phenolic compounds found in Norway spruce bark with a diaryl-ethene skeleton with known antifungal properties. During C. polonica infection, stilbene biosynthesis was up-regulated, as evidenced by elevated transcript levels of stilbene synthase genes. However, stilbene concentrations actually declined during infection, and this was due to fungal metabolism. C. polonica converted stilbenes to ring-opened, deglycosylated, and dimeric products. Chromatographic separation of C. polonica protein extracts confirmed that these metabolites arose from specific fungal enzyme activities. Comparison of C. polonica strains showed that rapid conversion of host phenolics is associated with higher virulence. C. polonica is so well adapted to its host’s chemical defenses that it is even able to use host phenolic compounds as its sole carbon source. PMID:23729780

Host-induced aneuploidy and phenotypic diversification in the Sudden Oak Death pathogen Phytophthora ramorum

USDA-ARS?s Scientific Manuscript database

Aneuploidy can result in significant phenotypic changes, which can sometimes be selectively advantageous. For example, aneuploidy confers resistance to antifungal drugs in human pathogenic fungi. Aneuploidy has also been observed in invasive fungal and oomycete plant pathogens in the field. Environm...

Bipolaris drechsleri Manamgoda & A.M. Minnis, sp. nov

USDA-ARS?s Scientific Manuscript database

The host Microstegium vimineum (Trin.) A. Camus, common name Japanese stilt grass, is an annual grass in the Poaceae, subfamily Panicoidiae, tribe Andropogonae. Currently M. vimineum is one of a serious non-native invasive species in the eastern United States. The fungal genus Bipolaris includes a n...

Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).

PubMed

Pappas, Peter G; Alexander, Barbara D; Andes, David R; Hadley, Susan; Kauffman, Carol A; Freifeld, Alison; Anaissie, Elias J; Brumble, Lisa M; Herwaldt, Loreen; Ito, James; Kontoyiannis, Dimitrios P; Lyon, G Marshall; Marr, Kieren A; Morrison, Vicki A; Park, Benjamin J; Patterson, Thomas F; Perl, Trish M; Oster, Robert A; Schuster, Mindy G; Walker, Randall; Walsh, Thomas J; Wannemuehler, Kathleen A; Chiller, Tom M

2010-04-15

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.

Temporal Effects on Internal Fluorescence Emissions Associated with Aflatoxin Contamination from Corn Kernel Cross-Sections Inoculated with Toxigenic and Atoxigenic Aspergillus flavus.

PubMed

Hruska, Zuzana; Yao, Haibo; Kincaid, Russell; Brown, Robert L; Bhatnagar, Deepak; Cleveland, Thomas E

2017-01-01

Non-invasive, easy to use and cost-effective technology offers a valuable alternative for rapid detection of carcinogenic fungal metabolites, namely aflatoxins, in commodities. One relatively recent development in this area is the use of spectral technology. Fluorescence hyperspectral imaging, in particular, offers a potential rapid and non-invasive method for detecting the presence of aflatoxins in maize infected with the toxigenic fungus Aspergillus flavus . Earlier studies have shown that whole maize kernels contaminated with aflatoxins exhibit different spectral signatures from uncontaminated kernels based on the external fluorescence emission of the whole kernels. Here, the effect of time on the internal fluorescence spectral emissions from cross-sections of kernels infected with toxigenic and atoxigenic A. flavus , were examined in order to elucidate the interaction between the fluorescence signals emitted by some aflatoxin contaminated maize kernels and the fungal invasion resulting in the production of aflatoxins. First, the difference in internal fluorescence emissions between cross-sections of kernels incubated in toxigenic and atoxigenic inoculum was assessed. Kernels were inoculated with each strain for 5, 7, and 9 days before cross-sectioning and imaging. There were 270 kernels (540 halves) imaged, including controls. Second, in a different set of kernels (15 kernels/group; 135 total), the germ of each kernel was separated from the endosperm to determine the major areas of aflatoxin accumulation and progression over nine growth days. Kernels were inoculated with toxigenic and atoxigenic fungal strains for 5, 7, and 9 days before the endosperm and germ were separated, followed by fluorescence hyperspectral imaging and chemical aflatoxin determination. A marked difference in fluorescence intensity was shown between the toxigenic and atoxigenic strains on day nine post-inoculation, which may be a useful indicator of the location of aflatoxin contamination. This finding suggests that both, the fluorescence peak shift and intensity as well as timing, may be essential in distinguishing toxigenic and atoxigenic fungi based on spectral features. Results also reveal a possible preferential difference in the internal colonization of maize kernels between the toxigenic and atoxigenic strains of A. flavus suggesting a potential window for differentiating the strains based on fluorescence spectra at specific time points.

Temporal Effects on Internal Fluorescence Emissions Associated with Aflatoxin Contamination from Corn Kernel Cross-Sections Inoculated with Toxigenic and Atoxigenic Aspergillus flavus

PubMed Central

Hruska, Zuzana; Yao, Haibo; Kincaid, Russell; Brown, Robert L.; Bhatnagar, Deepak; Cleveland, Thomas E.

2017-01-01

Non-invasive, easy to use and cost-effective technology offers a valuable alternative for rapid detection of carcinogenic fungal metabolites, namely aflatoxins, in commodities. One relatively recent development in this area is the use of spectral technology. Fluorescence hyperspectral imaging, in particular, offers a potential rapid and non-invasive method for detecting the presence of aflatoxins in maize infected with the toxigenic fungus Aspergillus flavus. Earlier studies have shown that whole maize kernels contaminated with aflatoxins exhibit different spectral signatures from uncontaminated kernels based on the external fluorescence emission of the whole kernels. Here, the effect of time on the internal fluorescence spectral emissions from cross-sections of kernels infected with toxigenic and atoxigenic A. flavus, were examined in order to elucidate the interaction between the fluorescence signals emitted by some aflatoxin contaminated maize kernels and the fungal invasion resulting in the production of aflatoxins. First, the difference in internal fluorescence emissions between cross-sections of kernels incubated in toxigenic and atoxigenic inoculum was assessed. Kernels were inoculated with each strain for 5, 7, and 9 days before cross-sectioning and imaging. There were 270 kernels (540 halves) imaged, including controls. Second, in a different set of kernels (15 kernels/group; 135 total), the germ of each kernel was separated from the endosperm to determine the major areas of aflatoxin accumulation and progression over nine growth days. Kernels were inoculated with toxigenic and atoxigenic fungal strains for 5, 7, and 9 days before the endosperm and germ were separated, followed by fluorescence hyperspectral imaging and chemical aflatoxin determination. A marked difference in fluorescence intensity was shown between the toxigenic and atoxigenic strains on day nine post-inoculation, which may be a useful indicator of the location of aflatoxin contamination. This finding suggests that both, the fluorescence peak shift and intensity as well as timing, may be essential in distinguishing toxigenic and atoxigenic fungi based on spectral features. Results also reveal a possible preferential difference in the internal colonization of maize kernels between the toxigenic and atoxigenic strains of A. flavus suggesting a potential window for differentiating the strains based on fluorescence spectra at specific time points. PMID:28966606

Rapid diagnosis of tinea incognito using handheld reflectance confocal microscopy: a paradigm shift in dermatology?

PubMed

Navarrete-Dechent, Cristián; Bajaj, Shirin; Marghoob, Ashfaq A; Marchetti, Michael A

2015-06-01

Dermatophytoses are common skin infections. Traditional diagnostic tests such as skin scrapings for light microscopy examination, fungal cultures and biopsies remain imperfect due to false-negative test results, cost, time required to perform the procedure, time delays in test results and/or a requirement for an invasive procedure. Herein, we present a case of an 80-year-old female whose tinea incognito was non-invasively diagnosed within seconds using handheld reflectance confocal microscopy (RCM). As non-invasive skin imaging continues to improve, we expect light-based office microscopy to be replaced with technologies such as RCM, which has multiple and continually expanding diagnostic applications. © 2015 Blackwell Verlag GmbH.

Role of histopathology as an aid to prognosis in rhino-orbito-cerebral zygomycosis.

PubMed

Goel, Ashina; Kini, Usha; Shetty, Subhaschandra

2010-01-01

Rhino-orbito-cerebral zygomycosis is a rapidly progressive opportunistic fungal infection characterized by a set of clinical and radiological findings that help in prognostication. The present study is aimed to evaluate its histopathologic features as an aid to prognosis in order to guide the physician at the stage of tissue diagnosis to optimize surgery, chemotherapy and immunosuppression. The study comprises of a microscopic analysis of specific histopathologic variables on 33 cases of zygomycosis that were diagnosed and treated in a seven-year period. Fungal load in the tissue (graded as mild, moderate and marked), mean diameter of fungus, degree of neutrophilic and granulomatous response, tissue invasion and necrosis were graded and assessed for their prognostic significance. Seasonal variation, signs and symptoms, extent of involvement and laboratory parameters were also analyzed to examine the trend of occurrence of the disease and to associate these with patient's outcome, which was categorized as either survived or expired. The follow-up ranged from 1 month to 7 years. Of all the histological variables, angioinvasion was directly related to the mortality rate. Diameter of the fungal hyphae and its intraorbital or intracranial invasion also proved to be significant indicators of poor prognosis. (P = 0.04 and 0.0037, respectively) though angioinvasion was directly related to the mortality rate. Thus, histopathology could assist the clinician in assessing patient's progress and thus optimize the treatment in such patients.

Entry Mode–Dependent Function of an Indole Glucosinolate Pathway in Arabidopsis for Nonhost Resistance against Anthracnose Pathogens[W

PubMed Central

Hiruma, Kei; Onozawa-Komori, Mariko; Takahashi, Fumika; Asakura, Makoto; Bednarek, Paweł; Okuno, Tetsuro; Schulze-Lefert, Paul; Takano, Yoshitaka

2010-01-01

When faced with nonadapted fungal pathogens, Arabidopsis thaliana mounts nonhost resistance responses, which typically result in the termination of early pathogenesis steps. We report that nonadapted anthracnose fungi engage two alternative entry modes during pathogenesis on leaves: turgor-mediated invasion beneath melanized appressoria, and a previously undiscovered hyphal tip–based entry (HTE) that is independent of appressorium formation. The frequency of HTE is positively regulated by carbohydrate nutrients and appears to be subject to constitutive inhibition by the fungal mitogen-activated protein kinase (MAPK) cascade of MAPK ESSENTIAL FOR APPRESSORIUM FORMATION1. The same MAPK cascade is essential for appressorium formation. Unexpectedly, the Arabidopsis indole glucosinolate pathway restricts entry of the nonadapted anthracnose fungi only when these pathogens employ HTE. Arabidopsis mutants defective in indole glucosinolate biosynthesis or metabolism support the initiation of postinvasion growth of nonadapted Colletotrichum gloeosporioides and Colletotrichum orbiculare. However, genetic disruption of Colletotrichum appressorium formation does not permit HTE on host plants. Thus, Colletotrichum appressoria play a critical role in the suppression of preinvasion plant defenses, in addition to their previously described role in turgor-mediated plant cell invasion. We also show that HTE is the predominant morphogenetic response of Colletotrichum at wound sites. This implies the existence of a fungal sensing system to trigger appropriate morphogenetic responses during pathogenesis at wound sites and on intact leaf tissue. PMID:20605856

Amid the possible causes of a very famous foxing: molecular and microscopic insight into Leonardo da Vinci's self-portrait.

PubMed

Piñar, Guadalupe; Tafer, Hakim; Sterflinger, Katja; Pinzari, Flavia

2015-12-01

Leonardo da Vinci's self-portrait is affected by foxing spots. The portrait has no fungal or bacterial infections in place, but is contaminated with airborne spores and fungal material that could play a role in its disfigurement. The knowledge of the nature of the stains is of great concern because future conservation treatments should be derived from scientific investigations. The lack of reliable scientific data, due to the non-culturability of the microorganisms inhabiting the portrait, prompted the investigation of the drawing using non-invasive and micro-invasive sampling, in combination with scanning electron microscope (SEM) imaging and molecular techniques. The fungus Eurotium halophilicum was found in foxing spots using SEM analyses. Oxalates of fungal origin were also documented. Both findings are consistent with the hypothesis that tonophilic fungi germinate on paper metabolizing organic acids, oligosaccharides and proteic compounds, which react chemically with the material at a low water activity, forming brown products and oxidative reactions resulting in foxing spots. Additionally, molecular techniques enabled a screening of the fungi inhabiting the portrait and showed differences when different sampling techniques were employed. Swabs samples showed a high abundance of lichenized Ascomycota, while the membrane filters showed a dominance of Acremonium sp. colonizing the drawing. © 2015 The Authors. Environmental Microbiology Reports published by Society for Applied Microbiology and John Wiley & Sons Ltd.

Bloodstream infections in patients with hematological malignancies: which is more fatal – cancer or resistant pathogens?

PubMed Central

Gedik, Habip; Şimşek, Funda; Kantürk, Arzu; Yildirmak, Taner; Arica, Deniz; Aydin, Demet; Demirel, Naciye; Yokuş, Osman

2014-01-01

Background The primary objective of this study was to report the incidence of bloodstream infections (BSIs) and clinically or microbiologically proven bacterial or fungal BSIs during neutropenic episodes in patients with hematological malignancies. Methods In this retrospective observational study, all patients in the hematology department older than 14 years who developed febrile neutropenia during chemotherapy for hematological cancers were evaluated. Patients were included if they had experienced at least one neutropenic episode between November 2010 and November 2012 due to chemotherapy in the hematology ward. Results During 282 febrile episodes in 126 patients, 66 (23%) episodes of bacteremia and 24 (8%) episodes of fungemia were recorded in 48 (38%) and 18 (14%) patients, respectively. Gram-negative bacteria caused 74% (n=49) of all bacteremic episodes. Carbapenem-resistant Gram-negative bacteria (n=6) caused 12% and 9% of Gram-negative bacteremia episodes and all bacteremia episodes, respectively. Carbapenem-resistant Gram-negative bacteria included Acinetobacter baumannii (n=4), Pseudomonas aeruginosa (n=1), and Serratia marcescens (n=1). Culture-proven invasive fungal infection occurred in 24 episodes in 18 cases during the study period, with 15 episodes in ten cases occurring in the first study year and nine episodes in eight cases in the second study year. In 13 of 18 cases (72%) with bloodstream yeast infections, previous azole exposure was recorded. Candida parapsilosis, C. glabrata, and C. albicans isolates were resistant to voriconazole and fluconazole. Conclusion BSIs that occur during febrile neutropenic episodes in hematology patients due to Gram-negative bacteria should be treated initially with non-carbapenem-based antipseudomonal therapy taking into consideration antimicrobial stewardship. Non-azole antifungal drugs, including caspofungin and liposomal amphotericin B, should be preferred as empirical antifungal therapy in the events of possible or probable invasive fungal infections with an absence of pulmonary findings due to increase azole resistance. PMID:25258539

TIL-type protease inhibitors may be used as targeted resistance factors to enhance silkworm defenses against invasive fungi.

PubMed

Li, Youshan; Zhao, Ping; Liu, Huawei; Guo, Xiaomeng; He, Huawei; Zhu, Rui; Xiang, Zhonghuai; Xia, Qingyou

2015-02-01

Entomopathogenic fungi penetrate the insect cuticle using their abundant hydrolases. These hydrolases, which include cuticle-degrading proteases and chitinases, are important virulence factors. Our recent findings suggest that many serine protease inhibitors, especially TIL-type protease inhibitors, are involved in insect resistance to pathogenic microorganisms. To clarify the molecular mechanism underlying this resistance to entomopathogenic fungi and identify novel genes to improve the silkworm antifungal capacity, we conducted an in-depth study of serine protease inhibitors. Here, we cloned and expressed a novel silkworm TIL-type protease inhibitor, BmSPI39. In activity assays, BmSPI39 potently inhibited the virulence protease CDEP-1 of Beauveria bassiana, suggesting that it might suppress the fungal penetration of the silkworm integument by inhibiting the cuticle-degrading proteases secreted by the fungus. Phenol oxidase activation studies showed that melanization is involved in the insect immune response to fungal invasion, and that fungus-induced excessive melanization is suppressed by BmSPI39 by inhibiting the fungal cuticle-degrading proteases. To better understand the mechanism involved in the inhibition of fungal virulence by protease inhibitors, their effects on the germination of B. bassiana conidia was examined. BmSPI38 and BmSPI39 significantly inhibited the germination of B. bassiana conidia. Survival assays showed that BmSPI38 and BmSPI39 markedly improved the survival rates of silkworms, and can therefore be used as targeted resistance proteins in the silkworm. These results provided new insight into the molecular mechanisms whereby insect protease inhibitors confer resistance against entomopathogenic fungi, suggesting their potential application in medicinal or agricultural fields. Copyright © 2014 Elsevier Ltd. All rights reserved.

[The burden of fungal infections in Algeria].

PubMed

Chekiri-Talbi, M; Denning, D W

2017-06-01

In Algeria, superficial mycoses are very commonly diagnosed. Deep fungal infections are less often observed. Few data from Algeria are found in the literature. We report for the first time the main causes of these diseases in our country and provide burden estimates. We searched for existing data and estimated the incidence and prevalence of fungal diseases based on the population at risk and available epidemiological data. Demographic data were derived from the Service (Office) of the Statistics (ONES), World Health Organization (WHO), The Joint Nations Programme on HIV/AIDS (UNAIDS) and national published reports. When no data existed, risk populations were used to estimate frequencies of fungal infections, using previously described methodology. Algeria has 40.4 million inhabitants and probably at least 568,900 (1.41 %) of Algerians have a serious fungal infection each year. Recurrent vulvovaginal candidiasis (485,000) and fungal asthma (72,000) are probably the commonest problems as there are over 1 million adult asthmatics. Candidaemia is estimated in 2020, invasive aspergillosis in 2865, intra-abdominal candidiasis in 303 people and are the most common life-threatening problems. AIDS is uncommon, but cancer is not (45,000 new cases of cancer among including 1500 in children) and nor is COPD (an estimated 317,762 patients of whom 20.3 % are admitted to hospital each year). A focus on improving the diagnosis and epidemiological data related to fungal infection is necessary in Algeria. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Invasive candidiasis: future directions in non-culture based diagnosis.

PubMed

Posch, Wilfried; Heimdörfer, David; Wilflingseder, Doris; Lass-Flörl, Cornelia

2017-09-01

Delayed initial antifungal therapy is associated with high mortality rates caused by invasive candida infections, since accurate detection of the opportunistic pathogenic yeast and its identification display a diagnostic challenge. diagnosis of candida infections relies on time-consuming methods such as blood cultures, serologic and histopathologic examination. to allow for fast detection and characterization of invasive candidiasis, there is a need to improve diagnostic tools. trends in diagnostics switch to non-culture-based methods, which allow specified diagnosis within significantly shorter periods of time in order to provide early and appropriate antifungal treatment. Areas covered: within this review comprise novel pathogen- and host-related testing methods, e.g. multiplex-PCR analyses, T2 magnetic resonance, fungus-specific DNA microarrays, microRNA characterization or analyses of IL-17 as biomarker for early detection of invasive candidiasis. Expert commentary: Early recognition and diagnosis of fungal infections is a key issue for improved patient management. As shown in this review, a broad range of novel molecular based tests for the detection and identification of Candida species is available. However, several assays are in-house assays and lack standardization, clinical validation as well as data on sensitivity and specificity. This underscores the need for the development of faster and more accurate diagnostic tests.

Fluconazole prophylaxis in preterm infants: a systematic review.

PubMed

Rios, Juliana Ferreira da Silva; Camargos, Paulo Augusto Moreira; Corrêa, Luísa Petri; Romanelli, Roberta Maia de Castro

This article aims to review the use of antifungal prophylaxis with intravenous fluconazole in premature newborns and the occurrence of Invasive Candidiasis. This is a systematic review with search at databases: PubMed, Capes Portal, Virtual Health Library (BVS - Biblioteca Virtual em Saúde)/Lilacs, Scopus and Cochrane. The keywords used were: "Antifungal", "Candida" "Fluconazole prophylaxis" and "Preterm infants". Invasive Candidiasis was evaluated in all the twelve items. In eleven of them, there was a statistically significant difference between the groups receiving prophylactic fluconazole, with lower frequency of Invasive Candidiasis, compared to placebo or no prophylaxis group. Colonization by Candida species was also evaluated in five studies; four of them presented statistically lower proportion of colonization in patients with Fluconazole prophylaxis, compared to placebo or no drugs. In one study, there was a significant difference, favoring the use of fluconazole, and reduction of death. Studies indicate the effectiveness of prophylaxis with fluconazole, with reduction in the incidence of colonization and invasive fungal disease. The benefits of prophylaxis should be evaluated considering the incidence of candidiasis in the unit, the mortality associated with candidiasis, the safety and toxicity of short and long-term medication, and the potential for development of resistant pathogens. Copyright © 2017 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.

Insecticide dip treatments to prevent walnut twig beetle colonization of black walnut logs

Treesearch

Jackson Audley; Adam Taylor; William E. Klingeman; Albert (Bud) Mayfield; Scott W. Myers

2016-01-01

The health, sustainability, and commercial viability of eastern black walnut (Juglans nigra) are currently under threat from thousand cankers disease. The disease is caused by an invasive bark beetle species, the walnut twig beetle (Pityophthorus juglandis), and its associated fungal pathogen (Geosmithia morbida...

Response of soybean fungal and oomycete pathogens to apigenin and genistein

USDA-ARS?s Scientific Manuscript database

Plants recognize invading pathogens and respond biochemically to prevent invasion or inhibit the colonization of plant cells. Many plant defense compounds are flavonoids and some of these are known to have a broad spectrum of biological activity. In this study, we tested two flavonoids, apigenin and...

Chemical ecology of Xyleborus glabratus: Attractants for detection and monitoring

USDA-ARS?s Scientific Manuscript database

The redbay ambrosia beetle, Xyleborus glabratus Eichhoff, is endemic to Southeast Asia, but over the past decade it has become a serious invasive pest of both agriculture and forest ecosystems in the USA. Females of X. glabratus are the primary vector of a fungal pathogen (Raffaelea lauricola) that...

Comparison of ambrosia beetle communities in two hosts with laurel wilt: swampbay vs. avocado

USDA-ARS?s Scientific Manuscript database

The invasive redbay ambrosia beetle, Xyleborus glabratus (Coleoptera: Curculionidae: Scolytinae), is an exotic wood-boring pest first detected in 2002 near Savannah, Georgia. The beetle’s dominant fungal symbiont, Raffaelea lauricola, is the pathogen that causes laurel wilt, a lethal disease of tre...

Ambrosia beetle communities in forest and agriculture ecosystems with laurel wilt disease

USDA-ARS?s Scientific Manuscript database

The invasive redbay ambrosia beetle, Xyleborus glabratus, is an exotic wood-boring pest first detected in 2002 near Savannah, Georgia. The beetle’s dominant fungal symbiont, Raffaelea lauricola, is the pathogen that causes laurel wilt, a lethal disease of trees in the family Lauraceae. Redbay ambro...

Spatio-temporal analysis of Xyleborus glabratus (Coleoptera: Circulionidae: Scolytinae) invasion in Eastern U.S. forests

Treesearch

F. H. Koch; W. D. Smith

2008-01-01

The non-native redbay ambrosia beetle, Xyleborus glabratus Eichhoff (Coleoptera: Curculionidae: Scolytinae), has recently emerged as a significant pest of southeastern u.s. coastal forests. Specifically, a fungal symbiont (Raffaelea sp.) of X. glabratus has caused mortality of redbay (Persea borbonia...

A prospective survey of air and surface fungal contamination in a medical mycology laboratory at a tertiary care university hospital.

PubMed

Sautour, Marc; Dalle, Frédéric; Olivieri, Claire; L'ollivier, Coralie; Enderlin, Emilie; Salome, Elsa; Chovelon, Isabelle; Vagner, Odile; Sixt, Nathalie; Fricker-Pap, Véronique; Aho, Serge; Fontaneau, Olivier; Cachia, Claire; Bonnin, Alain

2009-04-01

Invasive filamentous fungi infections resulting from inhalation of mold conidia pose a major threat in immunocompromised patients. The diagnosis is based on direct smears, cultural symptoms, and culturing fungi. Airborne conidia present in the laboratory environment may cause contamination of cultures, resulting in false-positive diagnosis. Baseline values of fungal contamination in a clinical mycology laboratory have not been determined to date. A 1-year prospective survey of air and surface contamination was conducted in a clinical mycology laboratory during a period when large construction projects were being conducted in the hospital. Air was sampled with a portable air system impactor, and surfaces were sampled with contact Sabouraud agar plates. The collected data allowed the elaboration of Shewhart graphic charts. Mean fungal loads ranged from 2.27 to 4.36 colony forming units (cfu)/m(3) in air and from 0.61 to 1.69 cfu/plate on surfaces. Strict control procedures may limit the level of fungal contamination in a clinical mycology laboratory even in the context of large construction projects at the hospital site. Our data and the resulting Shewhart graphic charts provide baseline values to use when monitoring for inappropriate variations of the fungal contamination in a mycology laboratory as part of a quality assurance program. This is critical to the appropriate management of the fungal risk in hematology, cancer and transplantation patients.

Candida parapsilosis Protects Premature Intestinal Epithelial Cells from Invasion and Damage by Candida albicans

PubMed Central

Gonia, Sara; Archambault, Linda; Shevik, Margaret; Altendahl, Marie; Fellows, Emily; Bliss, Joseph M.; Wheeler, Robert T.; Gale, Cheryl A.

2017-01-01

Candida is a leading cause of late-onset sepsis in premature infants and is thought to invade the host via immature or damaged epithelial barriers. We previously showed that the hyphal form of Candida albicans invades and causes damage to premature intestinal epithelial cells (pIECs), whereas the non-hyphal Candida parapsilosis, also a fungal pathogen of neonates, has less invasion and damage abilities. In this study, we investigated the potential for C. parapsilosis to modulate pathogenic interactions of C. albicans with the premature intestine. While a mixed infection with two fungal pathogens may be expected to result in additive or synergistic damage to pIECs, we instead found that C. parapsilosis was able to protect pIECs from invasion and damage by C. albicans. C. albicans-induced pIEC damage was reduced to a similar extent by multiple different C. parapsilosis strains, but strains differed in their ability to inhibit C. albicans invasion of pIECs, with the inhibitory activity correlating with their adhesiveness for C. albicans and epithelial cells. C. parapsilosis cell-free culture fractions were also able to significantly reduce C. albicans adhesion and damage to pIECs. Furthermore, coadministration of C. parapsilosis cell-free fractions with C. albicans was associated with decreased infection and mortality in zebrafish. These results indicate that C. parapsilosis is able to reduce invasion, damage, and virulence functions of C. albicans. Additionally, the results with cellular and cell-free fractions of yeast cultures suggest that inhibition of pathogenic interactions between C. albicans and host cells by C. parapsilosis occurs via secreted molecules as well as by physical contact with the C. parapsilosis cell surface. We propose that non-invasive commensals can be used to inhibit virulence features of pathogens and deserve further study as a non-pharmacological strategy to protect the fragile epithelial barriers of premature infants. PMID:28382297

Rapid Host Defense against Aspergillus fumigatus Involves Alveolar Macrophages with a Predominance of Alternatively Activated Phenotype

PubMed Central

Bhatia, Shikha; Fei, Mingjian; Yarlagadda, Manohar; Qi, Zengbiao; Akira, Shizuo; Saijo, Shinobu; Iwakura, Yoichiro; van Rooijen, Nico; Gibson, Gregory A.; St. Croix, Claudette M.; Ray, Anuradha; Ray, Prabir

2011-01-01

The ubiquitous fungus Aspergillus fumigatus is associated with chronic diseases such as invasive pulmonary aspergillosis in immunosuppressed patients and allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis or severe asthma. Because of constant exposure to this fungus, it is critical for the host to exercise an immediate and decisive immune response to clear fungal spores to ward off disease. In this study, we observed that rapidly after infection by A. fumigatus, alveolar macrophages predominantly express Arginase 1 (Arg1), a key marker of alternatively activated macrophages (AAMs). The macrophages were also found to express Ym1 and CD206 that are also expressed by AAMs but not NOS2, which is expressed by classically activated macrophages. The expression of Arg1 was reduced in the absence of the known signaling axis, IL-4Rα/STAT6, for AAM development. While both Dectin-1 and TLR expressed on the cell surface have been shown to sense A. fumigatus, fungus-induced Arg1 expression in CD11c+ alveolar macrophages was not dependent on either Dectin-1 or the adaptor MyD88 that mediates intracellular signaling by most TLRs. Alveolar macrophages from WT mice efficiently phagocytosed fungal conidia, but those from mice deficient in Dectin-1 showed impaired fungal uptake. Depletion of macrophages with clodronate-filled liposomes increased fungal burden in infected mice. Collectively, our studies suggest that alveolar macrophages, which predominantly acquire an AAM phenotype following A. fumigatus infection, have a protective role in defense against this fungus. PMID:21246055

Successful Treatment of Disseminated Cryptococcal Infection in a Pediatric Acute Lymphoblastic Leukemia Patient During Induction

PubMed Central

Heath, Jessica L.; Yin, Dwight E.; Wechsler, Daniel S.; Turner, David A.

2015-01-01

Disseminated cryptococcal infection is rarely reported in the setting of pediatric acute leukemia, despite the immunocompromised state of these patients. However, when present, disseminated cryptococcal infection poses treatment challenges and is associated with significant morbidity and mortality. Treatment of invasive fungal disease in a child with acute leukemia requires a delicate balance between anti-fungal and anti-neoplastic therapy. This balance is particularly important early in the course of leukemia, since both the underlying disease and overwhelming infection can be life threatening. We describe the successful management of life-threatening disseminated cryptococcosis in a child with acute lymphoblastic leukemia during induction therapy. PMID:22258349

Gene flow contributes to diversification of the major fungal pathogen Candida albicans.

PubMed

Ropars, Jeanne; Maufrais, Corinne; Diogo, Dorothée; Marcet-Houben, Marina; Perin, Aurélie; Sertour, Natacha; Mosca, Kevin; Permal, Emmanuelle; Laval, Guillaume; Bouchier, Christiane; Ma, Laurence; Schwartz, Katja; Voelz, Kerstin; May, Robin C; Poulain, Julie; Battail, Christophe; Wincker, Patrick; Borman, Andrew M; Chowdhary, Anuradha; Fan, Shangrong; Kim, Soo Hyun; Le Pape, Patrice; Romeo, Orazio; Shin, Jong Hee; Gabaldon, Toni; Sherlock, Gavin; Bougnoux, Marie-Elisabeth; d'Enfert, Christophe

2018-06-08

Elucidating population structure and levels of genetic diversity and recombination is necessary to understand the evolution and adaptation of species. Candida albicans is the second most frequent agent of human fungal infections worldwide, causing high-mortality rates. Here we present the genomic sequences of 182 C. albicans isolates collected worldwide, including commensal isolates, as well as ones responsible for superficial and invasive infections, constituting the largest dataset to date for this major fungal pathogen. Although, C. albicans shows a predominantly clonal population structure, we find evidence of gene flow between previously known and newly identified genetic clusters, supporting the occurrence of (para)sexuality in nature. A highly clonal lineage, which experimentally shows reduced fitness, has undergone pseudogenization in genes required for virulence and morphogenesis, which may explain its niche restriction. Candida albicans thus takes advantage of both clonality and gene flow to diversify.

The microbiome-metabolome crosstalk in the pathogenesis of respiratory fungal diseases.

PubMed

Gonçalves, Samuel M; Lagrou, Katrien; Duarte-Oliveira, Cláudio; Maertens, Johan A; Cunha, Cristina; Carvalho, Agostinho

2017-08-18

Filamentous fungi of the genus Aspergillus are responsible for several superficial and invasive infections and allergic syndromes. The risk of infection and its clinical outcome vary significantly even among patients with similar predisposing clinical factors and pathogen exposure. There is increasing evidence that the individual microbiome supervises the outcome of the host-fungus interaction by influencing mechanisms of immune regulation, inflammation, metabolism, and other physiological processes. Microbiome-mediated mechanisms of resistance allow therefore the control of fungal colonization, preventing the onset of overt disease, particularly in patients with underlying immune dysfunction. Here, we review this emerging area of research and discuss the contribution of the microbiota (and its dysbiosis), including its immunoregulatory properties and relationship with the metabolic activity of commensals, to respiratory fungal diseases. Finally, we highlight possible strategies aimed at decoding the microbiome-metabolome dialog and at its exploitation toward personalized medical interventions in patients at high risk of infection.

Hormones and the Resistance of Women to Paracoccidioidomycosis

PubMed Central

Shankar, Jata; Restrepo, Angela; Clemons, Karl V.; Stevens, David A.

2011-01-01

Summary: Paracoccidioidomycosis, one of the most important endemic and systemic mycoses in Latin America, presents several clinical pictures. Epidemiological studies indicate a striking rarity of disease (but not infection) in females, but only during the reproductive years. This suggested a hormonal interaction between female hormones and the etiologic dimorphic fungus Paracoccidioides brasiliensis. Many fungi have been shown to use hormonal (pheromonal) fungal molecules for intercellular communication, and there are increasing numbers of examples of interactions between mammalian hormones and fungi, including the specific binding of mammalian hormones by fungal proteins, and suggestions of mammalian hormonal modulation of fungal behavior. This suggests an evolutionary conservation of hormonal receptor systems. We recount studies showing the specific hormonal binding of mammalian estrogen to proteins in P. brasiliensis and an action of estrogen to specifically block the transition from the saprophytic form to the invasive form of the fungus in vitro. This block has been demonstrated to occur in vivo in animal studies. These unique observations are consistent with an estrogen-fungus receptor-mediated effect on pathogenesis. The fungal genes responsive to estrogen action are under study. PMID:21482727

Novel Disease Susceptibility Factors for Fungal Necrotrophic Pathogens in Arabidopsis

PubMed Central

García-Andrade, Javier; Angulo, Carlos; Neumetzler, Lutz; Persson, Staffan; Vera, Pablo

2015-01-01

Host cells use an intricate signaling system to respond to invasions by pathogenic microorganisms. Although several signaling components of disease resistance against necrotrophic fungal pathogens have been identified, our understanding for how molecular components and host processes contribute to plant disease susceptibility is rather sparse. Here, we identified four transcription factors (TFs) from Arabidopsis that limit pathogen spread. Arabidopsis mutants defective in any of these TFs displayed increased disease susceptibility to Botrytis cinerea and Plectosphaerella cucumerina, and a general activation of non-immune host processes that contribute to plant disease susceptibility. Transcriptome analyses revealed that the mutants share a common transcriptional signature of 77 up-regulated genes. We characterized several of the up-regulated genes that encode peptides with a secretion signal, which we named PROVIR (for provirulence) factors. Forward and reverse genetic analyses revealed that many of the PROVIRs are important for disease susceptibility of the host to fungal necrotrophs. The TFs and PROVIRs identified in our work thus represent novel genetic determinants for plant disease susceptibility to necrotrophic fungal pathogens. PMID:25830627

Hyperthyroidism secondary to disseminated mucormycosis in a child with acute lymphoblastic leukemia: case report and a review of published reports.

PubMed

Irga, Ninela; Kosiak, Wojciech; Jaworski, Radoslaw; Komarnicka, Jolanta; Birkholz, Dorota

2013-02-01

Thyroiditis due to fungal infection is an extremely rare cause of hyperthyroidism. The most common etiological factor of thyroiditis is Aspergillus. Infections due to members of the Mucorales have been an increasing clinical problem in recent years, and the prognosis in generalized infections due to those fungi is usually very poor. No hyperthyroidism in a child with thyroiditis due to mucormycosis has been reported in the literature so far. We describe a clinical course of generalized mucormycosis with thyroid involvement in a 12-year-old girl treated for acute lymphoblastic leukemia. The child underwent a hyperthyroidism connected with thyroid involvement due to a fungal process. The diagnosis was based on the clinical signs, laboratory findings and typical ultrasound scan; however, later attempt to amplify the fungi DNA from the tissue block has failed. The child died because of multiorgan failure due to general fungal infection 49 days after the invasive fungal infection was diagnosed. The generalized mucormycosis is always connected with poor prognosis and the mortality is high.

A Cationic Polymer That Shows High Antifungal Activity against Diverse Human Pathogens.

PubMed

Rank, Leslie A; Walsh, Naomi M; Liu, Runhui; Lim, Fang Yun; Bok, Jin Woo; Huang, Mingwei; Keller, Nancy P; Gellman, Samuel H; Hull, Christina M

2017-10-01

Invasive fungal diseases are generally difficult to treat and often fatal. The therapeutic agents available to treat fungi are limited, and there is a critical need for new agents to combat these deadly infections. Antifungal compound development has been hindered by the challenge of creating agents that are highly active against fungal pathogens but not toxic to the host. Host defense peptides (HDPs) are produced by eukaryotes as a component of the innate immune response to pathogens and have served as inspiration for the development of many new antibacterial compounds. HDP mimics, however, have largely failed to exhibit potent and selective antifungal activity. Here, we present an HDP-like nylon-3 copolymer that is effective against diverse fungi while displaying only mild to moderate toxicity toward mammalian cells. This polymer is active on its own and in synergy with existing antifungal drugs against multiple species of Candida and Cryptococcus , reaching levels of efficacy comparable to those of the clinical agents amphotericin B and fluconazole in some cases. In addition, the polymer acts synergistically with azoles against different species of Aspergillus , including some azole-resistant strains. These findings indicate that nylon-3 polymers are a promising lead for development of new antifungal therapeutic strategies. Copyright © 2017 American Society for Microbiology.

Molecular epidemiology and virulence assessment of Aspergillus fumigatus isolates from white stork chicks and their environment.

PubMed

Olias, Philipp; Gruber, Achim D; Hafez, Hafez M; Lierz, Michael; Slesiona, Silvia; Brock, Matthias; Jacobsen, Ilse D

2011-03-24

Aspergillus fumigatus is a common pathogen in poultry and captive wild birds and an emerging opportunistic fungal pathogen in immunocompromised humans. Although invasive aspergillosis is frequently reported in free-ranging wild birds, the incidence and epidemiology of the disease in a natural setting is unknown. We recently reported endemic outbreaks of invasive aspergillosis at white stork nesting sites close to human habitation in Germany with significant subsequent breeding losses. Therefore, we hypothesized that A. fumigatus strains with higher virulence in birds may have evolved in this environment and performed the first epidemiological analysis of invasive aspergillosis in free-ranging wild birds. Sixty-one clinical and environmental A. fumigatus isolates from six affected nesting sites were genotyped by microsatellite analysis using the STRAf-assay. The isolates showed a remarkable high genomic diversity and, contrary to the initial hypothesis, clinical and environmental isolates did not cluster significantly. Interestingly, storks were infected with two to four different genotypes and in most cases both mating types MAT-1.1 and MAT-1.2 were present within the same specimen. The majority of selected clinical and environmental strains exhibited similar virulence in an in vivo infection model using embryonated chicken eggs. Noteworthy, virulence was not associated with one distinct fungal mating type. These results further support the assumption that the majority of A. fumigatus strains have the potential to cause disease in susceptible hosts. In white storks, immaturity of the immune system during the first three weeks of age may enhance susceptibility to invasive aspergillosis. Copyright © 2010 Elsevier B.V. All rights reserved.

Glycerol-3-Phosphate Acyltransferase Contributes to Triacylglycerol Biosynthesis, Lipid Droplet Formation, and Host Invasion in Metarhizium robertsii

PubMed Central

Gao, Qiang; Shang, Yanfang; Huang, Wei

2013-01-01

Enzymes involved in the triacylglycerol (TAG) biosynthesis have been well studied in the model organisms of yeasts and animals. Among these, the isoforms of glycerol-3-phosphate acyltransferase (GPAT) redundantly catalyze the first and rate-limiting step in glycerolipid synthesis. Here, we report the functions of mrGAT, a GPAT ortholog, in an insect-pathogenic fungus, Metarhizium robertsii. Unlike in yeasts and animals, a single copy of the mrGAT gene is present in the fungal genome and the gene deletion mutant is viable. Compared to the wild type and the gene-rescued mutant, the ΔmrGAT mutant demonstrated reduced abilities to produce conidia and synthesize TAG, glycerol, and total lipids. More importantly, we found that mrGAT is localized to the endoplasmic reticulum and directly linked to the formation of lipid droplets (LDs) in fungal cells. Insect bioassay results showed that mrGAT is required for full fungal virulence by aiding fungal penetration of host cuticles. Data from this study not only advance our understanding of GPAT functions in fungi but also suggest that filamentous fungi such as M. robertsii can serve as a good model to elucidate the role of the glycerol phosphate pathway in fungal physiology, particularly to determine the mechanistic connection of GPAT to LD formation. PMID:24077712

[Diagnostic and therapeutic approach of intraabdominal candidiasis].

PubMed

Montero, A; Gilsanz, F; Maseda, E

2016-09-01

Invasive fungal disease is associated to a high mortality rate on critical ill patients. In the last decades an important epidemiological shift has been described. Early diagnosis and treatment are related with a better prognosis. The key factors lie in a set of predictive scores that allow to identify patients that will benefit of early treatment, as well as using diagnosis techniques that are culture independent. New diagnosis approximations are being developed with promising results: in situ hybridisation using PNA-FISH probes, MALDI-TOF MS and rapid nucleic acids detection assays. The use of echinocandin is recommended as antifungal therapy on critical ill patients with candida peritonitis.

Cryptococcus: from environmental saprophyte to global pathogen

PubMed Central

May, Robin C.; Stone, Neil R.H.; Wiesner, Darin L.; Bicanic, Tihana; Nielsen, Kirsten

2016-01-01

Cryptococcosis is a globally distributed invasive fungal infection that is caused by species within the genus Cryptococcus which presents substantial therapeutic challenges. Although natural human-to-human transmission has never been observed, recent work has identified multiple virulence mechanisms that enable cryptococci to infect, disseminate within and ultimately kill their human host. In this Review, we describe these recent discoveries that illustrate the intricacy of host-pathogen interactions and reveal new details about the host immune responses that either help to protect against disease or increase host susceptibility. In addition, we discuss how this improved understanding of both the host and the pathogen informs potential new avenues for therapeutic development. PMID:26685750

Cryptococcus: from environmental saprophyte to global pathogen.

PubMed

May, Robin C; Stone, Neil R H; Wiesner, Darin L; Bicanic, Tihana; Nielsen, Kirsten

2016-02-01

Cryptococcosis is a globally distributed invasive fungal infection that is caused by species within the genus Cryptococcus which presents substantial therapeutic challenges. Although natural human-to-human transmission has never been observed, recent work has identified multiple virulence mechanisms that enable cryptococci to infect, disseminate within and ultimately kill their human host. In this Review, we describe these recent discoveries that illustrate the intricacy of host-pathogen interactions and reveal new details about the host immune responses that either help to protect against disease or increase host susceptibility. In addition, we discuss how this improved understanding of both the host and the pathogen informs potential new avenues for therapeutic development.

a-Copaene and quercivorol lures: Chemical analysis and efficacy for detection of Euwallacea nr. fornicatus (Coleoptera: Curculionidae: Scolytinae)

USDA-ARS?s Scientific Manuscript database

Invasive ambrosia beetles in the Euwallacea nr. fornicatus complex vector a fungal pathogen responsible for Fusarium dieback, a disease that impacts avocado (Persea americana) and numerous native trees in the USA, Israel, and other countries. Currently, these pests are detected with quercivorol lure...

Spatio-temporal analysis of Xyleborus glabratus (Coleoptera: Circulionidae: Scolytinae) Invasion in Eastern U.S. Forests

Treesearch

F.H. Koch; W.D. Smith

2008-01-01

The non-native redbay ambrosia beetle, Xyleborus glabratus Eichhoff (Coleoptera: Curculionidae: Scolytinae), has recently emerged as a signiÞcant pest of southeastern U.S. coastal forests. SpeciÞcally, a fungal symbiont (Raffaelea sp.) of X. glabratus has caused mortality of redbay (Persea borbonia...

Evaluation of lure combinations containing essential oils and volatile spiroketals for detection of host-seeking Xyleborus glabratus (Coleoptera: Curculionidae: Scolytinae)

USDA-ARS?s Scientific Manuscript database

The invasive redbay ambrosia beetle, Xyleborus glabratus Eichhoff (Coleoptera: Curculionidae: Scolytinae) vectors the fungal pathogen (Raffaelea lauricola) that causes laurel wilt, a disease responsible for widespread mortality of trees in the Lauraceae in the southeastern U.S. Early detection of in...

Enrichment of alpha-copaene content results in improved lure for redbay ambrosia beetle, Xyleborus glabratus (Coleoptera: Curculionidae: Scolytinae)

USDA-ARS?s Scientific Manuscript database

The exotic redbay ambrosia beetle, Xyleborus glabratus Eichhoff, has become a serious invasive pest in the USA, now established in seven southeastern states. Females are the primary vectors of a fungal pathogen, Raffaelea lauricola, that causes laurel wilt. This vascular disease has caused extensi...

A review of oak wilt management: a summary of treatment options and their efficacy

Treesearch

Karrie A. Koch; Gina L. Quiram; Robert C. Venette

2010-01-01

Oak wilt, caused by the invasive fungal pathogen Ceratocystis fagacearum (Bretz) Hunt, is a serious and fatal disease of oaks, Quercus spp., with red oaks (section Lobatae) generally being more susceptible than white oaks (section Quercus). Oak wilt was first recognized in North America in 1944...

Distribution of bacterial endophytes in peanut seeds obtained from axenic and control plant material under field conditions

USDA-ARS?s Scientific Manuscript database

Since endophytic bacteria may play a role in the defense mechanism of peanut from fungal invasion, the internal bacterial colonization of peanut seeds was investigated. Bacteria-free young peanut plants from seed embryos were successfully grown to maturity in the field. Mature seeds from these pla...

Invasive Bark Beetles, Forest Insect& Disease Leaflet 176

Treesearch

J.C. Lee; R.A. Haack; J.F. Negron; J.J. Witcosky; S.J. Seybold

2007-01-01

Bark beetles (Scolytidae) are among the most damaging insects in Northern Hemisphere forests, killing trees by direct feeding and by vectoring fungal pathogens. In addition to an already formidable native bark beetle complex, the number of exotic scolytids in U.S. forests has increased rapidly, with 53 known species established as of June 2007.

Within gut physiochemical variation does not correspond to distinct resident fungal and bacterial communities in the tree-killing xylophage, Anolophora glabripennis

USDA-ARS?s Scientific Manuscript database

Insect guts harbor diverse microbial assemblages that can be influenced by multiple factors, including gut physiology and interactions by the host with its environment. The Asian longhorned beetle (ALB; Anoplophora glabripennis) is an invasive tree–killing insect, which harbors a diverse consortium ...

Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation.

PubMed

Groll, Andreas H; Castagnola, Elio; Cesaro, Simone; Dalle, Jean-Hugues; Engelhard, Dan; Hope, William; Roilides, Emmanuel; Styczynski, Jan; Warris, Adilia; Lehrnbecher, Thomas

2014-07-01

Invasive opportunistic fungal diseases (IFDs) are important causes of morbidity and mortality in paediatric patients with cancer and those who have had an allogeneic haemopoietic stem-cell transplantation (HSCT). Apart from differences in underlying disorders and comorbidities relative to those of adults, IFDs in infants, children, and adolescents are unique with respect to their epidemiology, the usefulness of diagnostic methods, the pharmacology and dosing of antifungal agents, and the absence of interventional phase 3 clinical trials for guidance of evidence-based decisions. To better define the state of knowledge on IFDs in paediatric patients with cancer and allogeneic HSCT and to improve IFD diagnosis, prevention, and management, the Fourth European Conference on Infections in Leukaemia (ECIL-4) in 2011 convened a group that reviewed the scientific literature on IFDs and graded the available quality of evidence according to the Infectious Diseases Society of America grading system. The final considerations and recommendations of the group are summarised in this manuscript. Copyright © 2014 Elsevier Ltd. All rights reserved.

A Pilot Study of a Computerized Decision Support System to Detect Invasive Fungal Infection in Pediatric Hematology/Oncology Patients.

PubMed

Bartlett, Adam; Goeman, Emma; Vedi, Aditi; Mostaghim, Mona; Trahair, Toby; O'Brien, Tracey A; Palasanthiran, Pamela; McMullan, Brendan

2015-11-01

Computerized decision support systems (CDSSs) can provide indication-specific antimicrobial recommendations and approvals as part of hospital antimicrobial stewardship (AMS) programs. The aim of this study was to assess the performance of a CDSS for surveillance of invasive fungal infections (IFIs) in an inpatient hematology/oncology cohort. Between November 1, 2012, and October 31, 2013, pediatric hematology/oncology inpatients diagnosed with an IFI were identified through an audit of the CDSS and confirmed by medical record review. The results were compared to hospital diagnostic-related group (DRG) coding for IFI throughout the same period. A total of 83 patients were prescribed systemic antifungals according to the CDSS for the 12-month period. The CDSS correctly identified 19 patients with IFI on medical record review, compared with 10 patients identified by DRG coding, of whom 9 were confirmed to have IFI on medical record review. CDSS was superior to diagnostic coding in detecting IFI in an inpatient pediatric hematology/oncology cohort. The functionality of CDSS lends itself to inpatient infectious diseases surveillance but depends on prescriber adherence.

Bacterial and fungal endophthalmitis in upper Egypt: related species and risk factors.

PubMed

Gharamah, A A; Moharram, A M; Ismail, M A; Al-Hussaini, A K

2012-08-01

To study risk factors, contributing factors of bacterial and fungal endophthalmitis in Upper Egypt, test the isolated species sensitive to some therapeutic agents, and to investigate the air-borne bacteria and fungi in opthalmology operating rooms. Thirty one cases of endophthalmitis were clinically diagnosed and microbiologically studied. Indoor air-borne bacteria and fungi inside four air-conditioned operating rooms in the Ophthalmology Department at Assiut University Hospitals were also investigated. The isolated microbes from endophthalmitis cases were tested for their ability to produce some extracellular enzymes including protease, lipase, urease, phosphatase and catalase. Also the ability of 5 fungal isolates from endophthalmitis origin to produce mycotoxins and their sensitivity to some therapeutic agents were studied. Results showed that bacteria and fungi were responsihle for infection in 10 and 6 cases of endophthalmitis, respectively and only 2 cases produced a mixture of bacteria and fungi. Trauma was the most prevalent risk factor of endophthalmitis where 58.1% of the 31 cases were due to trauma. In ophthalmology operating rooms, different bacterial and fungal species were isolated. 8 bacterial and 5 fungal isolates showed their ability to produce enzymes while only 3 fungal isolates were able to produce mycotoxins. Terbinafine showed the highest effect against most isolates in vitro. The ability of bacterial and fungal isolates to produce extracellular enzymes and mycotoxins may be aid in the invasion and destruction of eye tissues. Microbial contamination of operating rooms with air-borne bacteria and fungi in the present work may be a source of postoperative endophthalmitis.

State of the art diagnostic of mold diseases: a practical guide for clinicians.

PubMed

Beirão, F; Araujo, R

2013-01-01

The epidemiology of fungal diseases changed, and molds have been increasingly associated with high mortality in severe immunocompromised patients. Invasive mold diseases may originate from the airborne conidia through inhalation or inoculation in skin fissures associated with indwelling catheters, wounds, burns, or onychomycosis. The diagnosis and treatment of fungal diseases is problematic and raises considerable challenges. Diagnosis of invasive mold diseases includes several methodologies, of which the most commonly used are the cultural methods, antigen testing, nucleic acid detection, and radiological imaging. Galactomannan and (1 → 3)-β-D-glucan detection significantly improved mold diagnosis in the last decade. Several molecular strategies have been proposed over the years but no consensus was achieved for standardized protocols or cut-off values. Recently, the first commercially available molecular assay for detection of Aspergillus was tested and the results were highly reproducible. In addition, blood cultures may also be helpful for invasive aspergillosis by following a novel procedure for the recovery of Aspergillus spp. from blood cultures. The association of distinct diagnostic methods, particularly molecular tests, galactomannan, and/or (1 → 3)-β-D-glucan detection, may provide earlier and more sensitive diagnosis of mold diseases and be indicative for early antifungal treatment. Accurate routine use of diagnostic tests can be cost-effective for laboratories and be of great value to patients.

Isavuconazole treatment for rare fungal diseases and for invasive aspergillosis in patients with renal impairment: Challenges and lessons of the VITAL trial.

PubMed

Perfect, John R; Cornely, Oliver A; Heep, Markus; Ostrosky-Zeichner, Luis; Mullane, Kathleen M; Maher, Rochelle; Croos-Dabrera, Rodney; Lademacher, Christopher; Engelhardt, Marc; Chen, Caroline; Marty, Francisco M

2018-03-23

Invasive fungal disease (IFD) confers a substantial risk for morbidity and mortality to immunocompromised patients. Invasive aspergillosis (IA) is the most common IFD caused by moulds but the prevalence of other rare mould diseases, such as mucormycosis, hyalohyphomycosis and phaeohyphomycosis, may be increasing. Treatments are available for IA, but evidence to support efficacy and safety of antifungal agents for rare IFDs, or for IFDs in special patient populations, is limited or lacking. The VITAL trial was conducted to assess the efficacy and safety of isavuconazole for the treatment of patients with IA and renal impairment, or with IFDs caused by rare moulds, yeasts or dimorphic fungi. These patients stand to benefit most from a new treatment option but are unlikely to be included in a randomised, controlled trial. In this article, we review the challenges faced in the design and conduct of the VITAL trial. We also review the findings of VITAL, which included evidence of the efficacy and safety of isavuconazole. Finally, we consider the importance of trials such as VITAL to inform therapeutic decision making for clinicians faced with the challenge of treating patients with rare IFDs and as one paradigm of how to determine efficacy and safety of new drugs for rare and resistant infections without a suitable comparator. © 2018 The Authors. Mycoses Published by Blackwell Verlag GmbH.

Pythium invasion of plant-based life support systems: biological control and sources

NASA Technical Reports Server (NTRS)

Jenkins, D. G.; Cook, K. L.; Garland, J. L.; Board, K. F.; Sager, J. C. (Principal Investigator)

2000-01-01

Invasion of plant-based life support systems by plant pathogens could cause plant disease and disruption of life support capability. Root rot caused by the fungus, Pythium, was observed during tests of prototype plant growth systems containing wheat at the Kennedy Space Center (KSC). We conducted experiments to determine if the presence of complex microbial communities in the plant root zone (rhizosphere) resisted invasion by the Pythium species isolated from the wheat root. Rhizosphere inocula of different complexity (as assayed by community-level physiological profile: CLPP) were developed using a dilution/extinction approach, followed by growth in hydroponic rhizosphere. Pythium growth on wheat roots and concomitant decreases in plant growth were inversely related to the complexity of the inocula during 20-day experiments in static hydroponic systems. Pythium was found on the seeds of several different wheat cultivars used in controlled environmental studies, but it is unclear if the seed-borne fungal strain(s) were identical to the pathogenic strain recovered from the KSC studies. Attempts to control pathogens and their effects in hydroponic life support systems should include early inoculation with complex microbial communities, which is consistent with ecological theory.

The powdery mildew resistance protein RPW8.2 is carried on VAMP721/722 vesicles to the extrahaustorial membrane of haustorial complexes.

PubMed

Kim, Hyeran; O'Connell, Richard; Maekawa-Yoshikawa, Makoto; Uemura, Tomohiro; Neumann, Ulla; Schulze-Lefert, Paul

2014-09-01

Plants employ multiple cell-autonomous defense mechanisms to impede pathogenesis of microbial intruders. Previously we identified an exocytosis defense mechanism in Arabidopsis against pathogenic powdery mildew fungi. This pre-invasive defense mechanism depends on the formation of ternary protein complexes consisting of the plasma membrane-localized PEN1 syntaxin, the adaptor protein SNAP33 and closely sequence-related vesicle-resident VAMP721 or VAMP722 proteins. The Arabidopsis thaliana resistance to powdery mildew 8.2 protein (RPW8.2) confers disease resistance against powdery mildews upon fungal entry into host cells and is specifically targeted to the extrahaustorial membrane (EHM), which envelops the haustorial complex of the fungus. However, the secretory machinery involved in trafficking RPW8.2 to the EHM is unknown. Here we report that RPW8.2 is transiently located on VAMP721/722 vesicles, and later incorporated into the EHM of mature haustoria. Resistance activity of RPW8.2 against the powdery mildew Golovinomyces orontii is greatly diminished in the absence of VAMP721 but only slightly so in the absence of VAMP722. Consistent with this result, trafficking of RPW8.2 to the EHM is delayed in the absence of VAMP721. These findings implicate VAMP721/722 vesicles as key components of the secretory machinery for carrying RPW8.2 to the plant-fungal interface. Quantitative fluorescence recovery after photobleaching suggests that vesicle-mediated trafficking of RPW8.2-yellow fluorescent protein (YFP) to the EHM occurs transiently during early haustorial development and that lateral diffusion of RPW8.2-YFP within the EHM exceeds vesicle-mediated replenishment of RPW8.2-YFP in mature haustoria. Our findings imply the engagement of VAMP721/722 in a bifurcated trafficking pathway for pre-invasive defense at the cell periphery and post-invasive defense at the EHM. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis

PubMed Central

Zhu, Feng; Willette-Brown, Jami; Song, Na-Young; Lomada, Dakshayani; Song, Yongmei; Xue, Liyan; Gray, Zane; Zhao, Zitong; Davis, Sean R.; Sun, Zhonghe; Zhang, Peilin; Wu, Xiaolin; Zhan, Qimin; Richie, Ellen R.; Hu, Yinling

2018-01-01

SUMMARY Humans with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a T cell–driven autoimmune disease caused by impaired central tolerance, are susceptible to developing chronic fungal infection and esophageal squamous cell carcinoma (ESCC). However, the relationship between autoreactive T cells and chronic fungal infection in ESCC development remains unclear. We find that kinase-dead Ikkα knockin mice develop phenotypes reminiscent of APECED, including impaired central tolerance, autoreactive T cells, chronic fungal infection, and ESCCs expressing specific human ESCC markers. Using this model, we investigated the potential link between ESCC and fungal infection. Autoreactive CD4 T cells permit fungal infection and incite tissue injury and inflammation. Antifungal treatment or depletion of autoreactive CD4 T cells rescues, whereas oral fungal administration promotes, ESCC development. Inhibition of inflammation or EGFR activity decreases fungal burden. Importantly, fungal infection is highly associated with ESCCs in non-autoimmune human patients. Therefore, autoreactive T cells and chronic fungal infection, fostered by inflammation and epithelial injury, promote ESCC development. PMID:28407484

Central Role of the Trehalose Biosynthesis Pathway in the Pathogenesis of Human Fungal Infections: Opportunities and Challenges for Therapeutic Development

PubMed Central

Thammahong, Arsa; Puttikamonkul, Srisombat; Perfect, John R.; Brennan, Richard G.

2017-01-01

SUMMARY Invasive fungal infections cause significant morbidity and mortality in part due to a limited antifungal drug arsenal. One therapeutic challenge faced by clinicians is the significant host toxicity associated with antifungal drugs. Another challenge is the fungistatic mechanism of action of some drugs. Consequently, the identification of fungus-specific drug targets essential for fitness in vivo remains a significant goal of medical mycology research. The trehalose biosynthetic pathway is found in a wide variety of organisms, including human-pathogenic fungi, but not in humans. Genes encoding proteins involved in trehalose biosynthesis are mechanistically linked to the metabolism, cell wall homeostasis, stress responses, and virulence of Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. While there are a number of pathways for trehalose production across the tree of life, the TPS/TPP (trehalose-6-phosphate synthase/trehalose-6-phosphate phosphatase) pathway is the canonical pathway found in human-pathogenic fungi. Importantly, data suggest that proteins involved in trehalose biosynthesis play other critical roles in fungal metabolism and in vivo fitness that remain to be fully elucidated. By further defining the biology and functions of trehalose and its biosynthetic pathway components in pathogenic fungi, an opportunity exists to leverage this pathway as a potent antifungal drug target. The goal of this review is to cover the known roles of this important molecule and its associated biosynthesis-encoding genes in the human-pathogenic fungi studied to date and to employ these data to critically assess the opportunities and challenges facing development of this pathway as a therapeutic target. PMID:28298477

Looking for fungi in all the right places: screening for cryptococcal disease and other AIDS-related mycoses among patients with advanced HIV disease.

PubMed

Greene, Greg; Sriruttan, Charlotte; Le, Thuy; Chiller, Tom; Govender, Nelesh P

2017-03-01

As HIV treatment programmes scale up to meet the UNAIDS 90-90-90 goals, care must be taken to start antiretroviral treatment safely in patients with advanced disease (CD4 counts <200 cells/μl) who are simultaneously at risk for opportunistic infections and immune reconstitution inflammatory syndrome. Invasive fungal diseases pose a great threat at this critical time point, though the development of inexpensive and highly accurate rapid diagnostic tests has changed the approach HIV programmes are taking to reduce the high mortality associated with these opportunistic infections. This article summarizes recent advances and findings in fungal opportunistic infection diagnostics with a focus on screening to prevent cryptococcal meningitis. Cryptococcal antigen (CrAg) screening using a lateral flow assay platform is cost-effective and feasible to implement as either a laboratory reflex or point-of-care test. Recent CrAg screening pilots have elucidated the varying prevalence of cryptococcal antigenemia across geographic regions, which may aid programme planning. Evidence from recently completed clinical trials provides a strong motivation for the use of CrAg titer to refine treatment options for patients with subclinical cryptococcal disease. Although several operational barriers to programme effectiveness still need to be addressed, the utility of CrAg screening using inexpensive and accurate antigen assays has been demonstrated in real-world HIV programmes, paving the way for development and testing of other fungal opportunistic infection screening strategies and for an integrated advanced HIV disease testing package to reduce AIDS mortality and ensure safe antiretroviral treatment initiation.

Experimental Infection of Snakes with Ophidiomyces ophiodiicola Causes Pathological Changes That Typify Snake Fungal Disease

PubMed Central

Lankton, Julia; Werner, Katrien; Falendysz, Elizabeth A.; McCurley, Kevin; Blehert, David S.

2015-01-01

ABSTRACT   Snake fungal disease (SFD) is an emerging skin infection of wild snakes in eastern North America. The fungus Ophidiomyces ophiodiicola is frequently associated with the skin lesions that are characteristic of SFD, but a causal relationship between the fungus and the disease has not been established. We experimentally infected captive-bred corn snakes (Pantherophis guttatus) in the laboratory with pure cultures of O. ophiodiicola. All snakes in the infected group (n = 8) developed gross and microscopic lesions identical to those observed in wild snakes with SFD; snakes in the control group (n = 7) did not develop skin infections. Furthermore, the same strain of O. ophiodiicola used to inoculate snakes was recovered from lesions of all animals in the infected group, but no fungi were isolated from individuals in the control group. Monitoring progression of lesions throughout the experiment captured a range of presentations of SFD that have been described in wild snakes. The host response to the infection included marked recruitment of granulocytes to sites of fungal invasion, increased frequency of molting, and abnormal behaviors, such as anorexia and resting in conspicuous areas of enclosures. While these responses may help snakes to fight infection, they could also impact host fitness and may contribute to mortality in wild snakes with chronic O. ophiodiicola infection. This work provides a basis for understanding the pathogenicity of O. ophiodiicola and the ecology of SFD by using a model system that incorporates a host species that is easy to procure and maintain in the laboratory. PMID:26578676

Aspergillus felis sp. nov., an Emerging Agent of Invasive Aspergillosis in Humans, Cats, and Dogs

PubMed Central

Barrs, Vanessa R.; van Doorn, Tineke M.; Houbraken, Jos; Kidd, Sarah E.; Martin, Patricia; Pinheiro, Maria Dolores; Richardson, Malcolm; Varga, Janos; Samson, Robert A.

2013-01-01

We describe a novel heterothallic species in Aspergillus section Fumigati, namely A. felis (neosartorya-morph) isolated from three host species with invasive aspergillosis including a human patient with chronic invasive pulmonary aspergillosis, domestic cats with invasive fungal rhinosinusitis and a dog with disseminated invasive aspergillosis. Disease in all host species was often refractory to aggressive antifungal therapeutic regimens. Four other human isolates previously reported as A. viridinutans were identified as A. felis on comparative sequence analysis of the partial β-tubulin and/or calmodulin genes. A. felis is a heterothallic mold with a fully functioning reproductive cycle, as confirmed by mating-type analysis, induction of teleomorphs within 7 to 10 days in vitro and ascospore germination. Phenotypic analyses show that A. felis can be distinguished from the related species A. viridinutans by its ability to grow at 45°C and from A. fumigatus by its inability to grow at 50°C. Itraconazole and voriconazole cross-resistance was common in vitro. PMID:23798996

[Invasive fungal infections in children with cancer, neutropenia and fever, in Chile].

PubMed

Lucero, Yalda; Brücher, Roberto; Alvarez, Ana María; Becker, Ana; Cofré, José; Enríquez, Nancy; Payá, Ernesto; Salgado, Carmen; Santolaya, María Elena; Tordecilla, Juan; Varas, Mónica; Villarroel, Milena; Viviani, Tamara; Zubieta, Marcela; O'Ryan, Miguel

2002-10-01

Invasive fungal infections (IFI) cause prolonged hospitalizations and increase the possibility of death among patients with cancer and febrile neutropenia (FN). Up to 10% of febrile neutropenic episodes may be caused by IFI. To estimate the incidence of IFI among a large group of Chilean children with cancer and FN. Clinical and laboratory information was collected from a data base provided by the "Programa Infantil Nacional de Drogas Antineoplásicas" (PINDA) that included 445 FN episodes occurring in five hospitals in Santiago, Chile. This information was used to identify children that presented with signs and symptoms compatible with an IFI. According to predefined criteria based on a literature review, IFI episodes were categorized as "proven", "probable" or "possible". A total of 41/445 episodes (9.2%) were compatible with an IFI of which 4 (0.9%) were proven, 23 (5.2%) probable, and 14 (3.1%) possible. Hospitalization was longer (27 vs 8 days, p < .01), new infectious foci appeared with higher frequency (71 vs 38%, p < .01), and mortality was higher (10 vs 1.6%, p < .001) in children with IFI compatible episodes, when compared to children who did not have an IFI. The estimated incidence of IFI in Chilean children with cancer and FN ranged between 6-9% depending on the stringency of criteria selection used for classification. This estimate is similar to that reported by other studies. The low detection yield of clinically compatible IFI underscores the need of improved diagnosis of fungal infections in this population.

Systematic identification of substrates for profiling of secreted proteases from Aspergillus species.

PubMed

Schaal, René; Kupfahl, Claudio; Buchheidt, Dieter; Neumaier, Michael; Findeisen, Peter

2007-11-01

Reliable and early diagnosis of life-threatening invasive mycoses in neutropenic patients caused by fungi of the Aspergillus species remains challenging because current clinical diagnostic tools lack in sensitivity and/or specificity. During invasive growth a variety of fungal proteases are secreted into the bloodstream and protease profiling with reporter peptides might improve diagnosis of invasive aspergillosis in serum specimens. To characterise the specific protease activity of Aspergillus fumigatus and Aspergillus niger we analyzed Aspergillus culture supernatants, human serum and the mixture of both. A systematic screening for optimised protease substrates was performed using a random peptide library consisting of 360 synthetic peptides featuring fluorescence resonance energy transfer (FRET). We could identify numerous peptides that are selectively cleaved by fungus-specific proteases. These reporter peptides might be feasible for future protease profiling of serum specimens to improve diagnosis and monitoring of invasive aspergillosis.

Mucorales-Specific T Cells in Patients with Hematologic Malignancies

PubMed Central

Forghieri, Fabio; Candoni, Anna; Cesaro, Simone; Quadrelli, Chiara; Maertens, Johan; Rossi, Giulio; Morselli, Monica; Codeluppi, Mauro; Mussini, Cristina; Colaci, Elisabetta; Messerotti, Andrea; Paolini, Ambra; Maccaferri, Monica; Fantuzzi, Valeria; Del Giovane, Cinzia; Stefani, Alessandro; Morandi, Uliano; Maffei, Rossana; Marasca, Roberto; Narni, Franco; Fanin, Renato; Comoli, Patrizia; Romani, Luigina; Beauvais, Anne; Viale, Pier Luigi; Latgè, Jean Paul; Luppi, Mario

2016-01-01

Background Invasive mucormycosis (IM) is an emerging life-threatening fungal infection. It is difficult to obtain a definite diagnosis and to initiate timely intervention. Mucorales-specific T cells occur during the course of IM and are involved in the clearance of the infection. We have evaluated the feasibility of detecting Mucorales-specific T cells in hematological patients at risk for IM, and have correlated the detection of such cells with the clinical conditions of the patients. Methods and Findings By using an enzyme linked immunospot assay, the presence of Mucorales-specific T cells in peripheral blood (PB) samples has been investigated at three time points during high-dose chemotherapy for hematologic malignancies. Mucorales-specific T cells producing interferon-γ, interleukin-10 and interleukin-4 were analysed in order to detect a correlation between the immune response and the clinical picture. Twenty-one (10.3%) of 204 patients, accounting for 32 (5.3%) of 598 PB samples, tested positive for Mucorales-specific T cells. Two groups could be identified. Group 1, including 15 patients without signs or symptoms of invasive fungal diseases (IFD), showed a predominance of Mucorales-specific T cells producing interferon-gamma. Group 2 included 6 patients with a clinical picture consistent with invasive fungal disease (IFD): 2 cases of proven IM and 4 cases of possible IFD. The proven patients had significantly higher number of Mucorales-specific T cells producing interleukin-10 and interleukin-4 and higher rates of positive samples by using derived diagnostic cut-offs when compared with the 15 patients without IFD. Conclusions Mucorales-specific T cells can be detected and monitored in patients with hematologic malignancies at risk for IM. Mucorales-specific T cells polarized to the production of T helper type 2 cytokines are associated with proven IM and may be evaluated as a surrogate diagnostic marker for IM. PMID:26871570

Role of Therapeutic Drug Monitoring of Voriconazole in the Treatment of Invasive Fungal Infections

PubMed Central

Kuo, I fan; Ensom, Mary H H

2009-01-01

Background: Voriconazole is a broad-spectrum, second-generation triazole antifungal agent with demonstrated efficacy in the treatment of invasive fungal infections caused by Aspergillus spp. and Candida spp. Given the characteristically poor prognosis of patients with invasive fungal infections and the protracted duration of treatment required, therapeutic monitoring of voriconazole is, in theory, an attractive method to optimize antifungal therapy. Objective: To determine the utility of therapeutic drug monitoring for voriconazole. Methods: A previously published decision-making algorithm was used to assess the currently available literature on therapeutic drug monitoring of voriconazole. Results: Several analytical methods can be used to quantify plasma or serum concentrations of voriconazole. Reasons for therapeutic monitoring of this drug include wide variability both within and between individuals secondary to drug properties, drug–drug interactions, and disease states. Furthermore, voriconazole follows nonlinear pharmacokinetics with saturable hepatic clearance. Another potential factor in favour of therapeutic drug monitoring for voriconazole is genetic polymorphism of CYP2C19, whereby patients who are homozygous for poor metabolism (about 19% of non-Indian Asians) can have 4-fold greater exposure to voriconazole. The concentrations of this drug are also greater in patients with hepatic impairment. Drug–drug interactions with other substrates of CYP2C9, CYP2C19, and CYP3A4 can also alter voriconazole concentrations. However, the correlations between plasma concentrations of voriconazole and its efficacy and toxicity are not well defined. Although lower and upper target thresholds of 0.25–2 mg/L and 4–6 mg/L, respectively, have been suggested, studies to date have not been appropriately designed or powered to reveal any definitive association. Conclusions: Routine therapeutic drug monitoring of voriconazole is not recommended except in certain circumstances, such as lack of response to therapy or evidence of toxicity, in which case selective monitoring of voriconazole concentrations may be of clinical utility. PMID:22478935

Chronic Invasive Aspergillus Sinusitis and Otitis with Meningeal Extension Successfully Treated with Voriconazole.

PubMed

Morgand, Marjolaine; Rammaert, Blandine; Poirée, Sylvain; Bougnoux, Marie-Elisabeth; Tran, Hugo; Kania, Romain; Chrétien, Fabrice; Jouvion, Gregory; Lortholary, Olivier

2015-12-01

Invasive aspergillosis (IA) is a severe disseminated fungal disease that occurs mostly in immunocompromised patients. However, central nervous system IA, combining meningitis and skull base involvement, does not occur only in groups with classic risk factors for IA; patients with chronic renal failure and diabetes mellitus are also at risk for more chronic forms. In both of our proven IA cases, voriconazole monotherapy was effective without surgery, and cerebrospinal fluid and serum 1,3-β-d-glucan test results were initially positive, in contrast to galactomannan antigen results. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Effects of fungal deterioration on grain: nutritional value, toxicity, germination.

PubMed

Sauer, D B

1988-12-01

Moulds or fungi that grow in grains and seeds during storage and transport cause germination decrease, visible mouldiness, discoloration, musty or sour odours, caking, chemical and nutritional changes, reduction in processing quality, and form of mycotoxins. These deteriorative changes affect the grade and price of grain and contribute to customer dissatisfaction when the grain is marketed. The respiration of grain and fungi results in a loss in dry matter as well as the production of heat and moisture which contribute to further spoilage. Net changes in nutritional value and the risk of mycotoxin contamination are difficult to predict because they depend on a complex interaction of factors such as temperature, moisture, storage time, fungal species composition, kind of grain, and previous storage history. Moisture is the most important variable determining the rate of deterioration caused by fungi, with temperature being the second major factor. Problems with deterioration of grain in export shipments are not a recent development. They are related primarily to grain moisture at loading, and also to the extent of previous mould invasion.

Growth in rice cells requires de novo purine biosynthesis by the blast fungus Magnaporthe oryzae

PubMed Central

Fernandez, Jessie; Yang, Kuan Ting; Cornwell, Kathryn M.; Wright, Janet D.; Wilson, Richard A.

2013-01-01

Increasing incidences of human disease, crop destruction and ecosystem perturbations are attributable to fungi and threaten socioeconomic progress and food security on a global scale. The blast fungus Magnaporthe oryzae is the most devastating pathogen of cultivated rice, but its metabolic requirements in the host are unclear. Here we report that a purine-requiring mutant of M. oryzae could develop functional appressoria, penetrate host cells and undergo the morphogenetic transition to elaborate bulbous invasive hyphae from primary hyphae, but further in planta growth was aborted. Invasive hyphal growth following rice cell ingress is thus dependent on de novo purine biosynthesis by the pathogen and, moreover, plant sources of purines are neither available to the mutant nor required by the wild type during the early biotrophic phase of infection. This work provides new knowledge about the metabolic interface between fungus and host that might be applicable to other important intracellular fungal pathogens. PMID:23928947

Breakthrough Invasive Mold Infections in the Hematology Patient: Current Concepts and Future Directions.

PubMed

Lionakis, Michail S; Lewis, Russell E; Kontoyiannis, Dimitrios P

2018-05-31

Although the widespread use of mold-active agents (especially the new-generation of triazoles) has resulted in reductions of documented invasive mold infections (IMIs) in patients with hematological malignancies and allogeneic hematopoietic stem cell transplantation (HSCT), a subset of such patients still develop breakthrough IMIs (bIMIs). There are no data from prospective randomized clinical trials to guide therapeutic decisions in the different scenarios of bIMIs. In this viewpoint, we present the current status of our understanding of the clinical, diagnostic and treatment challenges of bIMIs in high-risk adult patients with hematological cancer and/or HSCT receiving mold-active antifungals and outline common clinical scenarios. As a rule, managing bIMIs demands an individualized treatment plan that takes into account the host, including co-morbidities, certainty of diagnosis and site of bIMIs, local epidemiology, considerations for fungal resistance, and antifungal pharmacological properties. Finally, we highlight areas that require future investigation in this complex area of clinical mycology.

[Nasal phaeohyphomycosis by Curvularia spicifera in pediatric patient with neutropenia and acute myeloid leukemia].

PubMed

Bay, Constanza; González, Tamara; Munoz, Gonzalo; Legarraga, Paulette; Vizcaya, Cecilia; Abarca, Katia

2017-06-01

There are very few reports of pediatric patients with infections by dematiaceous filamentous fungi. In this publication we report a case of invasive fungal infection of the nasal septum by Curvularia spicifera in a pediatric patient with acute myeloid leukemia. The patient presented with a painful scabby wound in the nasal vestibule. Culture and universal PCR were consistent with Curvularia spicifera. Early management with surgical debridement and bi-associated antifungal therapy achieved complete resolution of the lesions, with no evidence of dissemination and relapses. Clinical management of these fungal infections represents a challenge as the antifungal selection and duration of therapy is not yet well stablished.

Histopathology confirms white-nose syndrome in bats in Europe

USGS Publications Warehouse

Pikula, J.; Bandouchova, H.; Novotny, L.; Meteyer, C.U.; Zukal, J.; Irwin, N.R.; Zima, J.; Martinkova, N.

2012-01-01

White-nose syndrome, associated with the fungal skin infection geomycosis, caused regional population collapse in bats in North America. Our results, based on histopathology, show the presence of white-nose syndrome in Europe. Dermatohistopathology on two bats (Myotis myotis) found dead in March 2010 with geomycosis in the Czech Republic had characteristics resembling Geomyces destructans infection in bats confirmed with white-nose syndrome in US hibernacula. In addition, a live M. myotis, biopsied for histopathology during hibernation in April 2011, had typical fungal infection with cupping erosion and invasion of muzzle skin diagnostic for white-nose syndrome and conidiospores identical to G. destructans that were genetically confirmed as G. destructans. ?? Wildlife Disease Association 2012.

A Population Pharmacokinetic Model for a Solid Oral Tablet Formulation of Posaconazole.

PubMed

van Iersel, Marlou L P S; Rossenu, Stefaan; de Greef, Rik; Waskin, Hetty

2018-04-30

A delayed-release solid tablet formulation that releases posaconazole in the small intestine was developed to maximize systemic absorption. This study aimed to characterize the pharmacokinetics of the posaconazole solid tablet formulation in adult subjects and to investigate the potential impact of demographic and clinical factors on posaconazole exposure through a population pharmacokinetic approach. Nonlinear mixed-effects modeling was performed using data from several studies conducted in healthy volunteers and patients. The influence of demographic and clinical factors on pharmacokinetic parameters was evaluated using a stepwise forward inclusion/backward exclusion procedure. The final pharmacokinetic model was used to simulate posaconazole exposure in patients at high risk for invasive fungal diseases treated with the proposed posaconazole dose of 300 mg twice daily on day 1, followed by 300 mg daily for 27 days. A one-compartment pharmacokinetic model with sequential zero-order and first-order absorption and a first-order disposition from the central compartment adequately described the pharmacokinetic profile of the posaconazole solid tablet formulation. Significant covariates included disease state (acute myeloid leukemia/myelodysplasia vs allogeneic hematopoietic stem cell transplantation), body weight, and formulation on bioavailability; food status on first-order absorption rate; and dosing regimen (single dose vs multiple doses) on clearance. Except for body weight, the impact of these covariates on posaconazole exposure was considered clinically irrelevant. This population pharmacokinetic analysis confirmed that the proposed dose of the posaconazole solid tablet formulation provides adequate target therapeutic exposure (>0.5 mg/l) to a broad range of patients at high risk for invasive fungal disease. Copyright © 2018 American Society for Microbiology.

Risk Factors for Invasive Fungal Disease in Pediatric Cancer and Hematopoietic Stem Cell Transplantation: A Systematic Review.

PubMed

Fisher, Brian T; Robinson, Paula D; Lehrnbecher, Thomas; Steinbach, William J; Zaoutis, Theoklis E; Phillips, Bob; Sung, Lillian

2017-05-26

Although a number of risk factors have been associated with invasive fungal disease (IFD), a systematic review of the literature to document pediatric-specific factors has not been performed. We used the Ovid SP platform to search Medline, Medline In-Process, and Embase for studies that identified risk factors for IFD in children with cancer or those who undergo hematopoietic stem cell transplantation (HSCT). We included studies if they consisted of children or adolescents (<25 years) who were receiving treatment for cancer or undergoing HSCT and if the study evaluated risk factors among patients with and those without IFD. Among the 3566 studies screened, 22 studies were included. A number of pediatric factors commonly associated with an increased risk for IFD were confirmed, including prolonged neutropenia, high-dose steroid exposure, intensive-timing chemotherapy for acute myeloid leukemia, and acute and chronic graft-versus-host disease. Increasing age, a factor not commonly associated with IFD risk, was identified as a risk factor in multiple published cohorts. With this systematic review, we have confirmed IFD risk factors that are considered routinely in daily clinical practice. Increasing age should also be considered when assessing patient risk for IFD. Future efforts should focus on defining more precise thresholds for a particular risk factor (ie, age, neutropenia duration) and on development of prediction rules inclusive of individual factors to further refine the risk prediction. © The Author 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

First report of a sexual state in an ambrosia fungus: Ambrosiella cleistominuta sp. nov. associated with the ambrosia beetle Anisandrus maiche

USDA-ARS?s Scientific Manuscript database

Genera of ambrosia beetles in the tribe Xyleborini with large, mesonotal mycangia host unique fungal symbionts in the genus Ambrosiella. The symbiont of a recent invasive to the USA from Asia, Anisandrus maiche, had not been previously characterized. We consistently isolated a novel fungus, Ambrosie...

Bacterial and fungal midgut community dynamics and transfer between mother and brood in the Aisan longhorned beetle (Anoplophora glabipennis), an invasive xylophage

USDA-ARS?s Scientific Manuscript database

Microbial symbionts play pivotal roles in the ecology and physiology of insects feeding in woody plants. Both eukaryotic and bacterial members occur in these systems where they facilitate digestive and nutrition provisioning. The larval gut of the Asian longhorned beetle (Anoplophora glabripennis) i...

Laurel wilt in natural and agricultural ecosystems: Understanding the drivers and scales of complex pathosystems

Treesearch

Randy Ploetz; Paul Kendra; Robin Choudhury; Jeffrey Rollins; Alina Campbell; Karen Garrett; Marc Hughes; Tyler Dreaden

2017-01-01

Laurel wilt kills members of the Lauraceae plant family in the southeastern United States. It is caused by Raffaelea lauricola T.C. Harr., Fraedrich and Aghayeva, a nutritional fungal symbiont of an invasive Asian ambrosia beetle, Xyleborus glabratus Eichhoff, which was detected in Port Wentworth, Georgia, in 2002. The beetle...

Tree-mediated interactions between the jack pine budworm and a mountain pine beetle fungal

Treesearch

Nadir Erbilgin; Jessie Colgan

2012-01-01

Coniferous trees deploy a combination of constitutive (pre-existing) and induced (post-invasion) structural and biochemical defenses against invaders. Induced responses can also alter host suitability for other organisms sharing the same host, which may result in indirect, plant-mediated, interactions between different species of attacking organisms. Current range and...

The growth and phosphorus acquisition of invasive plants Rudbeckia laciniata and Solidago gigantea are enhanced by arbuscular mycorrhizal fungi.

PubMed

Majewska, Marta L; Rola, Kaja; Zubek, Szymon

2017-02-01

While a number of recent studies have revealed that arbuscular mycorrhizal fungi (AMF) can mediate invasive plant success, the influence of these symbionts on the most successful and high-impact invaders is largely unexplored. Two perennial herbs of this category of invasive plants, Rudbeckia laciniata and Solidago gigantea (Asteraceae), were thus tested in a pot experiment to determine whether AMF influence their growth, the concentration of phosphorus in biomass, and photosynthesis. The following treatments, including three common AMF species, were prepared on soils representative of two habitats that are frequently invaded by both plants, namely fallow and river valley: (1) control-soil without AMF, (2) Rhizophagus irregularis, (3) Funneliformis mosseae, and (4) Claroideoglomus claroideum. The invaders were strongly dependent on AMF for their growth. The mycorrhizal dependency of R. laciniata was 88 and 63 % and of S. gigantea 90 and 82 % for valley and fallow soils, respectively. The fungi also increased P concentration in their biomass. However, we found different effects of the fungal species in the stimulation of plant growth and P acquisition, with R. irregularis and C. claroideum being the most and least effective symbionts, respectively. None of AMF species had an impact on the photosynthetic performance indexes of both plants. Our findings indicate that AMF have a direct effect on the early stages of R. laciniata and S. gigantea growth. The magnitude of the response of both plant species to AMF was dependent on the fungal and soil identities. Therefore, the presence of particular AMF species in a site may determine the success of their invasion.

Five-year National Surveillance of Invasive Candidiasis: Species Distribution and Azole Susceptibility from the China Hospital Invasive Fungal Surveillance Net (CHIF-NET) Study.

PubMed

Xiao, Meng; Sun, Zi-Yong; Kang, Mei; Guo, Da-Wen; Liao, Kang; Chen, Sharon C-A; Kong, Fanrong; Fan, Xin; Cheng, Jing-Wei; Hou, Xin; Zhou, Meng-Lan; Li, Ying; Yu, Shu-Ying; Huang, Jing-Jing; Wang, He; Xu, Ying-Chun

2018-05-09

Data on the epidemiology of invasive candidiasis (IC) and antifungal susceptibility of Candida isolates in China are still limited. Here we report surveillance for IC from the China Hospital Invasive Fungal Surveillance Net (CHIF-NET) Study. Sixty-five tertiary hospitals collected 8,829 Candida isolates from August 1, 2009 to July 31, 2014. Matrix-assisted laser desorption/ionization -time of flight mass spectrometry supplemented by rDNA sequencing was used to define species, and fluconazole and voriconazole susceptibilities determined by the Clinical and Laboratory Standards Institute disk diffusion method. A total of 32 Candida species were identified. C. albicans was the most common species (44.9%) followed by C. parapsilosis complex (20.0%), C. tropicalis (17.2%) and C. glabrata complex (10.8%), with other species comprising <3%. However, in candidemia, the proportion of cases caused by C. albicans was only 32.3%. C. albicans and C. parapsilosis complex isolates were susceptible to fluconazole and voriconazole (<6% resistance), while fluconazole- and azole cross-resistant rates were high in C. tropicalis (13.3% and 12.9%), C. glabrata complex (18.7% and 14%) and uncommon Candida species (44.1% and 10.3%) isolates. Moreover, from year 1 to 5 of the study, there was a significant increase in resistant rates amongst C. glabrata complex isolates to fluconazole (12.2% to 24.0%), and amongst C. tropicalis isolates to both fluconazole (5.7% to 21.0%) and voriconazole (5.7% to 21.4%) (all P<0.01). Geographic variations in causative species and susceptibilities were noted. Our findings indicated that antifungal resistance have become noteworthy in China, and enhanced surveillance is warranted. Copyright © 2018 American Society for Microbiology.

The invasive species Alliaria petiolata (garlic mustard) increases soil nutrient availability in northern hardwood-conifer forests.

PubMed

Rodgers, Vikki L; Wolfe, Benjamin E; Werden, Leland K; Finzi, Adrien C

2008-09-01

The invasion of non-native plants can alter the diversity and activity of soil microorganisms and nutrient cycling within forests. We used field studies to analyze the impact of a successful invasive groundcover, Alliaria petiolata, on fungal diversity, soil nutrient availability, and pH in five northeastern US forests. We also used laboratory and greenhouse experiments to test three mechanisms by which A. petiolata may alter soil processes: (1) the release of volatile, cyanogenic glucosides from plant tissue; (2) the exudation of plant secondary compounds from roots; and (3) the decomposition of litter. Fungal community composition was significantly different between invaded and uninvaded soils at one site. Compared to uninvaded plots, plots invaded by A. petiolata were consistently and significantly higher in N, P, Ca and Mg availability, and soil pH. In the laboratory, the release of volatile compounds from the leaves of A. petiolata did not significantly alter soil N availability. Similarly, in the greenhouse, the colonization of native soils by A. petiolata roots did not alter soil nutrient cycling, implying that the exudation of secondary compounds has little effect on soil processes. In a leaf litter decomposition experiment, however, green rosette leaves of A. petiolata significantly increased the rate of decomposition of native tree species. The accelerated decomposition of leaf litter from native trees in the presence of A. petiolata rosette leaves shows that the death of these high-nutrient-content leaves stimulates decomposition to a greater extent than any negative effect that secondary compounds may have on the activity of the microbes decomposing the native litter. The results presented here, integrated with recent related studies, suggest that this invasive plant may change soil nutrient availability in such a way as to create a positive feedback between site occupancy and continued proliferation.

Mycorrhizal preference promotes habitat invasion by a native Australian orchid: Microtis media

PubMed Central

De Long, Jonathan R.; Swarts, Nigel D.; Dixon, Kingsley W.; Egerton-Warburton, Louise M.

2013-01-01

Background and Aims Mycorrhizal specialization has been shown to limit recruitment capacity in orchids, but an increasing number of orchids are being documented as invasive or weed-like. The reasons for this proliferation were examined by investigating mycorrhizal fungi and edaphic correlates of Microtis media, an Australian terrestrial orchid that is an aggressive ecosystem and horticultural weed. Methods Molecular identification of fungi cultivated from M. media pelotons, symbiotic in vitro M. media seed germination assays, ex situ fungal baiting of M. media and co-occurring orchid taxa (Caladenia arenicola, Pterostylis sanguinea and Diuris magnifica) and soil physical and chemical analyses were undertaken. Key Results It was found that: (1) M. media associates with a broad taxonomic spectrum of mycobionts including Piriformospora indica, Sebacina vermifera, Tulasnella calospora and Ceratobasidium sp.; (2) germination efficacy of mycorrhizal isolates was greater for fungi isolated from plants in disturbed than in natural habitats; (3) a higher percentage of M. media seeds germinate than D. magnifica, P. sanguinea or C. arenicola seeds when incubated with soil from M. media roots; and (4) M. media–mycorrhizal fungal associations show an unusual breadth of habitat tolerance, especially for soil phosphorus (P) fertility. Conclusions The findings in M. media support the idea that invasive terrestrial orchids may associate with a diversity of fungi that are widespread and common, enhance seed germination in the host plant but not co-occurring orchid species and tolerate a range of habitats. These traits may provide the weedy orchid with a competitive advantage over co-occurring orchid species. If so, invasive orchids are likely to become more broadly distributed and increasingly colonize novel habitats. PMID:23275632

The Dark Side Is Not Fastidious – Dark Septate Endophytic Fungi of Native and Invasive Plants of Semiarid Sandy Areas

PubMed Central

Knapp, Dániel G.; Pintye, Alexandra; Kovács, Gábor M.

2012-01-01

Dark septate endophytic (DSE) fungi represent a frequent root-colonizing fungal group common in environments with strong abiotic stress, such as (semi)arid ecosystems. This work aimed to study the DSE fungi colonizing the plants of semiarid sandy grasslands with wood steppe patches on the Great Hungarian Plain. As we may assume that fungi colonizing both invasive and native species are generalists, root associated fungi (RAF) were isolated from eight native and three invasive plant species. The nrDNA sequences of the isolates were used for identification. To confirm that the fungi were endophytes an artificial inoculation system was used to test the isolates: we considered a fungus as DSE if it colonized the roots without causing a negative effect on the plant and formed microsclerotia in the roots. According to the analyses of the ITS sequence of nrDNA the 296 isolates clustered into 41 groups. We found that 14 of these 41 groups were DSE, representing approximately 60% of the isolates. The main DSE groups were generalist and showed no specificity to area or season and colonized both native and invasive species, demonstrating that exotic plants are capable of using the root endophytic fungi of the invaded areas. The DSE community of the region shows high similarity to those found in arid grasslands of North America. Taking into account a previous hypothesis about the common root colonizers of those grasslands and our results reported here, we hypothesize that plants of (semi)arid grasslands share common dominant members of the DSE fungal community on a global scale. PMID:22393417

Plant and root endophyte assembly history: interactive effects on native and exotic plants.

PubMed

Sikes, Benjamin A; Hawkes, Christine V; Fukami, Tadashi

2016-02-01

Differences in the arrival timing of plants and soil biota may result in different plant communities through priority effects, potentially affecting the success of native vs. exotic plants, but experimental evidence is largely lacking. We conducted a greenhouse experiment to investigate whether the assembly history of plants and fungal root endophytes could interact to influence plant emergence and biomass. We introduced a grass species and eight fungal species from one of three land-use types (undisturbed, disturbed, or pasture sites in a Florida scrubland) in factorial combinations. We then introduced all plants and fungi from the other land-use types 2 weeks later. Plant emergence was monitored for 6 months, and final plant biomass and fungal species composition assessed. The emergence and growth of the exotic Melinis repens and the native Schizacharyium niveum were affected negatively when introduced early with their "home" fungi, but early introduction of a different plant species or fungi from a different site type eliminated these negative effects, providing evidence for interactive priority effects. Interactive effects of plant and fungal arrival history may be an overlooked determinant of plant community structure and may provide an effective management tool to inhibit biological invasion and aid ecosystem restoration.

The early response during the interaction of fungal phytopathogen and host plant.

PubMed

Shen, Yilin; Liu, Na; Li, Chuang; Wang, Xin; Xu, Xiaomeng; Chen, Wan; Xing, Guozhen; Zheng, Wenming

2017-05-01

Plants can be infected by a variety of pathogens, most of which can cause severe economic losses. The plants resist the invasion of pathogens via the innate or acquired immune system for surviving biotic stress. The associations between plants and pathogens are sophisticated beyond imaging and the interactions between them can occur at a very early stage after their touching each other. A number of researchers in the past decade have shown that many biochemical events appeared even as early as 5 min after their touching for plant disease resistance response. The early molecular interactions of plants and pathogens are likely to involve protein phosphorylation, ion fluxes, reactive oxygen species (ROS) and other signalling transduction. Here, we reviewed the recent progress in the study for molecular interaction response of fungal pathogens and host plant at the early infection stage, which included many economically important crop fungal pathogens such as cereal rust fungi, tomato Cladosporium fulvum , rice blast and so on. By dissecting the earlier infection stage of the diseases, the avirulent/virulent genes of pathogen or resistance genes of plant could be defined more clearly and accurately, which would undoubtedly facilitate fungal pathogenesis study and resistant crop breeding. © 2017 The Authors.

The early response during the interaction of fungal phytopathogen and host plant

PubMed Central

Shen, Yilin; Liu, Na; Li, Chuang; Wang, Xin; Xu, Xiaomeng; Chen, Wan; Xing, Guozhen

2017-01-01

Plants can be infected by a variety of pathogens, most of which can cause severe economic losses. The plants resist the invasion of pathogens via the innate or acquired immune system for surviving biotic stress. The associations between plants and pathogens are sophisticated beyond imaging and the interactions between them can occur at a very early stage after their touching each other. A number of researchers in the past decade have shown that many biochemical events appeared even as early as 5 min after their touching for plant disease resistance response. The early molecular interactions of plants and pathogens are likely to involve protein phosphorylation, ion fluxes, reactive oxygen species (ROS) and other signalling transduction. Here, we reviewed the recent progress in the study for molecular interaction response of fungal pathogens and host plant at the early infection stage, which included many economically important crop fungal pathogens such as cereal rust fungi, tomato Cladosporium fulvum, rice blast and so on. By dissecting the earlier infection stage of the diseases, the avirulent/virulent genes of pathogen or resistance genes of plant could be defined more clearly and accurately, which would undoubtedly facilitate fungal pathogenesis study and resistant crop breeding. PMID:28469008

Krüppel-like Factor 4 modulates interleukin-6 release in human dendritic cells after in vitro stimulation with Aspergillus fumigatus and Candida albicans.

PubMed

Czakai, Kristin; Leonhardt, Ines; Dix, Andreas; Bonin, Michael; Linde, Joerg; Einsele, Hermann; Kurzai, Oliver; Loeffler, Jürgen

2016-06-27

Invasive fungal infections are associated with high mortality rates and are mostly caused by the opportunistic fungi Aspergillus fumigatus and Candida albicans. Immune responses against these fungi are still not fully understood. Dendritic cells (DCs) are crucial players in initiating innate and adaptive immune responses against fungal infections. The immunomodulatory effects of fungi were compared to the bacterial stimulus LPS to determine key players in the immune response to fungal infections. A genome wide study of the gene regulation of human monocyte-derived dendritic cells (DCs) confronted with A. fumigatus, C. albicans or LPS was performed and Krüppel-like factor 4 (KLF4) was identified as the only transcription factor that was down-regulated in DCs by both fungi but induced by stimulation with LPS. Downstream analysis demonstrated the influence of KLF4 on the interleukine-6 expression in human DCs. Furthermore, KLF4 regulation was shown to be dependent on pattern recognition receptor ligation. Therefore KLF4 was identified as a controlling element in the IL-6 immune response with a unique expression pattern comparing fungal and LPS stimulation.

Plant phenolic compounds and oxidative stress: integrated signals in fungal-plant interactions.

PubMed

Shalaby, Samer; Horwitz, Benjamin A

2015-08-01

Upon invasion of a host, fungal pathogens are exposed to a variety of stresses. Plants release reactive oxygen species, and mount a variety of preformed and induced chemical defenses. Phenolic compounds are one example: they are ubiquitous in plants, and an invading pathogen encounters them already at the leaf surface, or for soil-borne pathogens, in the rhizosphere. Phenolic and related aromatic compounds show varying degrees of toxicity to cells. Some compounds are quite readily metabolized, and others less so. It was known already from classical studies that phenolic substrates induce the expression of the enzymes for their degradation. Recently, the ability to degrade phenolics was shown to be a virulence factor. Conversely, phenolic compounds can increase the effectiveness of antifungals. Phenolics are known antioxidants, yet they have been shown to elicit cellular responses that would usually be triggered to counter oxidant stress. Here, we review the evidence for a connection between the fungal response to phenolics as small-molecule signals, and the response to oxidants. The connections proposed here should enable genetic screens to identify specific fungal receptors for plant phenolics. Furthermore, understanding how the pathogen detects plant phenolic compounds as a stress signal may facilitate new antifungal strategies.

Mutualism-disrupting allelopathic invader drives carbon stress and vital rate decline in a forest perennial herb.

PubMed

Brouwer, Nathan L; Hale, Alison N; Kalisz, Susan

2015-02-27

Invasive plants can negatively affect belowground processes and alter soil microbial communities. For native plants that depend on soil resources from root fungal symbionts (RFS), invasion could compromise their resource status and subsequent ability to manufacture and store carbohydrates. Herbaceous perennials that depend on RFS-derived resources dominate eastern North American forest understories. Therefore, we predict that forest invasion by Alliaria petiolata, an allelopathic species that produces chemicals that are toxic to RFS, will diminish plant carbon storage and fitness. Over a single growing season, the loss of RFS could reduce a plant's photosynthetic physiology and carbon storage. If maintained over multiple growing seasons, this could create a condition of carbon stress and declines in plant vital rates. Here we characterize the signals of carbon stress over a short timeframe and explore the long-term consequence of Alliaria invasion using Maianthemum racemosum, an RFS-dependent forest understory perennial. First, in a greenhouse experiment, we treated the soil of potted Maianthemum with fresh leaf tissue from either Alliaria or Hesperis matronalis (control) for a single growing season. Alliaria-treated plants exhibit significant overall reductions in total non-structural carbohydrates and have 17 % less storage carbohydrates relative to controls. Second, we monitored Maianthemum vital rates in paired experimental plots where we either removed emerging Alliaria seedlings each spring or left Alliaria at ambient levels for 7 years. Where Alliaria is removed, Maianthemum size and vital rates improve significantly: flowering probability increases, while the probability of plants regressing to non-flowering stages or entering prolonged dormancy are reduced. Together, our results are consistent with the hypothesis that disruption of a ubiquitous mutualism following species invasion creates symptoms of carbon stress for species dependent on RFS. Disruption of plant-fungal mutualisms may generally contribute to the common, large-scale declines in forest biodiversity observed in the wake of allelopathic invaders. Published by Oxford University Press on behalf of the Annals of Botany Company.

Stimulation with lysates of Aspergillus terreus, Candida krusei and Rhizopus oryzae maximizes cross-reactivity of anti-fungal T cells.

PubMed

Deo, Shivashni S; Virassamy, Balaji; Halliday, Catriona; Clancy, Leighton; Chen, Sharon; Meyer, Wieland; Sorrell, Tania C; Gottlieb, David J

2016-01-01

Invasive fungal diseases caused by filamentous fungi and yeasts are significant causes of morbidity and mortality in immunosuppressed hematology patients. We previously published a method to expand Aspergillus fumigatus-specific T cells for clinical cell therapy. In the present study, we investigated expansion of T cells specific for other fungal pathogens and creation of a broadly reactive panfungal T-cell product. Fungal strains selected were those frequently observed in the clinical hematology setting and included Aspergillus, Candida, Fusarium, Rhizopus and Lomentospora/Scedosporium. Four T-cell cultures specific to each fungus were established. We selected lysates of Aspergillus terreus, Candida krusei and Rhizopus oryzae to expand panfungal T cells. Allelic restriction of anti-fungal activity was determined through the use of specific major histocompatibility complex class II-blocking antibodies. Individual T-cell cultures specific to each fungus could be expanded in vitro, generating predominantly CD4(+) T cells of which 8% to 20% were fungus-specific. We successfully expanded panfungal T cells from the peripheral blood (n = 8) and granulocyte-colony-stimulating factor-primed stem cell products (n = 3) of normal donors by using a combination of lysates from Aspergillus terreus, Candida krusei and Rhizopus oryzae. Anti-fungal activity was mediated through human leukocyte antigen (HLA)-DR alleles and was maintained when antigen-presenting cells from partially HLA-DRB1-matched donors were used to stimulate T cells. We demonstrate a method to manufacture panfungal T-cell products with specificity against a range of clinical fungal pathogens by use of the blood and stem cells of healthy donors as the starting material. The safety and efficacy of these products will need to be tested clinically. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Severe plant invasions can increase mycorrhizal fungal abundance and diversity.

PubMed

Lekberg, Ylva; Gibbons, Sean M; Rosendahl, Søren; Ramsey, Philip W

2013-07-01

Invasions by non-native plants can alter ecosystem functions and reduce native plant diversity, but relatively little is known about their effect on belowground microbial communities. We show that invasions by knapweed (Centaurea stoebe) and leafy spurge (Euphorbia esula, hereafter spurge)--but not cheatgrass (Bromus tectorum)--support a higher abundance and diversity of symbiotic arbuscular mycorrhizal fungi (AMF) than multi-species native plant communities. The higher AMF richness associated with knapweed and spurge is unlikely due to a co-invasion by AMF, because a separate sampling showed that individual native forbs hosted a similar AMF abundance and richness as exotic forbs. Native grasses associated with fewer AMF taxa, which could explain the reduced AMF richness in native, grass-dominated communities. The three invasive plant species harbored distinct AMF communities, and analyses of co-occurring native and invasive plants indicate that differences were partly driven by the invasive plants and were not the result of pre-invasion conditions. Our results suggest that invasions by mycotrophic plants that replace poorer hosts can increase AMF abundance and richness. The high AMF richness in monodominant plant invasions also indicates that the proposed positive relationship between above and belowground diversity is not always strong. Finally, the disparate responses among exotic plants and consistent results between grasses and forbs suggest that AMF respond more to plant functional group than plant provenance.

Severe plant invasions can increase mycorrhizal fungal abundance and diversity

PubMed Central

Lekberg, Ylva; Gibbons, Sean M; Rosendahl, Søren; Ramsey, Philip W

2013-01-01

Invasions by non-native plants can alter ecosystem functions and reduce native plant diversity, but relatively little is known about their effect on belowground microbial communities. We show that invasions by knapweed (Centaurea stoebe) and leafy spurge (Euphorbia esula, hereafter spurge)—but not cheatgrass (Bromus tectorum)—support a higher abundance and diversity of symbiotic arbuscular mycorrhizal fungi (AMF) than multi-species native plant communities. The higher AMF richness associated with knapweed and spurge is unlikely due to a co-invasion by AMF, because a separate sampling showed that individual native forbs hosted a similar AMF abundance and richness as exotic forbs. Native grasses associated with fewer AMF taxa, which could explain the reduced AMF richness in native, grass-dominated communities. The three invasive plant species harbored distinct AMF communities, and analyses of co-occurring native and invasive plants indicate that differences were partly driven by the invasive plants and were not the result of pre-invasion conditions. Our results suggest that invasions by mycotrophic plants that replace poorer hosts can increase AMF abundance and richness. The high AMF richness in monodominant plant invasions also indicates that the proposed positive relationship between above and belowground diversity is not always strong. Finally, the disparate responses among exotic plants and consistent results between grasses and forbs suggest that AMF respond more to plant functional group than plant provenance. PMID:23486251

Starvation and Imidacloprid Exposure Influence Immune Response by Anoplophora glabripennis (Coleoptera: Cerambycidae) to a Fungal Pathogen.

PubMed

Fisher, Joanna J; Castrillo, Louela A; Donzelli, Bruno G G; Hajek, Ann E

2017-08-01

In several insect systems, fungal entomopathogens synergize with neonicotinoid insecticides which results in accelerated host death. Using the Asian longhorned beetle, Anoplophora glabripennis (Motschulsky), an invasive woodborer inadvertently introduced into North America and Europe, we investigated potential mechanisms in the synergy between the entomopathogenic fungus Metarhizium brunneum Petch and the insecticide imidacloprid. A potential mechanism underlying this synergy could be imidacloprid's ability to prevent feeding shortly after administration. We investigated whether starvation would have an impact similar to imidacloprid exposure on the mortality of fungal-inoculated beetles. Using real-time PCR to quantify fungal load in inoculated beetles, we determined how starvation and pesticide exposure impacted beetles' ability to tolerate or resist a fungal infection. The effect of starvation and pesticide exposure on the encapsulation and melanization immune responses of the beetles was also quantified. Starvation had a similar impact on the survival of M. brunneum-inoculated beetles compared to imidacloprid exposure. The synergy, however, was not completely due to starvation, as imidacloprid reduced the beetles' melanotic encapsulation response and capsule area, while starvation did not significantly reduce these immune responses. Our results suggest that there are multiple interacting mechanisms involved in the synergy between M. brunneum and imidacloprid. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Estimating the Burden of Serious Fungal Infections in Uruguay

PubMed Central

Macedo-Viñas, Marina

2018-01-01

We aimed to estimate for the first time the burden of fungal infections in Uruguay. Data on population characteristics and underlying conditions were extracted from the National Statistics Institute, the World Bank, national registries, and published articles. When no data existed, risk populations were used to estimate frequencies extrapolating from the literature. Population structure (inhabitants): total 3,444,006; 73% adults; 35% women younger than 50 years. Size of populations at risk (total cases per year): HIV infected 12,000; acute myeloid leukemia 126; hematopoietic stem cell transplantation 30; solid organ transplants 134; COPD 272,006; asthma in adults 223,431; cystic fibrosis in adults 48; tuberculosis 613; lung cancer 1400. Annual incidence estimations per 100,000: invasive aspergillosis, 22.4; candidemia, 16.4; Candida peritonitis, 3.7; Pneumocystis jirovecii pneumonia, 1.62; cryptococcosis, 0.75; severe asthma with fungal sensitization, 217; allergic bronchopulmonary aspergillosis, 165; recurrent Candida vaginitis, 6323; oral candidiasis, 74.5; and esophageal candidiasis, 25.7. Although some under and overestimations could have been made, we expect that at least 127,525 people suffer from serious fungal infections each year. Sporothrichosis, histoplasmosis, paracoccidioidomycosis, and dermatophytosis are known to be frequent but no data are available to make accurate estimations. Given the magnitude of the burden of fungal infections in Uruguay, efforts should be made to improve surveillance, strengthen laboratory diagnosis, and warrant access to first line antifungals. PMID:29562641

Functional characterization of electron-transferring flavoprotein and its dehydrogenase required for fungal development and plant infection by the rice blast fungus

PubMed Central

Li, Ya; Zhu, Jindong; Hu, Jiexiong; Meng, Xiuli; Zhang, Qi; Zhu, Kunpeng; Chen, Xiaomin; Chen, Xuehang; Li, Guangpu; Wang, Zonghua; Lu, Guodong

2016-01-01

Electron-transferring flavoprotein (ETF) and its dehydrogenase (ETFDH) are highly conserved electron carriers which mainly function in mitochondrial fatty acid β oxidation. Here, we report the identification and characterization of ETF α and β subunit encoding genes (ETFA and ETFB) and ETFDH encoding gene (ETFDH) in the rice blast fungus Magnaporthe oryzae. It was demonstrated that, by impacting fatty acid metabolism, ETF and ETFDH mutations led to severe growth and conidiation defects, which could be largely rescued by exogenous acetate or carbonate. Furthermore, although conidium germination and appressorium formation appeared to be normal in ETF and ETFDH mutants, most appressoria failed to penetrate the host epidermis due to low turgor pressure. The few appressoria that succeeded in penetration were severely restricted in invasive growth and consequently failed to cause disease. Moreover, ETF mutant etfb− induced ROS accumulation in infected host cells and exogenous antioxidant GSH accelerated mutant invading growth without increasing the penetration rate. In addition, mutant etfb− displayed elevated lipid body accumulation and reduced ATP synthesis. Taken together, ETF and ETFDH play an important role in fungal development and plant infection in M. oryzae by regulation of fatty acid metabolism, turgor establishment and induction of host ROS accumulation. PMID:27113712

Functional characterization of electron-transferring flavoprotein and its dehydrogenase required for fungal development and plant infection by the rice blast fungus.

PubMed

Li, Ya; Zhu, Jindong; Hu, Jiexiong; Meng, Xiuli; Zhang, Qi; Zhu, Kunpeng; Chen, Xiaomin; Chen, Xuehang; Li, Guangpu; Wang, Zonghua; Lu, Guodong

2016-04-26

Electron-transferring flavoprotein (ETF) and its dehydrogenase (ETFDH) are highly conserved electron carriers which mainly function in mitochondrial fatty acid β oxidation. Here, we report the identification and characterization of ETF α and β subunit encoding genes (ETFA and ETFB) and ETFDH encoding gene (ETFDH) in the rice blast fungus Magnaporthe oryzae. It was demonstrated that, by impacting fatty acid metabolism, ETF and ETFDH mutations led to severe growth and conidiation defects, which could be largely rescued by exogenous acetate or carbonate. Furthermore, although conidium germination and appressorium formation appeared to be normal in ETF and ETFDH mutants, most appressoria failed to penetrate the host epidermis due to low turgor pressure. The few appressoria that succeeded in penetration were severely restricted in invasive growth and consequently failed to cause disease. Moreover, ETF mutant etfb(-) induced ROS accumulation in infected host cells and exogenous antioxidant GSH accelerated mutant invading growth without increasing the penetration rate. In addition, mutant etfb(-) displayed elevated lipid body accumulation and reduced ATP synthesis. Taken together, ETF and ETFDH play an important role in fungal development and plant infection in M. oryzae by regulation of fatty acid metabolism, turgor establishment and induction of host ROS accumulation.

Fungal Zinc Homeostasis - A Tug of War Between the Pathogen and Host.

PubMed

Walencik, Paulina K; Watly, Joanna; Rowinska-Zyrek, Magdalena

2016-01-01

In the last decade, drug resistant invasive mycoses have become significantly more common and new antifungal drugs and ways to specifically deliver them to the fungal cell are being looked for. One of the biggest obstacles in finding such comes from the fact that fungi share essential metabolic pathways with humans. One significant difference in the metabolism of those two cells that can be challenged when looking for possible selective therapeutics is the uptake of zinc, a nutrient crucial for the fungal survival and virulence. This work summarizes the recent advances in the biological inorganic chemistry of zinc metabolism in fungi. The regulation of zinc uptake, various types of its transmembrane transport, storage and the maintenance of intracellular zinc homeostasis is discussed in detail, with a special focus on the concept of a constant 'tug of war' over zinc between the fungus and its host, with the host trying to withhold essential Zn(II), and the fungus counteracting by producing high-affinity zinc binding molecules.

Miscellaneous fungal diseases

USGS Publications Warehouse

Friend, M.

1999-01-01

As for other types of disease, fungal infections probably are more common causes of disease in wild birds than is currently recognized. Also, the similarity in gross lesions produced by some fungi mask the detection of less common fungi as disease agents. Numerous types of disease-causing fungi in addition to Aspergillus fumigatus and Candida albicans have been isolated from birds; most isolations have been from poultry and wild birds being maintained in captivity. Enhanced disease surveillance that is often associated with privately owned birds and greater opportunity to detect disease in confined birds are reasons for these findings rather than any known differences in the occurrence of fungal diseases in free-ranging and captive birds. Many of the reported infections appear to have been opportunistic invasions by the fungi involved. The important points are that many fungi are capable of causing disease in birds but their collective impacts do not rival A. fumigatus as a single cause of disease in wild birds. Nevertheless, it is important to be aware of the diversity of pathogenic or disease causing fungi.

The Mitochondrial GTPase Gem1 Contributes to the Cell Wall Stress Response and Invasive Growth of Candida albicans.

PubMed

Koch, Barbara; Tucey, Timothy M; Lo, Tricia L; Novakovic, Stevan; Boag, Peter; Traven, Ana

2017-01-01

The interactions of mitochondria with the endoplasmic reticulum (ER) are crucial for maintaining proper mitochondrial morphology, function and dynamics. This enables cells to utilize their mitochondria optimally for energy production and anabolism, and it further provides for metabolic control over developmental decisions. In fungi, a key mechanism by which ER and mitochondria interact is via a membrane tether, the protein complex ERMES (ER-Mitochondria Encounter Structure). In the model yeast Saccharomyces cerevisiae , the mitochondrial GTPase Gem1 interacts with ERMES, and it has been proposed to regulate its activity. Here we report on the first characterization of Gem1 in a human fungal pathogen. We show that in Candida albicans Gem1 has a dominant role in ensuring proper mitochondrial morphology, and our data is consistent with Gem1 working with ERMES in this role. Mitochondrial respiration and steady state cellular phospholipid homeostasis are not impacted by inactivation of GEM1 in C. albicans . There are two major virulence-related consequences of disrupting mitochondrial morphology by GEM1 inactivation: C. albicans becomes hypersusceptible to cell wall stress, and is unable to grow invasively. In the gem1 Δ / Δ mutant, it is specifically the invasive capacity of hyphae that is compromised, not the ability to transition from yeast to hyphal morphology, and this phenotype is shared with ERMES mutants. As a consequence of the hyphal invasion defect, the gem1 Δ / Δ mutant is drastically hypovirulent in the worm infection model. Activation of the mitogen activated protein (MAP) kinase Cek1 is reduced in the gem1 Δ / Δ mutant, and this function could explain both the susceptibility to cell wall stress and lack of invasive growth. This result establishes a new, respiration-independent mechanism of mitochondrial control over stress signaling and hyphal functions in C. albicans . We propose that ER-mitochondria interactions and the ER-Mitochondria Organizing Network (ERMIONE) play important roles in adaptive responses in fungi, in particular cell surface-related mechanisms that drive invasive growth and stress responsive behaviors that support fungal pathogenicity.

The Mitochondrial GTPase Gem1 Contributes to the Cell Wall Stress Response and Invasive Growth of Candida albicans

PubMed Central

Koch, Barbara; Tucey, Timothy M.; Lo, Tricia L.; Novakovic, Stevan; Boag, Peter; Traven, Ana

2017-01-01

The interactions of mitochondria with the endoplasmic reticulum (ER) are crucial for maintaining proper mitochondrial morphology, function and dynamics. This enables cells to utilize their mitochondria optimally for energy production and anabolism, and it further provides for metabolic control over developmental decisions. In fungi, a key mechanism by which ER and mitochondria interact is via a membrane tether, the protein complex ERMES (ER-Mitochondria Encounter Structure). In the model yeast Saccharomyces cerevisiae, the mitochondrial GTPase Gem1 interacts with ERMES, and it has been proposed to regulate its activity. Here we report on the first characterization of Gem1 in a human fungal pathogen. We show that in Candida albicans Gem1 has a dominant role in ensuring proper mitochondrial morphology, and our data is consistent with Gem1 working with ERMES in this role. Mitochondrial respiration and steady state cellular phospholipid homeostasis are not impacted by inactivation of GEM1 in C. albicans. There are two major virulence-related consequences of disrupting mitochondrial morphology by GEM1 inactivation: C. albicans becomes hypersusceptible to cell wall stress, and is unable to grow invasively. In the gem1Δ/Δ mutant, it is specifically the invasive capacity of hyphae that is compromised, not the ability to transition from yeast to hyphal morphology, and this phenotype is shared with ERMES mutants. As a consequence of the hyphal invasion defect, the gem1Δ/Δ mutant is drastically hypovirulent in the worm infection model. Activation of the mitogen activated protein (MAP) kinase Cek1 is reduced in the gem1Δ/Δ mutant, and this function could explain both the susceptibility to cell wall stress and lack of invasive growth. This result establishes a new, respiration-independent mechanism of mitochondrial control over stress signaling and hyphal functions in C. albicans. We propose that ER-mitochondria interactions and the ER-Mitochondria Organizing Network (ERMIONE) play important roles in adaptive responses in fungi, in particular cell surface-related mechanisms that drive invasive growth and stress responsive behaviors that support fungal pathogenicity. PMID:29326680

Predicting invasive fungal disease due to Candida species in non-neutropenic, critically ill, adult patients in United Kingdom critical care units.

PubMed

Shahin, Jason; Allen, Elizabeth J; Patel, Krishna; Muskett, Hannah; Harvey, Sheila E; Edgeworth, Jonathan; Kibbler, Christopher C; Barnes, Rosemary A; Biswas, Sharmistha; Soni, Neil; Rowan, Kathryn M; Harrison, David A

2016-09-09

Given the predominance of invasive fungal disease (IFD) amongst the non-immunocompromised adult critically ill population, the potential benefit of antifungal prophylaxis and the lack of generalisable tools to identify high risk patients, the aim of the current study was to describe the epidemiology of IFD in UK critical care units, and to develop and validate a clinical risk prediction tool to identify non-neutropenic, critically ill adult patients at high risk of IFD who would benefit from antifungal prophylaxis. Data on risk factors for, and outcomes from, IFD were collected for consecutive admissions to adult, general critical care units in the UK participating in the Fungal Infection Risk Evaluation (FIRE) Study. Three risk prediction models were developed to model the risk of subsequent Candida IFD based on information available at three time points: admission to the critical care unit, at the end of 24 h and at the end of calendar day 3 of the critical care unit stay. The final model at each time point was evaluated in the three external validation samples. Between July 2009 and April 2011, 60,778 admissions from 96 critical care units were recruited. In total, 359 admissions (0.6 %) were admitted with, or developed, Candida IFD (66 % Candida albicans). At the rate of candidaemia of 3.3 per 1000 admissions, blood was the most common Candida IFD infection site. Of the initial 46 potential variables, the final admission model and the 24-h model both contained seven variables while the end of calendar day 3 model contained five variables. The end of calendar day 3 model performed the best with a c index of 0.709 in the full validation sample. Incidence of Candida IFD in UK critical care units in this study was consistent with reports from other European epidemiological studies, but lower than that suggested by previous hospital-wide surveillance in the UK during the 1990s. Risk modeling using classical statistical methods produced relatively simple risk models, and associated clinical decision rules, that provided acceptable discrimination for identifying patients at 'high risk' of Candida IFD. The FIRE Study was reviewed and approved by the Bolton NHS Research Ethics Committee (reference: 08/H1009/85), the Scotland A Research Ethics Committee (reference: 09/MRE00/76) and the National Information Governance Board (approval number: PIAG 2-10(f)/2005).

Universal fungal vaccines

PubMed Central

Hamad, Mawieh

2012-01-01

The complex nature of fungal pathogens, the intricate host-pathogen relationship and the health status of subjects in need of antifungal vaccination continue to hamper efforts to develop fungal vaccines for clinical use. That said, the rise of the universal vaccine concept is hoped to revive fungal vaccine research by expanding the pool of vaccine candidates worthy of clinical evaluation. It can do so through antigenic commonality-based screening for vaccine candidates from a wide range of pathogens and by reassessing the sizable collection of already available experimental and approved vaccines. Development of experimental vaccines protective against multiple fungal pathogens is evidence of the utility of this concept in fungal vaccine research. However, universal fungal vaccines are not without difficulties; for instance, development of vaccines with differential effectiveness is an issue that should be addressed. Additionally, rationalizing the development of universal fungal vaccines on health or economic basis could be contentious. Herein, universal fungal vaccines are discussed in terms of their potential usefulness and possible drawbacks. PMID:22922769

Phylogenetics of a fungal invasion: Origins and widespread dispersal of white-nose syndrome

USGS Publications Warehouse

Drees, Kevin P.; Lorch, Jeffrey M.; Puechmaille, Sebastein J.; Parise, Katy L.; Wibbelt, Gudrun; Hoyt, Joseph R.; Sun, Keping; Jargalsaikhan, Ariunbold; Dalannast, Munkhnast; Palmer, Jonathan M.; Linder, Daniel L.; Kilpatrick, Marm; Pearson, Talima; Keim, Paul S.; Blehert, David; Foster, Jeffrey T.

2017-01-01

Globalization has facilitated the worldwide movement and introduction of pathogens, but epizoological reconstructions of these invasions are often hindered by limited sampling and insufficient genetic resolution among isolates. Pseudogymnoascus destructans, a fungal pathogen causing the epizootic of white-nose syndrome in North American bats, has exhibited few genetic polymorphisms in previous studies, presenting challenges for both epizoological tracking of the spread of this fungus and for determining its evolutionary history. We used single nucleotide polymorphisms (SNPs) from whole-genome sequencing and microsatellites to construct high-resolution phylogenies of P. destructans. Shallow genetic diversity and the lack of geographic structuring among North American isolates support a recent introduction followed by expansion via clonal reproduction across the epizootic zone. Moreover, the genetic relationships of isolates within North America suggest widespread mixing and long-distance movement of the fungus. Genetic diversity among isolates of P. destructans from Europe was substantially higher than in those from North America. However, genetic distance between the North American isolates and any given European isolate was similar to the distance between the individual European isolates. In contrast, the isolates we examined from Asia were highly divergent from both European and North American isolates. Although the definitive source for introduction of the North American population has not been conclusively identified, our data support the origin of the North American invasion by P. destructans from Europe rather than Asia.

Phylogenetics of a Fungal Invasion: Origins and Widespread Dispersal of White-Nose Syndrome

PubMed Central

Drees, Kevin P.; Lorch, Jeffrey M.; Puechmaille, Sebastien J.; Parise, Katy L.; Wibbelt, Gudrun; Hoyt, Joseph R.; Sun, Keping; Jargalsaikhan, Ariunbold; Dalannast, Munkhnast; Lindner, Daniel L.; Marm Kilpatrick, A.; Pearson, Talima; Blehert, David S.

2017-01-01

ABSTRACT Globalization has facilitated the worldwide movement and introduction of pathogens, but epizoological reconstructions of these invasions are often hindered by limited sampling and insufficient genetic resolution among isolates. Pseudogymnoascus destructans, a fungal pathogen causing the epizootic of white-nose syndrome in North American bats, has exhibited few genetic polymorphisms in previous studies, presenting challenges for both epizoological tracking of the spread of this fungus and for determining its evolutionary history. We used single nucleotide polymorphisms (SNPs) from whole-genome sequencing and microsatellites to construct high-resolution phylogenies of P. destructans. Shallow genetic diversity and the lack of geographic structuring among North American isolates support a recent introduction followed by expansion via clonal reproduction across the epizootic zone. Moreover, the genetic relationships of isolates within North America suggest widespread mixing and long-distance movement of the fungus. Genetic diversity among isolates of P. destructans from Europe was substantially higher than in those from North America. However, genetic distance between the North American isolates and any given European isolate was similar to the distance between the individual European isolates. In contrast, the isolates we examined from Asia were highly divergent from both European and North American isolates. Although the definitive source for introduction of the North American population has not been conclusively identified, our data support the origin of the North American invasion by P. destructans from Europe rather than Asia. PMID:29233897

Deep dermatophytosis and inherited CARD9 deficiency.

PubMed

Lanternier, Fanny; Pathan, Saad; Vincent, Quentin B; Liu, Luyan; Cypowyj, Sophie; Prando, Carolina; Migaud, Mélanie; Taibi, Lynda; Ammar-Khodja, Aomar; Stambouli, Omar Boudghene; Guellil, Boumediene; Jacobs, Frederique; Goffard, Jean-Christophe; Schepers, Kinda; Del Marmol, Véronique; Boussofara, Lobna; Denguezli, Mohamed; Larif, Molka; Bachelez, Hervé; Michel, Laurence; Lefranc, Gérard; Hay, Rod; Jouvion, Gregory; Chretien, Fabrice; Fraitag, Sylvie; Bougnoux, Marie-Elisabeth; Boudia, Merad; Abel, Laurent; Lortholary, Olivier; Casanova, Jean-Laurent; Picard, Capucine; Grimbacher, Bodo; Puel, Anne

2013-10-31

Deep dermatophytosis is a severe and sometimes life-threatening fungal infection caused by dermatophytes. It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection and has been reported in patients with no known immunodeficiency. Patients are mostly from North African, consanguineous, multiplex families, which strongly suggests a mendelian genetic cause. We studied the clinical features of deep dermatophytosis in 17 patients with no known immunodeficiency from eight unrelated Tunisian, Algerian, and Moroccan families. Because CARD9 (caspase recruitment domain-containing protein 9) deficiency has been reported in an Iranian family with invasive fungal infections, we also sequenced CARD9 in the patients. Four patients died, at 28, 29, 37, and 39 years of age, with clinically active deep dermatophytosis. No other severe infections, fungal or otherwise, were reported in the surviving patients, who ranged in age from 37 to 75 years. The 15 Algerian and Tunisian patients, from seven unrelated families, had a homozygous Q289X CARD9 allele, due to a founder effect. The 2 Moroccan siblings were homozygous for the R101C CARD9 allele. Both alleles are rare deleterious variants. The familial segregation of these alleles was consistent with autosomal recessive inheritance and complete clinical penetrance. All the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. Deep dermatophytosis appears to be an important clinical manifestation of CARD9 deficiency. (Funded by Agence Nationale pour la Recherche and others.).

Deep Dermatophytosis and Inherited CARD9 Deficiency

PubMed Central

Vincent, Quentin B.; Liu, Luyan; Cypowyj, Sophie; Prando, Carolina; Migaud, Mélanie; Taibi, Lynda; Ammar-Khodja, Aomar; Stambouli, Omar Boudghene; Guellil, Boumediene; Jacobs, Frederique; Goffard, Jean-Christophe; Schepers, Kinda; del Marmol, Véronique; Boussofara, Lobna; Denguezli, Mohamed; Larif, Molka; Bachelez, Hervé; Michel, Laurence; Lefranc, Gérard; Hay, Rod; Jouvion, Gregory; Chretien, Fabrice; Fraitag, Sylvie; Bougnoux, Marie-Elisabeth; Boudia, Merad

2014-01-01

BACKGROUND Deep dermatophytosis is a severe and sometimes life-threatening fungal infection caused by dermatophytes. It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection and has been reported in patients with no known immunodeficiency. Patients are mostly from North African, consanguineous, multiplex families, which strongly suggests a mendelian genetic cause. METHODS We studied the clinical features of deep dermatophytosis in 17 patients with no known immunodeficiency from eight unrelated Tunisian, Algerian, and Moroccan families. Because CARD9 (caspase recruitment domain–containing protein 9) deficiency has been reported in an Iranian family with invasive fungal infections, we also sequenced CARD9 in the patients. RESULTS Four patients died, at 28, 29, 37, and 39 years of age, with clinically active deep dermatophytosis. No other severe infections, fungal or otherwise, were reported in the surviving patients, who ranged in age from 37 to 75 years. The 15 Algerian and Tunisian patients, from seven unrelated families, had a homozygous Q289X CARD9 allele, due to a founder effect. The 2 Moroccan siblings were homozygous for the R101C CARD9 allele. Both alleles are rare deleterious variants. The familial segregation of these alleles was consistent with autosomal recessive inheritance and complete clinical penetrance. CONCLUSIONS All the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. Deep dermatophytosis appears to be an important clinical manifestation of CARD9 deficiency. (Funded by Agence Nationale pour la Recherche and others.) PMID:24131138

Multicenter Comparison of Serum and Whole-Blood Specimens for Detection of Aspergillus DNA in High-Risk Hematological Patients

PubMed Central

Springer, Jan; Morton, C. O.; Perry, Michael; Heinz, Werner J.; Paholcsek, Melinda; Alzheimer, Mona; Rogers, T. R.; Barnes, Rosemary A.; Einsele, Hermann; White, P. Lewis

2013-01-01

Samples from patients at high risk for invasive aspergillosis (IA) were prospectively collected and analyzed for the presence of molecular markers of fungal infection. Serum specimens were screened for galactomannan and Aspergillus DNA, and whole-blood specimens were screened only for Aspergillus DNA. Fungal infections were categorized according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group, National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. Forty-seven cases (proven and probable IA) and 31 controls (no evidence of IA) were selected retrospectively for this case-control study, comprising 803 samples, in order to determine the performance of whole-blood PCR, serum PCR, and serum galactomannan testing. Although no single assay was able to detect every case of IA, a combination of different assays provided the best performance. There was no significant difference between the use of whole-blood and serum specimens for PCR-based diagnosis of IA, but there was a trend for whole blood to be more sensitive (85% versus 79%) and to yield an earlier positive result (36 days versus 15 days) than for serum. However, DNA extraction from serum specimens is easier and faster than that from whole-blood specimens, and it allows the same specimen to be used for both galactomannan and PCR assays. In conclusion, the appropriate sample type for DNA extraction should be determined by the local requirements and the technical platforms available at each individual center. A combination of biomarker tests offered the best diagnostic utility for detecting IA. PMID:23426930

Serious fungal infections in the Philippines.

PubMed

Batac, M C R; Denning, D

2017-06-01

The Philippines is a low middle-income, tropical country in Southeast Asia. Infectious diseases remain the main causes of morbidity, including tuberculosis. AIDS/HIV prevalence is still low at <1%, but is rapidly increasing. Fungal disease surveillance has not been done, and its burden has never been estimated. This becomes more important as the population of immunocompromised patients increases, drawn from patients with AIDS, TB, malignancies, and autoimmune diseases requiring chronic steroid use. Using the methodology of the LIFE program ( www.LIFE-worldwide.org ), estimates were derived from data gathered from WHO, UNAIDS, Philippine Health Statistics 2011, Philippine Dermatological Society Health Information System database, HIV/AIDS and ART registry of the Philippines, epidemiological studies such as The TREAT Asia HIV Observational Database 2005, and personal communication. Aspergillosis and candidiasis were the top causes of fungal infections in the Philippines. Chronic pulmonary aspergillosis (CPA), drawn from the number of tuberculosis patients, affects 77,172 people. Allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS) frequencies, which were derived from the number of asthmatic patients, affect 121,113 and 159,869 respectively. Recurrent vulvovaginal candidiasis (RVVC) affects 1,481,899 women. Other estimates were cryptococcal meningitis 84, Pneumocystis pneumonia 391, oral candidiasis 3,467, esophageal candidiasis 1,522 (all in HIV-infected people), invasive aspergillosis (IA) 3,085, candidemia 1,968, candida peritonitis 246, mucormycosis 20, fungal keratitis 358, tinea capitis 846 and mycetoma 97 annually. A total of 1,852,137 (1.9% of population) are afflicted with a serious fungal infection. Epidemiological studies are needed to validate these estimates, facilitating appropriate medical care of patients and proper prioritization of limited resources.

Deletion of Aspergillus nidulans GDP-mannose transporters affects hyphal morphometry, cell wall architecture, spore surface character, cell adhesion, and biofilm formation.

PubMed

Kadry, Ashraf A; El-Ganiny, Amira M; Mosbah, Rasha A; Kaminskyj, Susan G W

2018-07-01

Systemic human fungal infections are increasingly common. Aspergillus species cause most of the airborne fungal infections. Life-threatening invasive aspergillosis was formerly found only in immune-suppressed patients, but recently some strains of A. fumigatus have become primary pathogens. Many fungal cell wall components are absent from mammalian systems, so they are potential drug targets. Cell-wall-targeting drugs such as echinocandins are used clinically, although echinocandin-resistant strains were discovered shortly after their introduction. Currently there are no fully effective anti-fungal drugs. Fungal cell wall glycoconjugates modulate human immune responses, as well as fungal cell adhesion, biofilm formation, and drug resistance. Guanosine diphosphate (GDP) mannose transporters (GMTs) transfer GDP-mannose from the cytosol to the Golgi lumen prior to mannosylation. Aspergillus nidulans GMTs are encoded by gmtA and gmtB. Here we elucidate the roles of A. nidulans GMTs. Strains engineered to lack either or both GMTs were assessed for hyphal and colonial morphology, cell wall ultrastructure, antifungal susceptibility, spore hydrophobicity, adherence and biofilm formation. The gmt-deleted strains had smaller colonies with reduced sporulation and with thicker hyphal walls. The gmtA deficient spores had reduced hydrophobicity and were less adherent and less able to form biofilms in vitro. Thus, gmtA not only participates in maintaining the cell wall integrity but also plays an important role in biofilm establishment and adherence of A. nidulans. These findings suggested that GMTs have roles in A. nidulans growth and cell-cell interaction and could be a potential target for new antifungals that target virulence determinants.

Fungal Burn Wound Infection

DTIC Science & Technology

1991-01-01

Aspergillus), Blasto- T he use of effective topical chemotherapeutic agents to myces (Candida), and Zygomycetes ( Mucor , Rhizopus).6 reduce...species, 18%; Mucor species and Rhizopus species, acetate in the morning and silver sulfadiazine in the evening. Prophy- 9.1%; and Microspora species and...sensitivity reports, and the patient’s sue, including one patient who required a hip disarticulation response. to control an invasive Mucor burn wound

Host identity matters in the amphibian-Batrachochytrium dendrobatidis system: fine-scale patterns of variation in responses to a multi-host pathogen

Treesearch

Stephanie Gervasi; Carmen Gondhalekar; Deanna H. Olson; Andrew R. Blaustein

2013-01-01

Species composition within ecological assemblages can drive disease dynamics including pathogen invasion, spread, and persistence. In multi-host pathogen systems, interspecific variation in responses to infection creates important context dependency when predicting the outcome of disease. Here, we examine the responses of three sympatric host species to a single fungal...

Putative source of the invasive Sirex noctilio fungal symbiont, Amylostereum areolatum, in the eastern United States and its association with native siricid woodwasps

Treesearch

Ann E. Hajek; Charlotte Nielsen; David W. Williams

2011-01-01

The white rot basidiomycete fungus Amylostereum areolatum is carried by females of Sirex noctilio in mycangia at the base of their ovipositors and inserted into pine trees when eggs are deposited. S. noctilio and A. areolatum are native to Europe but have been introduced throughout many areas...

Suitability of California bay laurel and other species as potential hosts for the non-native redbay ambrosia beetle and granulate ambrosia beetle

USDA-ARS?s Scientific Manuscript database

The redbay ambrosia beetle (Xyleborus glabratus Eichhoff) is a non-native invasive forest pest and vector of the pathogen that causes laurel wilt, a deadly disease of trees in the family Lauraceae in the southeastern United States (U.S.). Concern exists that X. glabratus and its fungal symbiont cou...

A novel plant-fungal mutualism associated with fire

Treesearch

Melissa Baynes; George Newcombe; Linley Dixon; Lisa Castlebury; Kerry O' Donnell

2012-01-01

Bromus tectorum, or cheatgrass, is native to Eurasia and widely invasive in western North America. By late spring, this annual plant has dispersed its seed and died; its aboveground biomass then becomes fine fuel that burns as frequently as once every 3-5 y in its invaded range. Cheatgrass has proven to be better adapted to fire there than many competing plants, but...

Antifungal defense of probiotic Lactobacillus rhamnosus GG is mediated by blocking adhesion and nutrient depletion.

PubMed

Mailänder-Sánchez, Daniela; Braunsdorf, Christina; Grumaz, Christian; Müller, Christoph; Lorenz, Stefan; Stevens, Philip; Wagener, Jeanette; Hebecker, Betty; Hube, Bernhard; Bracher, Franz; Sohn, Kai; Schaller, Martin

2017-01-01

Candida albicans is an inhabitant of mucosal surfaces in healthy individuals but also the most common cause of fungal nosocomial blood stream infections, associated with high morbidity and mortality. As such life-threatening infections often disseminate from superficial mucosal infections we aimed to study the use of probiotic Lactobacillus rhamnosus GG (LGG) in prevention of mucosal C. albicans infections. Here, we demonstrate that LGG protects oral epithelial tissue from damage caused by C. albicans in our in vitro model of oral candidiasis. Furthermore, we provide insights into the mechanisms behind this protection and dissect direct and indirect effects of LGG on C. albicans pathogenicity. C. albicans viability was not affected by LGG. Instead, transcriptional profiling using RNA-Seq indicated dramatic metabolic reprogramming of C. albicans. Additionally, LGG had a significant impact on major virulence attributes, including adhesion, invasion, and hyphal extension, whose reduction, consequently, prevented epithelial damage. This was accompanied by glucose depletion and repression of ergosterol synthesis, caused by LGG, but also due to blocked adhesion sites. Therefore, LGG protects oral epithelia against C. albicans infection by preventing fungal adhesion, invasion and damage, driven, at least in parts, by metabolic reprogramming due to nutrient limitation caused by LGG.

Curcumin and its promise as an anticancer drug: An analysis of its anticancer and antifungal effects in cancer and associated complications from invasive fungal infections.

PubMed

Chen, Jin; He, Zheng-Min; Wang, Feng-Ling; Zhang, Zheng-Sheng; Liu, Xiu-zhen; Zhai, Dan-Dan; Chen, Wei-Dong

2016-02-05

Invasive fungal infections (IFI) are important complications of cancer, and they have become a major cause of morbidity and mortality in cancer patients. Effective anti-infection therapy is necessary to inhibit significant deterioration from these infections. However, they are difficult to treat, and increasing antifungal drug resistance often leads to a relapse. Curcumin, a natural component that is isolated from the rhizome of Curcuma longa plants, has attracted great interest among many scientists studying solid cancers over the last half century. Interestingly, curcumin provides an ideal alternative to current therapies because of its relatively safe profile, even at high doses. To date, curcumin's potent antifungal activity against different strains of Candida, Cryptococcus, Aspergillus, Trichosporon and Paracoccidioides have been reported, indicating that curcumin anticancer drugs may also possess an antifungal role, helping cancer patients to resist IFI complications. The aim of this review is to discuss curcumin's dual pharmacological activities regarding its applications as a natural anticancer and antifungal agent. These dual pharmacological activities are expected to lead to clinical trials and to improve infection survival among cancer patients. Copyright © 2015 Elsevier B.V. All rights reserved.

Multiple introductions of divergent genetic lineages in an invasive fungal pathogen, Cryphonectria parasitica, in France.

PubMed

Dutech, C; Fabreguettes, O; Capdevielle, X; Robin, C

2010-08-01

The occurrence of multiple introductions may be a crucial factor in the successful establishment of invasive species, but few studies focus on the introduction of fungal pathogens, despite their significant effect on invaded habitats. Although Cryphonectria parasitica, the chestnut blight fungus introduced in North America and Europe from Asia during the 20th century, caused dramatic changes in its new range, the history of its introduction is not well retraced in Europe. Using 10 microsatellite loci, we investigated the genetic diversity of 583 isolates in France, where several introductions have been hypothesized. Our analyses showed that the seven most frequent multilocus genotypes belonged to three genetic lineages, which had a different and geographically limited distribution. These results suggest that different introduction events occurred in France. Genetic recombination was low among these lineages, despite the presence of the two mating types in each chestnut stand analysed. The spatial distribution of lineages suggests that the history of introductions in France associated with the slow expansion of the disease has contributed to the low observed rate of recombination among the divergent lineages. However, we discuss the possibility that environmental conditions or viral interactions could locally reduce recombination among genotypes.

Fungal diseases: could nanostructured drug delivery systems be a novel paradigm for therapy?

PubMed Central

Voltan, Aline Raquel; Quindós, Guillermo; Alarcón, Kaila P Medina; Fusco-Almeida, Ana Marisa; Mendes-Giannini, Maria José Soares; Chorilli, Marlus

2016-01-01

Invasive mycoses are a major problem for immunocompromised individuals and patients in intensive care units. Morbidity and mortality rates of these infections are high because of late diagnosis and delayed treatment. Moreover, the number of available antifungal agents is low, and there are problems with toxicity and resistance. Alternatives for treating invasive fungal infections are necessary. Nanostructured systems could be excellent carriers for antifungal drugs, reducing toxicity and targeting their action. The use of nanostructured systems for antifungal therapy began in the 1990s, with the appearance of lipid formulations of amphotericin B. This review encompasses different antifungal drug delivery systems, such as liposomes, carriers based on solid lipids and nanostructure lipids, polymeric nanoparticles, dendrimers, and others. All these delivery systems have advantages and disadvantages. Main advantages are the improvement in the antifungal properties, such as bioavailability, reduction in toxicity, and target tissue, which facilitates innovative therapeutic techniques. Conversely, a major disadvantage is the high cost of production. In the near future, the use of nanosystems for drug delivery strategies can be used for delivering peptides, including mucoadhesive systems for the treatment of oral and vaginal candidiasis. PMID:27540288

Quantifying the associations between fungal endophytes and biocontrol-induced herbivory of invasive purple loosestrife (Lythrum salicaria L.).

PubMed

David, Aaron S; Quiram, Gina L; Sirota, Jennie I; Seabloom, Eric W

2016-01-01

Fungal endophytes are one of several groups of heterotrophic organisms that associate with living plants. The net effects of these groups of organisms on each other and ultimately on their host plants depend in part on how they facilitate or antagonize one another. In this study we quantified the associations between endophyte communities and herbivory induced by a biological control in the invasive Lythrum salicaria at various spatial scales using a culture-based approach. We found positive associations between herbivory damage and endophyte isolation frequency and richness at the site level and weak, positive associations at the leaf level. Herbivory damage was more strongly influenced by processes at the site level than were endophyte isolation frequency and community structure, which were influenced by processes at the plant and leaf levels. Furthermore, endophytic taxa found in low herbivory sites were nested subsets of those taxa found at high herbivory sites. Our findings suggest that endophyte communities of L. salicaria are associated with, and potentially facilitated by, biocontrol-induced herbivory. Quantifying the associations between heterotrophic groups ultimately may lead to a clearer understanding of their complex interactions with plants. © 2016 by The Mycological Society of America.

Central Role of the Trehalose Biosynthesis Pathway in the Pathogenesis of Human Fungal Infections: Opportunities and Challenges for Therapeutic Development.

PubMed

Thammahong, Arsa; Puttikamonkul, Srisombat; Perfect, John R; Brennan, Richard G; Cramer, Robert A

2017-06-01

Invasive fungal infections cause significant morbidity and mortality in part due to a limited antifungal drug arsenal. One therapeutic challenge faced by clinicians is the significant host toxicity associated with antifungal drugs. Another challenge is the fungistatic mechanism of action of some drugs. Consequently, the identification of fungus-specific drug targets essential for fitness in vivo remains a significant goal of medical mycology research. The trehalose biosynthetic pathway is found in a wide variety of organisms, including human-pathogenic fungi, but not in humans. Genes encoding proteins involved in trehalose biosynthesis are mechanistically linked to the metabolism, cell wall homeostasis, stress responses, and virulence of Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus . While there are a number of pathways for trehalose production across the tree of life, the TPS/TPP (trehalose-6-phosphate synthase/trehalose-6-phosphate phosphatase) pathway is the canonical pathway found in human-pathogenic fungi. Importantly, data suggest that proteins involved in trehalose biosynthesis play other critical roles in fungal metabolism and in vivo fitness that remain to be fully elucidated. By further defining the biology and functions of trehalose and its biosynthetic pathway components in pathogenic fungi, an opportunity exists to leverage this pathway as a potent antifungal drug target. The goal of this review is to cover the known roles of this important molecule and its associated biosynthesis-encoding genes in the human-pathogenic fungi studied to date and to employ these data to critically assess the opportunities and challenges facing development of this pathway as a therapeutic target. Copyright © 2017 American Society for Microbiology.

[The diagnostic methods applied in mycology].

PubMed

Kurnatowska, Alicja; Kurnatowski, Piotr

2008-01-01

The systemic fungal invasions are recognized with increasing frequency and constitute a primary cause of morbidity and mortality, especially in immunocompromised patients. Early diagnosis improves prognosis, but remains a problem because there is lack of sensitive tests to aid in the diagnosis of systemic mycoses on the one hand, and on the other the patients only present unspecific signs and symptoms, thus delaying early diagnosis. The diagnosis depends upon a combination of clinical observation and laboratory investigation. The successful laboratory diagnosis of fungal infection depends in major part on the collection of appropriate clinical specimens for investigations and on the selection of appropriate microbiological test procedures. So these problems (collection of specimens, direct techniques, staining methods, cultures on different media and non-culture-based methods) are presented in article.

Fungal histidine phosphotransferase plays a crucial role in photomorphogenesis and pathogenesis in Magnaporthe oryzae

NASA Astrophysics Data System (ADS)

Mohanan, Varsha C.; Chandarana, Pinal M.; Chattoo, Bharat. B.; Patkar, Rajesh N.; Manjrekar, Johannes

2017-05-01

Two-component signal transduction (TCST) pathways play crucial roles in many cellular functions such as stress responses, biofilm formation and sporulation. The histidine phosphotransferase (HPt), which is an intermediate phosphotransfer protein in a two-component system, transfers a phosphate group to a phosphorylatable aspartate residue in the target protein(s), and up-regulates stress-activated MAP kinase cascades. Most fungal genomes carry a single copy of the gene coding for HPt, which are potential antifungal targets. However, unlike the histidine kinases (HK) or the downstream response regulators (RR) in two-component system, the HPts have not been well studied in phytopathogenic fungi. In this study, we investigated the role of HPt in the model rice-blast fungal pathogen Magnaporthe oryzae. We found that in M. oryzae an additional isoform of the HPT gene YPD1 was expressed specifically in response to light. Further, the expression of light-regulated genes such as those encoding envoy and blue-light-harvesting protein, and PAS domain containing HKs was significantly reduced upon down-regulation of YPD1 in M. oryzae. Importantly, down-regulation of YPD1 led to a significant decrease in the ability to penetrate the host cuticle and in light-dependent conidiation in M. oryzae. Thus, our results indicate that Ypd1 plays an important role in asexual development and host invasion, and suggest that YPD1 isoforms likely have distinct roles to play in the rice-blast pathogen M. oryzae.

Human and Murine Innate Immune Cell Populations Display Common and Distinct Response Patterns during Their In Vitro Interaction with the Pathogenic Mold Aspergillus fumigatus.

PubMed

Hellmann, Anna-Maria; Lother, Jasmin; Wurster, Sebastian; Lutz, Manfred B; Schmitt, Anna Lena; Morton, Charles Oliver; Eyrich, Matthias; Czakai, Kristin; Einsele, Hermann; Loeffler, Juergen

2017-01-01

Aspergillus fumigatus is the main cause of invasive fungal infections occurring almost exclusively in immunocompromised patients. An improved understanding of the initial innate immune response is key to the development of better diagnostic tools and new treatment options. Mice are commonly used to study immune defense mechanisms during the infection of the mammalian host with A. fumigatus . However, little is known about functional differences between the human and murine immune response against this fungal pathogen. Thus, we performed a comparative functional analysis of human and murine dendritic cells (DCs), macrophages, and polymorphonuclear cells (PMNs) using standardized and reproducible working conditions, laboratory protocols, and readout assays. A. fumigatus did not provoke identical responses in murine and human immune cells but rather initiated relatively specific responses. While human DCs showed a significantly stronger upregulation of their maturation markers and major histocompatibility complex molecules and phagocytosed A. fumigatus more efficiently compared to their murine counterparts, murine PMNs and macrophages exhibited a significantly stronger release of reactive oxygen species after exposure to A. fumigatus . For all studied cell types, human and murine samples differed in their cytokine response to conidia or germ tubes of A. fumigatus . Furthermore, Dectin-1 showed inverse expression patterns on human and murine DCs after fungal stimulation. These specific differences should be carefully considered and highlight potential limitations in the transferability of murine host-pathogen interaction studies.

Human and Murine Innate Immune Cell Populations Display Common and Distinct Response Patterns during Their In Vitro Interaction with the Pathogenic Mold Aspergillus fumigatus

PubMed Central

Hellmann, Anna-Maria; Lother, Jasmin; Wurster, Sebastian; Lutz, Manfred B.; Schmitt, Anna Lena; Morton, Charles Oliver; Eyrich, Matthias; Czakai, Kristin; Einsele, Hermann; Loeffler, Juergen

2017-01-01

Aspergillus fumigatus is the main cause of invasive fungal infections occurring almost exclusively in immunocompromised patients. An improved understanding of the initial innate immune response is key to the development of better diagnostic tools and new treatment options. Mice are commonly used to study immune defense mechanisms during the infection of the mammalian host with A. fumigatus. However, little is known about functional differences between the human and murine immune response against this fungal pathogen. Thus, we performed a comparative functional analysis of human and murine dendritic cells (DCs), macrophages, and polymorphonuclear cells (PMNs) using standardized and reproducible working conditions, laboratory protocols, and readout assays. A. fumigatus did not provoke identical responses in murine and human immune cells but rather initiated relatively specific responses. While human DCs showed a significantly stronger upregulation of their maturation markers and major histocompatibility complex molecules and phagocytosed A. fumigatus more efficiently compared to their murine counterparts, murine PMNs and macrophages exhibited a significantly stronger release of reactive oxygen species after exposure to A. fumigatus. For all studied cell types, human and murine samples differed in their cytokine response to conidia or germ tubes of A. fumigatus. Furthermore, Dectin-1 showed inverse expression patterns on human and murine DCs after fungal stimulation. These specific differences should be carefully considered and highlight potential limitations in the transferability of murine host–pathogen interaction studies. PMID:29270175

Serious fungal infections in Ecuador.

PubMed

Zurita, J; Denning, D W; Paz-Y-Miño, A; Solís, M B; Arias, L M

2017-06-01

There is a dearth of data from Ecuador on the burden of life-threatening fungal disease entities; therefore, we estimated the burden of serious fungal infections in Ecuador based on the populations at risk and available epidemiological databases and publications. A full literature search was done to identify all epidemiology papers reporting fungal infection rates. WHO, ONU-AIDS, Index Mundi, Global Asthma Report, Globocan, and national data [Instituto Nacional de Estadística y Censos (INEC), Ministerio de Salud Pública (MSP), Sociedad de Lucha Contra el Cáncer (SOLCA), Instituto Nacional de Donación y Trasplante de Órganos, Tejidos y Células (INDOT)] were reviewed. When no data existed, risk populations were used to estimate frequencies of fungal infections, using previously described methodology by LIFE. Ecuador has a variety of climates from the cold of the Andes through temperate to humid hot weather at the coast and in the Amazon basin. Ecuador has a population of 15,223,680 people and an average life expectancy of 76 years. The median estimate of the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) population at risk for fungal disease (<200 CD4 cell counts) is ∼10,000, with a rate of 11.1% (1100) of histoplasma, 7% (700) of cryptococcal meningitis, and 11% (1070) of Pneumocystis pneumonia. The burden of candidemia is 1037. Recurrent Candida vaginitis (≥4 episodes per year) affects 307,593 women aged 15-50 years. Chronic pulmonary aspergillosis probably affects ∼476 patients following tuberculosis (TB). Invasive aspergillosis is estimated to affect 748 patients (∼5.5/100,000). In addition, allergic bronchopulmonary aspergillosis (ABPA) in asthma and severe asthma with fungal sensitization (SAFS) were estimated to affect 26,642 and 45,013 people, respectively. Our estimates indicate that 433,856 (3%) of the population in Ecuador is affected by serious fungal infection.

Invasive tracheobronchial aspergillosis in a patient with systemic lupus erythematosus-dermatomyositis overlap syndrome.

PubMed

Sada, Mitsuru; Saraya, Takeshi; Tanaka, Yasutaka; Sato, Shinji; Wakayama, Megumi; Shibuya, Kazutoshi; Uchiyama, Takashi; Ogata, Hideo; Takizawa, Hajime; Goto, Hajime

2013-01-01

A 45-year-old man was referred to our hospital with a 3-month history of dyspnea, polyarthralgia, myalgia and weight loss. He was diagnosed with systemic lupus erythematosus/dermatomyositis overlap syndrome with lung involvement, which presented as organizing pneumonia. However, a bronchoscopic examination revealed the presence of multiple plaque-like white lesions with ulcers on the bronchial membrane, located mainly in the central airway. The pathological specimens obtained from bronchoscopy showed numerous filamentous fungal hyphae that were aggressively invading the bronchial walls, suggesting a diagnosis of invasive tracheobronchial aspergillosis. The present case, along with a review of the literature, demonstrates that invasive tracheobronchial aspergillosis can occur in patients who do not appear to be immunosuppressed. This case of aspergillosis should thus be recognized as an extremely rare presentation of an Aspergillus infection.

Invasive candidiasis and oral manifestations in premature newborns.

PubMed

Tinoco-Araujo, José Endrigo; Araújo, Diana Ferreira Gadelha; Barbosa, Patrícia Gomes; Santos, Paulo Sérgio da Silva; Medeiros, Ana Myriam Costa de

2013-01-01

To investigate prevalence of invasive candidiasis in a Neonatal Intensive Care Unit and to evaluate oral diseases and Candida spp. colonization in low birth weight preterm newborns. A descriptive epidemiological study performed in two stages. First, prevalence of candidiasis was analyzed in a database of 295 preterm patients admitted to hospital for over 10 days and birth weight less than 2,000g. In the second stage, oral changes and Candida spp. colonization were assessed in 65 patients weighing less than 2,000g, up to 4 week-old, hospitalized for over 10 days and presenting oral abnormalities compatible with fungal lesions. Swab samples were collected in the mouth to identify fungi. Prevalence of candidiasis was 5.4% in the database analyzed. It correlated with prolonged hospital length of stay (p<0.001), in average, 31 days, and 85% risk of developing infection in the first 25 days. It correlated with low birth weight (p<0.001), with mean of 1,140g. The most frequent alterations were white soft plaques, detachable, in oral mucosa and tongue. Intense oral colonization by Candida spp was observed (80%). The frequency of invasive candidiasis was low and correlated with low birth weight and prolonged hospital stay. The most common oral changes were white plaques compatible with pseudomembranous candidiasis and colonization by Candida spp. was above average.

Milbemycins: More than Efflux Inhibitors for Fungal Pathogens

PubMed Central

Silva, Luis Vale; Sanguinetti, Maurizio; Vandeputte, Patrick; Torelli, Riccardo; Rochat, Bertrand

2013-01-01

Existing antifungal agents are still confronted to activities limited to specific fungal species and to the development of resistance. Several improvements are possible either by tackling and overcoming resistance or exacerbating the activity of existing antifungal agents. In Candida glabrata, azole resistance is almost exclusively mediated by ABC transporters (including C. glabrata CDR1 [CgCDR1] and CgCDR2) via gain-of-function mutations in the transcriptional activator CgPDR1 or by mitochondrial dysfunctions. We also observed that azole resistance was correlating with increasing virulence and fitness of C. glabrata in animal models of infection. This observation motivated the re-exploitation of ABC transporter inhibitors as a possible therapeutic intervention to decrease not only the development of azole resistance but also to interfere with the virulence of C. glabrata. Milbemycins are known ABC transporter inhibitors, and here we used commercially available milbemycin A3/A4 oxim derivatives to verify this effect. As expected, the derivatives were inhibiting C. glabrata efflux with the highest activity for A3 oxim below 1 μg/ml. More surprising was that oxim derivatives had intrinsic fungicidal activity above 3.2 μg/ml, thus highlighting effects additional to the efflux inhibition. Similar values were obtained with C. albicans. Our data show that the fungicidal activity could be related to reactive oxygen species formation in these species. Transcriptional analysis performed both in C. glabrata and C. albicans exposed to A3 oxim highlighted a core of commonly regulated genes involved in stress responses, including genes involved in oxidoreductive processes, protein ubiquitination, and vesicle trafficking, as well as mitogen-activated protein kinases. However, the transcript profiles contained also species-specific signatures. Following these observations, experimental treatments of invasive infections were performed in mice treated with the commercial A3/A4 oxim preparation alone or in combination with fluconazole. Tissue burden analysis revealed that oxims on their own were able to decrease fungal burdens in both Candida species. In azole-resistant isolates, oxims acted synergistically in vivo with fluconazole to reduce fungal burden to levels of azole-susceptible isolates. In conclusion, we show here the potential of milbemycins not only as drug efflux inhibitors but also as effective fungal growth inhibitors in C. glabrata and C. albicans. PMID:23208712

Initial fungal colonizer affects mass loss and fungal community development in Picea abies logs 6 yr after inoculation

Treesearch

Daniel L. Lindner; Rimvydas Vasaitis; Ariana Kubartova; Johan Allmer; Hanna Johannesson; Mark T. Banik; Jan. Stenlid

2011-01-01

Picea abies logs were inoculated with Resinicium bicolor, Fomitopsis pinicola or left un-inoculated and placed in an old-growth boreal forest. Mass loss and fungal community data were collected after 6 yr to test whether simplification of the fungal community via inoculation affects mass loss and fungal community development. Three...

Epidemiology of Hospitalizations Associated with Invasive Candidiasis, United States, 2002–20121

PubMed Central

Strollo, Sara; Lionakis, Michail S.; Adjemian, Jennifer; Steiner, Claudia A.

2017-01-01

Invasive candidiasis is a major nosocomial fungal disease in the United States associated with high rates of illness and death. We analyzed inpatient hospitalization records from the Healthcare Cost and Utilization Project to estimate incidence of invasive candidiasis–associated hospitalizations in the United States. We extracted data for 33 states for 2002–2012 by using codes from the International Classification of Diseases, 9th Revision, Clinical Modification, for invasive candidiasis; we excluded neonatal cases. The overall age-adjusted average annual rate was 5.3 hospitalizations/100,000 population. Highest risk was for adults >65 years of age, particularly men. Median length of hospitalization was 21 days; 22% of patients died during hospitalization. Median unadjusted associated cost for inpatient care was $46,684. Age-adjusted annual rates decreased during 2005–2012 for men (annual change –3.9%) and women (annual change –4.5%) and across nearly all age groups. We report a high mortality rate and decreasing incidence of hospitalizations for this disease. PMID:27983497

Epidemiology of Hospitalizations Associated with Invasive Candidiasis, United States, 2002-20121.

PubMed

Strollo, Sara; Lionakis, Michail S; Adjemian, Jennifer; Steiner, Claudia A; Prevots, D Rebecca

2016-01-01

Invasive candidiasis is a major nosocomial fungal disease in the United States associated with high rates of illness and death. We analyzed inpatient hospitalization records from the Healthcare Cost and Utilization Project to estimate incidence of invasive candidiasis-associated hospitalizations in the United States. We extracted data for 33 states for 2002-2012 by using codes from the International Classification of Diseases, 9th Revision, Clinical Modification, for invasive candidiasis; we excluded neonatal cases. The overall age-adjusted average annual rate was 5.3 hospitalizations/100,000 population. Highest risk was for adults >65 years of age, particularly men. Median length of hospitalization was 21 days; 22% of patients died during hospitalization. Median unadjusted associated cost for inpatient care was $46,684. Age-adjusted annual rates decreased during 2005-2012 for men (annual change -3.9%) and women (annual change -4.5%) and across nearly all age groups. We report a high mortality rate and decreasing incidence of hospitalizations for this disease.

Sentinel trees as a tool to forecast invasions of alien plant pathogens.

PubMed

Vettraino, AnnaMaria; Roques, Alain; Yart, Annie; Fan, Jian-ting; Sun, Jiang-hua; Vannini, Andrea

2015-01-01

Recent disease outbreaks caused by alien invasive pathogens into European forests posed a serious threat to forest sustainability with relevant environmental and economic effects. Many of the alien tree pathogens recently introduced into Europe were not previously included on any quarantine lists, thus they were not subject to phytosanitary inspections. The identification and description of alien fungi potentially pathogenic to native European flora before their introduction in Europe, is a paramount need in order to limit the risk of invasion and the impact to forest ecosystems. To determine the potential invasive fungi, a sentinel trees plot was established in Fuyang, China, using healthy seedlings of European tree species including Quercus petreae, Q. suber, and Q. ilex. The fungal assemblage associated with symptomatic specimens was studied using the tag-encoded 454 pyrosequencing of the nuclear ribosomal internal transcribed spacer-1 (ITS 1). Taxa with probable Asiatic origin were identified and included plant pathogenic genera. These results indicate that sentinel plants may be a strategic tool to improve the prevention of bioinvasions.

Consensus guidelines for the treatment of invasive mould infections in haematological malignancy and haemopoietic stem cell transplantation, 2014.

PubMed

Blyth, C C; Gilroy, N M; Guy, S D; Chambers, S T; Cheong, E Y; Gottlieb, T; McGuinness, S L; Thursky, K A

2014-12-01

Mould species represent the pathogens most commonly associated with invasive fungal disease in patients with haematological malignancies and patients of haemopoietic stem cell transplants. Invasive mould infections in these patient populations, particularly in the setting of neutropenia, are associated with high morbidity and mortality, and significantly increase the complexity of management. While Aspergillus species remain the most prevalent cause of invasive mould infections, Scedosporium and Fusarium species and the Mucormycetes continue to place a significant burden on the immunocompromised host. Evidence also suggests that infections caused by rare and emerging pathogens are increasing within the setting of broad-spectrum antifungal prophylaxis and improved survival times placing immunosuppressed patients at risk for longer. These guidelines present evidence-based recommendations for the antifungal management of common, rare and emerging mould infections in both adult and paediatric populations. Where relevant, the role of surgery, adjunctive therapy and immunotherapy is also discussed. © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.

Role of caspofungin in restoring the impaired phagocyte-dependent innate immunity towards Candida albicans in chronic haemodialysis patients.

PubMed

Scalas, Daniela; Banche, Giuliana; Merlino, Chiara; Giacchino, Franca; Allizond, Valeria; Garneri, Giuseppe; Patti, Rosaria; Roana, Janira; Mandras, Narcisa; Tullio, Vivian; Cuffini, Anna Maria

2012-01-01

Phagocyte-dependent cellular immunity in chronic kidney disease patients undergoing haemodialysis treatment is frequently impaired owing to the uraemic state, resulting in an intrinsic susceptibility to developing invasive fungal infections with high mortality rates. Since synergism between phagocytic cells and antifungal drugs may be crucial for successful therapy, the aim of this study was to evaluate the effects exerted by caspofungin (CAS) on the functional activities of polymorphonuclear cells (PMNs) in haemodialysed patients (HDs) towards Candida albicans compared with those of PMNs from healthy subjects (HSs). PMNs were separated from venous blood samples of 66 HDs and 30 HSs (as controls), and measurement of phagocytic and intracellular fungicidal activities of HD-PMNs and HS-PMNs was performed in the presence of CAS at the minimum inhibitory concentration (MIC) and at sub-MICs. CAS-free controls were also included. In the drug-free test condition, no significant difference between the phagocytic activity of HD-PMNs and HS-PMNs was detected. In contrast, a progressive decline in the intracellular killing activity of HD-PMNs against proliferating yeasts was observed. CAS at MIC and sub-MIC levels was able to improve significantly the intracellular fungicidal activity of HD-PMNs against C. albicans, restoring their functionality. These findings provide evidence that CAS exerts a synergistic effect on HD-PMNs against C. albicans, being able to strength the depressed intracellular killing activity. These results corroborate the use of CAS as an effective therapeutic option for the treatment of invasive fungal infections in HDs, in whom even a marginal influence of antifungal drugs on host response may have a relevant effect. Copyright © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Risks and outcomes of invasive fungal infections in pediatric allogeneic hematopoietic stem cell transplant recipients receiving fluconazole prophylaxis: a multicenter cohort study by the Turkish Pediatric Bone Marrow Transplantation Study Group.

PubMed

Hazar, Volkan; Karasu, Gülsün Tezcan; Uygun, Vedat; Öztürk, Gülyüz; Kiliç, Suar Çaki; Küpesiz, Alphan; Daloglu, Hayriye; Aksoylar, Serap; Atay, Didem; Ince, Elif Ünal; Karakükçü, Musa; Özbek, Namik; Tayfun, Funda; Kansoy, Savas; Özyürek, Emel; Akçay, Arzu; Gürsel, Orhan; Haskologlu, Sule; Kaya, Zühre; Yilmaz, Sebnem; Tanyeli, Atila; Yesilipek, Akif

2018-03-27

Invasive fungal infections (IFIs) are a major cause of infection-related morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Data from pediatric settings are scarce. To determine the incidence, risk factors and outcomes of IFIs in a 180-day period post-transplantation, 408 pediatric patients who underwent allogeneic HSCT were retrospectively analyzed. The study included only proven and probable IFIs. The cumulative incidences of IFI were 2.7%, 5.0%, and 6.5% at 30, 100, and 180 days post-transplantation, respectively. According to the multivariate analysis, the factors associated with increased IFI risk in the 180-day period post-HSCT were previous HSCT history (hazard ratio [HR], 4.57; 95% confidence interval [CI] 1.42-14.71; P = .011), use of anti-thymocyte globulin (ATG) (HR, 2.94; 95% CI 1.27-6.80; P = .012), grade III-IV acute graft-versus-host-disease (GVHD) (HR, 2.91; 95% CI 1.24-6.80; P = .014) and late or no lymphocyte engraftment (HR, 2.71; 95% CI 1.30-5.62; P = .007). CMV reactivation was marginally associated with an increased risk of IFI development (HR, 1.91; 95% CI 0.97-3.74; P = .063). IFI-related mortality was 1.5%, and case fatality rate was 27.0%.The close monitoring of IFIs in pediatric patients with severe acute GVHD who receive ATG during conditioning is critical to reduce morbidity and mortality after allogeneic HSCT, particularly among those with prior HSCT and no or late lymphocyte engraftment.

Clinical characteristics and outcome of invasive fungal infections in pediatric acute myeloid leukemia patients in a medical center in Taiwan.

PubMed

Lin, Gu-Lung; Chang, Hsiu-Hao; Lu, Chun-Yi; Chen, Chung-Ming; Lu, Meng-Yao; Lee, Ping-Ing; Jou, Shiann-Tarng; Yang, Yung-Li; Huang, Li-Min; Chang, Luan-Yin

2018-04-01

Invasive fungal infection (IFI) causes significant morbidity and mortality in patients with hematological malignancies, especially those with acute myeloid leukemia (AML), recurrent acute leukemia, high-risk acute lymphoblastic leukemia, and after allogeneic hematopoietic stem cell transplantation. The study aimed to investigate the clinical characteristics and outcome of IFIs in pediatric AML patients in a medical center in Taiwan. We performed retrospective chart reviews. We enrolled pediatric AML patients who were admitted to National Taiwan University Hospital between January 2005 and December 2014. IFI was defined according to the European Organization for Research and Treatment of Cancer/Mycosis Study Group 2008 consensus criteria. In total, 78 patients were included for analysis. Twenty two episodes of IFIs were identified in 16 patients. The incidence for IFIs was 20.5% (16/78), and no specific trend of increase or decrease was observed through the study period (p=0.374). Candida species caused the majority (59.1%) of IFIs. Prolonged neutropenia and elevated alanine aminotransferase and creatinine values were factors associated with IFIs (p<0.001, p<0.001, and p=0.001, respectively). Patients with endotracheal intubation or inotropes usage had a higher probability of developing IFIs (p<0.001 and p=0.001, respectively). The overall mortality of IFIs was 53% (8/15) over 10 years, and patients with pulmonary aspergillosis had the highest mortality (80%). IFIs continue to pose significant morbidity and mortality in pediatric AML patients, and patients with other hematology-oncology cancers. Recognition of factors associated with IFIs may help us early identify IFIs and promptly initiate antifungal therapy. Copyright © 2017. Published by Elsevier B.V.

Determining the analytical specificity of PCR-based assays for the diagnosis of IA: What is Aspergillus?

PubMed

Morton, C Oliver; White, P Lewis; Barnes, Rosemary A; Klingspor, Lena; Cuenca-Estrella, Manuel; Lagrou, Katrien; Bretagne, Stéphane; Melchers, Willem; Mengoli, Carlo; Caliendo, Angela M; Cogliati, Massimo; Debets-Ossenkopp, Yvette; Gorton, Rebecca; Hagen, Ferry; Halliday, Catriona; Hamal, Petr; Harvey-Wood, Kathleen; Jaton, Katia; Johnson, Gemma; Kidd, Sarah; Lengerova, Martina; Lass-Florl, Cornelia; Linton, Chris; Millon, Laurence; Morrissey, C Orla; Paholcsek, Melinda; Talento, Alida Fe; Ruhnke, Markus; Willinger, Birgit; Donnelly, J Peter; Loeffler, Juergen

2017-06-01

A wide array of PCR tests has been developed to aid the diagnosis of invasive aspergillosis (IA), providing technical diversity but limiting standardisation and acceptance. Methodological recommendations for testing blood samples using PCR exist, based on achieving optimal assay sensitivity to help exclude IA. Conversely, when testing more invasive samples (BAL, biopsy, CSF) emphasis is placed on confirming disease, so analytical specificity is paramount. This multicenter study examined the analytical specificity of PCR methods for detecting IA by blind testing a panel of DNA extracted from a various fungal species to explore the range of Aspergillus species that could be detected, but also potential cross reactivity with other fungal species. Positivity rates were calculated and regression analysis was performed to determine any associations between technical specifications and performance. The accuracy of Aspergillus genus specific assays was 71.8%, significantly greater (P < .0001) than assays specific for individual Aspergillus species (47.2%). For genus specific assays the most often missed species were A. lentulus (25.0%), A. versicolor (24.1%), A. terreus (16.1%), A. flavus (15.2%), A. niger (13.4%), and A. fumigatus (6.2%). There was a significant positive association between accuracy and using an Aspergillus genus PCR assay targeting the rRNA genes (P = .0011). Conversely, there was a significant association between rRNA PCR targets and false positivity (P = .0032). To conclude current Aspergillus PCR assays are better suited for detecting A. fumigatus, with inferior detection of most other Aspergillus species. The use of an Aspergillus genus specific PCR assay targeting the rRNA genes is preferential. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Histidine biosynthesis plays a crucial role in metal homeostasis and virulence of Aspergillus fumigatus

PubMed Central

Dietl, Anna-Maria; Amich, Jorge; Leal, Sixto; Beckmann, Nicola; Binder, Ulrike; Beilhack, Andreas; Pearlman, Eric; Haas, Hubertus

2016-01-01

Abstract Aspergillus fumigatus is the most prevalent airborne fungal pathogen causing invasive fungal infections in immunosuppressed individuals. The histidine biosynthetic pathway is found in bacteria, archaebacteria, lower eukaryotes, and plants, but is absent in mammals. Here we demonstrate that deletion of the gene encoding imidazoleglycerol-phosphate dehydratase (HisB) in A. fumigatus causes (i) histidine auxotrophy, (ii) decreased resistance to both starvation and excess of various heavy metals, including iron, copper and zinc, which play a pivotal role in antimicrobial host defense, (iii) attenuation of pathogenicity in 4 virulence models: murine pulmonary infection, murine systemic infection, murine corneal infection, and wax moth larvae. In agreement with the in vivo importance of histidine biosynthesis, the HisB inhibitor 3-amino-1,2,4-triazole reduced the virulence of the A. fumigatus wild type and histidine supplementation partially rescued virulence of the histidine-auxotrophic mutant in the wax moth model. Taken together, this study reveals limited histidine availability in diverse A. fumigatus host niches, a crucial role for histidine in metal homeostasis, and the histidine biosynthetic pathway as being an attractive target for development of novel antifungal therapy approaches. PMID:26854126

Histidine biosynthesis plays a crucial role in metal homeostasis and virulence of Aspergillus fumigatus.

PubMed

Dietl, Anna-Maria; Amich, Jorge; Leal, Sixto; Beckmann, Nicola; Binder, Ulrike; Beilhack, Andreas; Pearlman, Eric; Haas, Hubertus

2016-05-18

Aspergillus fumigatus is the most prevalent airborne fungal pathogen causing invasive fungal infections in immunosuppressed individuals. The histidine biosynthetic pathway is found in bacteria, archaebacteria, lower eukaryotes, and plants, but is absent in mammals. Here we demonstrate that deletion of the gene encoding imidazoleglycerol-phosphate dehydratase (HisB) in A. fumigatus causes (i) histidine auxotrophy, (ii) decreased resistance to both starvation and excess of various heavy metals, including iron, copper and zinc, which play a pivotal role in antimicrobial host defense, (iii) attenuation of pathogenicity in 4 virulence models: murine pulmonary infection, murine systemic infection, murine corneal infection, and wax moth larvae. In agreement with the in vivo importance of histidine biosynthesis, the HisB inhibitor 3-amino-1,2,4-triazole reduced the virulence of the A. fumigatus wild type and histidine supplementation partially rescued virulence of the histidine-auxotrophic mutant in the wax moth model. Taken together, this study reveals limited histidine availability in diverse A. fumigatus host niches, a crucial role for histidine in metal homeostasis, and the histidine biosynthetic pathway as being an attractive target for development of novel antifungal therapy approaches.

Immunoevasive Aspergillus virulence factors.

PubMed

Chotirmall, Sanjay H; Mirkovic, Bojana; Lavelle, Gillian M; McElvaney, Noel G

2014-12-01

Individuals with structural lung disease or defective immunity are predisposed to Aspergillus-associated disease. Manifestations range from allergic to cavitary or angio-invasive syndromes. Despite daily spore inhalation, immunocompetence facilitates clearance through initiation of innate and adaptive host responses. These include mechanical barriers, phagocyte activation, antimicrobial peptide release and pattern recognition receptor activation. Adaptive responses include Th1 and Th2 approaches. Understanding Aspergillus virulence mechanisms remains critical to the development of effective research and treatment strategies to counteract the fungi. Major virulence factors relate to fungal structure, protease release and allergens; however, mechanisms utilized to evade immune recognition continue to be important in establishing infection. These include the fungal rodlet layer, dihydroxynaphthalene-melanin, detoxifying systems for reactive oxygen species and toxin release. One major immunoevasive toxin, gliotoxin, plays a key role in mediating Aspergillus-associated colonization in the context of cystic fibrosis. Here, it down-regulates vitamin D receptor expression which following itraconazole therapy is rescued concurrent with decreased Th2 cytokine (IL-5 and IL-13) concentrations in the CF airway. This review focuses on the interaction between Aspergillus pathogenic mechanisms, host immune responses and the immunoevasive strategies employed by the organism during disease states such as that observed in cystic fibrosis.

The pathogenicity of Aspergillus fumigatus, drug resistance, and nanoparticle delivery.

PubMed

Szalewski, David A; Hinrichs, Victoria S; Zinniel, Denise K; Barletta, Raúl G

2018-03-27

The genus Aspergillus includes fungal species that cause major health issues of significant economic importance. These microorganisms are also the culprit for production of carcinogenic aflatoxins in grain storages, contaminating crops, and economically straining the production process. Aspergillus fumigatus is a very important pathogenic species, being responsible for high human morbidity and mortality on a global basis. The prevalence of these infections in immunosuppressed individuals is on the rise, and physicians struggle with the diagnosis of these deadly pathogens. Several virulence determinants facilitate fungal invasion and evasion of the host immune response. Metabolic functions are also important for virulence and drug resistance, since they allow fungi to obtain nutrients for their own survival and growth. Following a positive diagnostic identification, mortality rates remain high due, in part, to emerging resistance to frequently used antifungal drugs. In this review, we discuss the role of the main virulence, drug target, and drug resistance determinants. We conclude with the review of new technologies being developed to treat aspergillosis. In particular, microsphere and nanoparticle delivery systems are discussed in the context of improving drug bioavailability. Aspergillus will likely continue to cause problematic infections in immunocompromised patients, so it is imperative to improve treatment options.

[Characteristics of arbuscular mycorrhizal fungal diversity and functions in saline-alkali land].

PubMed

Yang, Hai-xia; Guo, Shao-xia; Liu, Run-jin

2015-01-01

Arbuscular mycorrhizal (AM) fungi, widely distributing in various terrestrial ecosys- tems, are one of the important functional biotic components in soil habitats and play a vital role in improving soil evolution, maintaining soil health and sustainable productivity. Saline-alkali soil is a special habitat affecting plant growth and grain yield. Under the influence of a series of factors, such as human activities on the nature, S and N deposition, ozone, greenhouse effect, climate anomalies, and alien species invasions etc., soil salinization, biodiversity and functions of saline farmlands may be greatly affected, which could consequently influence agricultural production and the sustainable development of ecosystems. Followed by an introduction of the changing characteristics of saline soil area and the secondary salinization under the background of global changes, the present review mainly discussed the changing features of diversity and functions of AM fungi in saline habitats, summarized the factors influencing AM fungal diversity and functions, and the factors' changing characters under the global changes, in order to provide new ideas and ways in further elucidating the position, role and function of AM fungi in saline soil, and in strengthening saline farmland remediation in response to global changes.

Emerging issues with diagnosis and management of fungal infections in solid organ transplant recipients.

PubMed

Farmakiotis, D; Kontoyiannis, D P

2015-05-01

Invasive fungal infections (IFIs) are being increasingly recognized in solid organ transplant (SOT) recipients, and delayed diagnosis can lead to graft loss and death. Therefore, there is a low threshold for prophylaxis and early initiation of empiric antifungal treatment, in this patient population. Meanwhile, the increasing consumption of antifungals is associated with high cost, medication toxicities and the emergence of resistance in Candida species, all of which call for rational use of antifungal agents. The implementation of fungal biomarkers, molecular diagnostic methods and direct detection of volatile fungal metabolites in breath samples could lead to faster diagnosis, early appropriate treatment and improved clinical outcomes, but also aid in the de-escalation of antifungal treatment. Those novel diagnostic modalities need to be validated specifically in SOT recipients. Infectious diseases consultation can contribute to optimization of care through prompt initiation and appropriate modification of antifungal treatment, management of medication toxicities and drug-drug interactions, as well as source control. In this review, we conceptually summarize recent advances in the diagnosis and management of IFI in SOT recipients, and highlight the importance of early diagnostic tools and good stewardship of antifungal drugs. © 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Trojan Horse Transit Contributes to Blood-Brain Barrier Crossing of a Eukaryotic Pathogen

PubMed Central

Santiago-Tirado, Felipe H.; Onken, Michael D.; Cooper, John A.; Klein, Robyn S.

2017-01-01

ABSTRACT The blood-brain barrier (BBB) protects the central nervous system (CNS) by restricting the passage of molecules and microorganisms. Despite this barrier, however, the fungal pathogen Cryptococcus neoformans invades the brain, causing a meningoencephalitis that is estimated to kill over 600,000 people annually. Cryptococcal infection begins in the lung, and experimental evidence suggests that host phagocytes play a role in subsequent dissemination, although this role remains ill defined. Additionally, the disparate experimental approaches that have been used to probe various potential routes of BBB transit make it impossible to assess their relative contributions, confounding any integrated understanding of cryptococcal brain entry. Here we used an in vitro model BBB to show that a “Trojan horse” mechanism contributes significantly to fungal barrier crossing and that host factors regulate this process independently of free fungal transit. We also, for the first time, directly imaged C. neoformans-containing phagocytes crossing the BBB, showing that they do so via transendothelial pores. Finally, we found that Trojan horse crossing enables CNS entry of fungal mutants that cannot otherwise traverse the BBB, and we demonstrate additional intercellular interactions that may contribute to brain entry. Our work elucidates the mechanism of cryptococcal brain invasion and offers approaches to study other neuropathogens. PMID:28143979

Resistance to echinocandin-class antifungal drugs

PubMed Central

Perlin, David S.

2009-01-01

Invasive fungal infections cause morbidity and mortality in severely ill patients, and limited drug classes restrict treatment choices. The echinocandins drugs are the first new class of antifungal compounds that target the fungal cell wall by blocking β-1,3-D-glucan synthase. Elevated MIC values with occasional treatment failure have been reported for strains of Candida. Yet, an uncertain correlation exists between clinical failure and elevated MIC values for the echinocandin drugs. Fungi display several adaptive physiological mechanisms that result in elevated MIC values. However, resistance to echinocandin drugs among clinical isolates is associated with amino acid substitutions in two “hot-spot” regions of Fks1, the major subunit of glucan synthase. The mutations, yielding highly elevated MIC values, are genetically dominant and confer cross-resistance to all echinocandin drugs. Prominent Fks1 mutations decrease the sensitivity of glucan synthase for drug by one thousand-fold or more, and strains harboring such mutations may require a concomitant increase in drug to reduce fungal organ burdens in animal infection models. The Fks1-mediated resistance mechanism is conserved in a wide variety of Candida spp. and can account for intrinsic reduced susceptibility of certain species. Fks1 mutations confer resistance in both yeasts and moulds suggesting that this mechanism is pervasive in the fungal kingdom. PMID:17569573

Emerging issues, challenges, and changing epidemiology of fungal disease outbreaks.

PubMed

Benedict, Kaitlin; Richardson, Malcolm; Vallabhaneni, Snigdha; Jackson, Brendan R; Chiller, Tom

2017-12-01

Several high-profile outbreaks have drawn attention to invasive fungal infections (IFIs) as an increasingly important public health problem. IFI outbreaks are caused by many different fungal pathogens and are associated with numerous settings and sources. In the community, IFI outbreaks often occur among people without predisposing medical conditions and are frequently precipitated by environmental disruption. Health-care-associated IFI outbreaks have been linked to suboptimal hospital environmental conditions, transmission via health-care workers' hands, contaminated medical products, and transplantation of infected organs. Outbreak investigations provide important insights into the epidemiology of IFIs, uncover risk factors for infection, and identify opportunities for preventing similar events in the future. Well recognised challenges with IFI outbreak recognition, response, and prevention include the need for improved rapid diagnostic methods, the absence of routine surveillance for most IFIs, adherence to infection control practices, and health-care provider awareness. Additionally, IFI outbreak investigations have revealed several emerging issues, including new populations at risk because of travel or relocation, occupation, or immunosuppression; fungal pathogens appearing in geographical areas in which they have not been previously recognised; and contaminated compounded medications. This report highlights notable IFI outbreaks in the past decade, with an emphasis on these emerging challenges in the USA. Copyright © 2017 Elsevier Ltd. All rights reserved.

Resin duct characteristics in the wood of fire-scarred North American conifers

Treesearch

Estelle Arbellay; Markus Stoffel; Elaine K. Sutherland; Kevin T. Smith; Donald A. Falk

2013-01-01

Traumatic resin ducts form in xylem and phloem tissue of conifers in response to abiotic wounding, fungal invasion, and insect attack. Little is known about resin duct characteristics in the wood of fire-scarred trees. The aim of this study is to quantify changes in traits of both axial and radial resin ducts, along with those of associated epithelial cells and...

Walnut twig beetle (Coleoptera: Curculionidae: Scolytinae) Colonization of eastern black walnut nursery trees

Treesearch

Jackson Audley; William E. Klingeman; Albert Mayfield; Scott Myers; Adam Taylor

2017-01-01

Thousand cankers disease, caused by the invasive bark beetle Pityophthorus juglandis Blackman and an associ-ated fungal pathogen Geosmithia morbida M. .Kolank , E. Freeland, C. Utley, N. Tisserat, currently threatens the health of eastern black walnut (Juglans nigra L.) in North America. Both the beetle and pathogen have ex- panded beyond their native range via...

Effect of fire on a seed bank pathogen and on seeds of its host Bromus tectorum

Treesearch

J. Beckstead; S.E. Meyer; L.E. Street; P.S. Allen

2010-01-01

The generalist pathogen Pyrenophora semeniperda (Brittlebank and Adam) Shoemaker occurs primarily in cheatgrass (Bromus tectorum L.) seed banks, where it causes high seed mortality (Beckstead et al. 2007; Meyer et al. 2007). How does fire impact survival of a fungal seed pathogen, P. semeniperda, versus survival of the seeds of its cheatgrass host, the invasive Bromus...

Cochliotoxin, a Dihydropyranopyran-4,5-dione, and its analogues produced by Cochliobolus australiensis display phytotoxic activity against buffelgrass (Cenchrus ciliaris)

Treesearch

Marco Masi; Susan Meyer; Suzette Clement; Alessio Cimmino; Massimo Cristofaro; Antonio Evidente

2017-01-01

Buffelgrass (Pennisetum ciliare or Cenchrus ciliaris) is a perennial grass that has become highly invasive in the Sonoran Desert of southern Arizona. In the search for novel control strategies against this weed, strains of the foliar fungal pathogen Cochliobolus australiensis from buffelgrass have been screened for their ability to produce phytotoxic metabolites that...

Characterization of Beauveria bassiana (Ascomycota: Hypocreales) isolates associated with Agrilus planipennis (Coleoptera: Buprestidae) populations in Michigan

Treesearch

Louela A. Castrillo; Leah S. Bauer; Houping Liu; Michael H. Griggs; John D. Vandenberg

2010-01-01

Earlier research in Michigan on fungal entomopathogens of the emerald ash borer (EAB), a major invasive pest of ash trees, resulted in the isolation of Beauveria bassiana from late-instar larvae and pre-pupae. In the present study, some of these isolates were characterized and compared to ash bark- and soil-derived isolates to determine their...

Assessment of bacterial and fungal growth on natural substrates: consequences for preserving caves with prehistoric paintings.

PubMed

Stomeo, Francesca; Portillo, Maria C; Gonzalez, Juan M

2009-09-01

The most representative bacterium (Pseudonocardia sp.) and fungus (Fusarium sp.) from the microbial communities of a cave containing paleolithic paintings were isolated and their growth on natural substrates assessed. Growth was tested at the in situ and optimal, laboratory growth temperature. Development was analyzed with and without supplemented nutrients (glucose, ammonium, phosphate, peptone). Results showed that the assayed bacterium on natural substrate was able to develop best at in situ temperature and the addition of organic nutrients and/or phosphate enhanced its growth. The growth of the assayed fungus, however, was limited by low temperature and the availability of ammonium. These results confirm a differential behavior of microorganisms between the laboratory and the natural environments and could explain previous invasion of fungi reported for some caves with prehistoric paintings.

Patient Susceptibility to Candidiasis—A Potential for Adjunctive Immunotherapy

PubMed Central

Davidson, Linda; Netea, Mihai G.; Kullberg, Bart Jan

2018-01-01

Candida spp. are colonizing fungi of human skin and mucosae of the gastrointestinal and genitourinary tract, present in 30–50% of healthy individuals in a population at any given moment. The host defense mechanisms prevent this commensal fungus from invading and causing disease. Loss of skin or mucosal barrier function, microbiome imbalances, or defects of immune defense mechanisms can lead to an increased susceptibility to severe mucocutaneous or invasive candidiasis. A comprehensive understanding of the immune defense against Candida is essential for developing adjunctive immunotherapy. The important role of underlying genetic susceptibility to Candida infections has become apparent over the years. In most patients, the cause of increased susceptibility to fungal infections is complex, based on a combination of immune regulation gene polymorphisms together with other non-genetic predisposing factors. Identification of patients with an underlying genetic predisposition could help determine which patients could benefit from prophylactic antifungal treatment or adjunctive immunotherapy. This review will provide an overview of patient susceptibility to mucocutaneous and invasive candidiasis and the potential for adjunctive immunotherapy. PMID:29371502

Development of soils and communities of plants and arbuscular mycorrhizal fungi on West Virginia surface mines.

PubMed

Levy, Michael A; Cumming, Jonathan R

2014-11-01

Surface mining followed by reclamation to pasture is a major driver of land use and cover change in Appalachia. Prior research suggests that many aspects of ecosystem recovery are either slow or incomplete. We examined ecosystem structure-including soil physical and chemical properties, arbuscular mycorrhizal fungal (AMF) infectivity and community composition, and plant diversity and community composition-on a chronosequence of pasture-reclaimed surface mines and a non-mined pasture in northern West Virginia. Surface mining and reclamation dramatically altered ecosystem structure. Some aspects of ecosystem structure, including many measures of soil chemistry and infectivity of AMF, returned rapidly to levels found on the non-mined reference site. Other aspects of ecosystem structure, notably soil physical properties and AMF and plant communities, showed incomplete or no recovery over the short-to-medium term. In addition, invasive plants were prevalent on reclaimed mine sites. The results point to the need for investigation on how reclamation practices could minimize establishment of exotic invasive plant species and reduce the long-term impacts of mining on ecosystem structure and function.

Development of Soils and Communities of Plants and Arbuscular Mycorrhizal Fungi on West Virginia Surface Mines

NASA Astrophysics Data System (ADS)

Levy, Michael A.; Cumming, Jonathan R.

2014-11-01

Surface mining followed by reclamation to pasture is a major driver of land use and cover change in Appalachia. Prior research suggests that many aspects of ecosystem recovery are either slow or incomplete. We examined ecosystem structure—including soil physical and chemical properties, arbuscular mycorrhizal fungal (AMF) infectivity and community composition, and plant diversity and community composition—on a chronosequence of pasture-reclaimed surface mines and a non-mined pasture in northern West Virginia. Surface mining and reclamation dramatically altered ecosystem structure. Some aspects of ecosystem structure, including many measures of soil chemistry and infectivity of AMF, returned rapidly to levels found on the non-mined reference site. Other aspects of ecosystem structure, notably soil physical properties and AMF and plant communities, showed incomplete or no recovery over the short-to-medium term. In addition, invasive plants were prevalent on reclaimed mine sites. The results point to the need for investigation on how reclamation practices could minimize establishment of exotic invasive plant species and reduce the long-term impacts of mining on ecosystem structure and function.

[Fungemia due to Trichosporon asahii in a patient with hematological malignancy].

PubMed

Odero, Valle; Galán-Sánchez, Fátima; García-Agudo, Lidia; García-Tapia, Ana M; Guerrero-Lozano, Inmaculada; Rodríguez-Iglesias, Manuel A

2015-01-01

Trichosporonosis is an opportunistic infection caused by the genus Trichosporon. The majority of cases of invasive trichosporonosis occurs in immunocompromised individuals. We describe a case of disseminated infection by Trichosporon asahii in a hematology patient. A 52-year-old man diagnosed with acute lymphoblastic leukemia developed a febrile episode during the third cycle of the induction chemotherapy. The blood cultures were positive after 24h incubation, showing elongated structures compatible with fungal elements in the Gram stain. The identification of the fungus as Trichosporon asahii was carried out by the assimilation of compounds of carbon and the amplification and sequencing of the D1/D2 domain and the internal transcribed spacer of the ribosomal DNA. The fungus was also isolated from the pustular lesions that the patient had in the chest. After treatment with amphotericin B, the patient progressed satisfactorily. Trichosporon asahii is an emergent pathogen in immunosupressed patients and its presence should not be considered as colonization, as there is risk of invasive infection. Copyright © 2013 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

Diversity of fungal endophytes in non-native Phragmites australis in the Great Lakes

USGS Publications Warehouse

Clay, Keith; Shearin, Zachery; Bourke, Kimberly; Bickford, Wesley A.; Kowalski, Kurt P.

2016-01-01

Plant–microbial interactions may play a key role in plant invasions. One common microbial interaction takes place between plants and fungal endophytes when fungi asymptomatically colonize host plant tissues. The objectives of this study were to isolate and sequence fungal endophytes colonizing non-native Phragmites australis in the Great Lakes region to evaluate variation in endophyte community composition among three host tissue types and three geographical regions. We collected entire ramets from multiple clones and populations, surface sterilized plant tissues, and plated replicate tissue samples from leaves, stems, and rhizomes on corn meal agar plates to culture and isolate fungal endophytes. Isolates were then subjected to Sanger sequencing of the ITS region of the nuclear ribosomal DNA. Sequences were compared to fungal databases to define operational taxonomic units (OTUs) that were analyzed statistically for community composition. In total, we obtained 173 endophyte isolates corresponding to 55 OTUs, 39 of which were isolated only a single time. The most common OTU corresponded most closely to Sarocladium strictum and comprised 25 % of all fungal isolates. More OTUs were found in stem tissues, but endophyte diversity was greatest in rhizome tissues. PERMANOVA analyses indicated significant differences in endophyte communities among tissue types, geographical regions, and the interaction between those factors, but no differences among individual ramets were detected. The functional role of the isolated endophytes is not yet known, but one genus isolated here (Stagonospora) has been reported to enhance Phragmites growth. Understanding the diversity and functions of Phragmites endophytes may provide targets for control measures based on disrupting host plant/endophyte interactions.

Invasion of the French paleolithic painted cave of Lascaux by members of the Fusarium solani species complex.

PubMed

Dupont, Joëlle; Jacquet, Claire; Dennetière, Bruno; Lacoste, Sandrine; Bousta, Faisl; Orial, Geneviève; Cruaud, Corinne; Couloux, Arnaud; Roquebert, Marie-France

2007-01-01

A major fungal invasion was discovered in the prehistoric painted cave of Lascaux in France in Sep 2001. At least three species of the Fusarium solani complex were isolated and identified with a portion of the translation elongation factor 1alpha gene (EF-1alpha), a portion of the nuclear large subunit rDNA (LSU) and nuclear ribosomal intergenic spacer region (ITS). This study represents the first time that Fusarium species have been reported from a cave containing prehistoric paintings. Significant interspecific molecular variability was observed, suggesting that there might have been repeated introduction of the species, possibly carried by water from soils above the cave.

Aspergillus vertebral osteomyelitis in chronic leukocyte leukemia patient diagnosed by a novel panfungal polymerase chain reaction method.

PubMed

Dayan, Lior; Sprecher, Hannah; Hananni, Amos; Rosenbaum, Hana; Milloul, Victor; Oren, Ilana

2007-01-01

Vertebral osteomyelitis and disciitis caused by Aspergillus spp is a rare event. Early diagnosis and early antifungal therapy are critical in improving the prognosis for these patients. The diagnosis of invasive fungal infections is, in many cases, not straightforward and requires invasive procedures so that histological examination and culture can be performed. Furthermore, current traditional microbiological tests (ie, cultures and stains) lack the sensitivity for diagnosis of invasive aspergillosis. To present a case of vertebral osteomyelitis caused by Aspergillus spp diagnosed using a novel polymerase chain reaction (PCR) assay. Case report. Aspergillus DNA was detected in DNA extracted from the necrotic bone tissue by using a "panfungal" PCR novel method. Treatment with voriconazole was started based on the diagnosis. Using this novel technique enabled us to diagnose accurately an unusual bone pathogen that requires a unique treatment.

Red turpentine beetle: innocuous native becomes invasive tree killer in China.

PubMed

Sun, Jianghua; Lu, Min; Gillette, Nancy E; Wingfield, Michael J

2013-01-01

The red turpentine beetle (RTB), Dendroctonus valens LeConte (Coleoptera: Curculionidae: Scolytinae), is a secondary pest of pines in its native range in North and Central America. Outbreaks and tree mortality attributed to RTB alone are rare in its native range. RTB was introduced into China in the early 1980s and spread rapidly from Shanxi Province to four adjacent provinces; it has infested over 500,000 ha of pine forest and has caused extensive tree mortality since 1999. We provide a historical background on RTB outbreaks, explanations for its invasive success, management options, and economic impacts of RTB in China. Genetic variation in RTB fungal associates, interactions between RTB and its associated fungi, behavioral differences in Chinese RTB, and other factors favoring RTB outbreaks are considered in an effort to explain the invasiveness of RTB in China. The promise of semiochemicals as a management tool is also discussed.

Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis.

PubMed

Dagenais, Taylor R T; Keller, Nancy P

2009-07-01

Aspergillus species are globally ubiquitous saprophytes found in a variety of ecological niches. Almost 200 species of aspergilli have been identified, less than 20 of which are known to cause human disease. Among them, Aspergillus fumigatus is the most prevalent and is largely responsible for the increased incidence of invasive aspergillosis (IA) in the immunocompromised patient population. IA is a devastating illness, with mortality rates in some patient groups reaching as high as 90%. Studies identifying and assessing the roles of specific factors of A. fumigatus that contribute to the pathogenesis of IA have traditionally focused on single-gene deletion and mutant characterization. In combination with recent large-scale approaches analyzing global fungal responses to distinct environmental or host conditions, these studies have identified many factors that contribute to the overall pathogenic potential of A. fumigatus. Here, we provide an overview of the significant findings regarding A. fumigatus pathogenesis as it pertains to invasive disease.

Aspergillus Galactosaminogalactan Mediates Adherence to Host Constituents and Conceals Hyphal β-Glucan from the Immune System

PubMed Central

Liu, Hong; Lee, Mark J.; Snarr, Brendan D.; Chen, Dan; Xu, Wenjie; Kravtsov, Ilia; Hoareau, Christopher M. Q.; Vanier, Ghyslaine; Urb, Mirjam; Campoli, Paolo; Al Abdallah, Qusai; Lehoux, Melanie; Chabot, Josée C.; Ouimet, Marie-Claude; Baptista, Stefanie D.; Fritz, Jörg H.; Nierman, William C.; Latgé, Jean Paul; Mitchell, Aaron P.; Filler, Scott G.; Fontaine, Thierry; Sheppard, Donald C.

2013-01-01

Aspergillus fumigatus is the most common cause of invasive mold disease in humans. The mechanisms underlying the adherence of this mold to host cells and macromolecules have remained elusive. Using mutants with different adhesive properties and comparative transcriptomics, we discovered that the gene uge3, encoding a fungal epimerase, is required for adherence through mediating the synthesis of galactosaminogalactan. Galactosaminogalactan functions as the dominant adhesin of A. fumigatus and mediates adherence to plastic, fibronectin, and epithelial cells. In addition, galactosaminogalactan suppresses host inflammatory responses in vitro and in vivo, in part through masking cell wall β-glucans from recognition by dectin-1. Finally, galactosaminogalactan is essential for full virulence in two murine models of invasive aspergillosis. Collectively these data establish a role for galactosaminogalactan as a pivotal bifunctional virulence factor in the pathogenesis of invasive aspergillosis. PMID:23990787

Pediatric invasive fungal rhinosinusitis: An investigation of 17 patients.

PubMed

Vinh, Daniel; Yim, Michael; Dutta, Ankhi; Jones, John K; Zhang, Wei; Sitton, Matthew

2017-08-01

To investigate outcomes of pediatric patients at a single institution with invasive fungal rhinosinusitis (IFRS) and to determine variables that impact overall survival. All pediatric patients at a large tertiary children's hospital diagnosed with IFRS confirmed by surgical pathology from 2009 to 2015 were retrospectively reviewed. Demographics, underlying diseases, symptoms, antifungal therapy, absolute neutrophil count (ANC), surgical management,and outcomes were analyzed. Seventeen patients were identified with IFRS with an average age of 8.7 years and 53% male. Hematologic malignancy was the most common (n = 13) underlying disease. The most common presenting symptoms were fever (82%) and congestion (41%). 15 patients had severe neutropenia (Absolute Neutrophil Count (ANC) < 500) within 2 weeks prior to diagnosis. The average ANC at time of diagnosis was 1420 cells/uL. 16 patients were treated with serial nasal endoscopy and debridement, while 1 patient was treated with an open approach. 16 received combination antifungals while 1 was treated with amphotericin monotherapy. The most common genus cultured was Fusarium (n = 6). The average number of surgical interventions was 3.4, with the average interval between interventions 6.2 days. 13 of 17 (76%) were cleared of IFRS. Overall survival at 6 months was 41%. Pediatric IFRS is a life-threatening disease that requires a coordinated surgical and medical approach. Despite a relatively high local control rate, overall mortality remains disappointingly high, reflecting the disease's underlying pathogenesis - lack of host defense and risk of disseminated fungal infection. Further investigation is necessary to reveal optimal management with regards to antifungal therapy, surgery, and utility of labs. Copyright © 2017 Elsevier B.V. All rights reserved.

Positive feedback between mycorrhizal fungi and plants influences plant invasion success and resistance to invasion.

PubMed

Zhang, Qian; Yang, Ruyi; Tang, Jianjun; Yang, Haishui; Hu, Shuijin; Chen, Xin

2010-08-24

Negative or positive feedback between arbuscular mycorrhizal fungi (AMF) and host plants can contribute to plant species interactions, but how this feedback affects plant invasion or resistance to invasion is not well known. Here we tested how alterations in AMF community induced by an invasive plant species generate feedback to the invasive plant itself and affect subsequent interactions between the invasive species and its native neighbors. We first examined the effects of the invasive forb Solidago canadensis L. on AMF communities comprising five different AMF species. We then examined the effects of the altered AMF community on mutualisms formed with the native legume forb species Kummerowia striata (Thunb.) Schindl. and on the interaction between the invasive and native plants. The host preferences of the five AMF were also assessed to test whether the AMF form preferred mutualistic relations with the invasive and/or the native species. We found that S. canadensis altered AMF spore composition by increasing one AMF species (Glomus geosporum) while reducing Glomus mosseae, which is the dominant species in the field. The host preference test showed that S. canadensis had promoted the abundance of AMF species (G. geosporum) that most promoted its own growth. As a consequence, the altered AMF community enhanced the competitiveness of invasive S. canadensis at the expense of K. striata. Our results demonstrate that the invasive S. canadensis alters soil AMF community composition because of fungal-host preference. This change in the composition of the AMF community generates positive feedback to the invasive S. canadensis itself and decreases AM associations with native K. striata, thereby making the native K. striata less dominant.

Standard methods for fungal brood disease research

PubMed Central

Jensen, Annette Bruun; Aronstein, Kathrine; Flores, José Manuel; Vojvodic, Svjetlana; Palacio, María Alejandra; Spivak, Marla

2013-01-01

Summary Chalkbrood and stonebrood are two fungal diseases associated with honey bee brood. Chalkbrood, caused by Ascosphaera apis, is a common and widespread disease that can result in severe reduction of emerging worker bees and thus overall colony productivity. Stonebrood is caused by Aspergillus spp. that are rarely observed, so the impact on colony health is not very well understood. A major concern with the presence of Aspergillus in honey bees is the production of airborne conidia, which can lead to allergic bronchopulmonary aspergillosis, pulmonary aspergilloma, or even invasive aspergillosis in lung tissues upon inhalation by humans. In the current chapter we describe the honey bee disease symptoms of these fungal pathogens. In addition, we provide research methodologies and protocols for isolating and culturing, in vivo and in vitro assays that are commonly used to study these host pathogen interactions. We give guidelines on the preferred methods used in current research and the application of molecular techniques. We have added photographs, drawings and illustrations to assist bee-extension personnel and bee scientists in the control of these two diseases. PMID:24198438

Proteomic analysis during of spore germination of Moniliophthora perniciosa, the causal agent of witches' broom disease in cacao.

PubMed

Mares, Joise Hander; Gramacho, Karina Peres; Santos, Everton Cruz; da Silva Santiago, André; Santana, Juliano Oliveira; de Sousa, Aurizângela Oliveira; Alvim, Fátima Cerqueira; Pirovani, Carlos Priminho

2017-08-17

Moniliophthora perniciosa is a phytopathogenic fungus responsible for witches' broom disease of cacao trees (Theobroma cacao L.). Understanding the molecular events during germination of the pathogen may enable the development of strategies for disease control in these economically important plants. In this study, we determined a comparative proteomic profile of M. perniciosa basidiospores during germination by two-dimensional SDS-PAGE and mass spectrometry. A total of 316 proteins were identified. Molecular changes during the development of the germinative tube were identified by a hierarchical clustering analysis based on the differential accumulation of proteins. Proteins associated with fungal filamentation, such as septin and kinesin, were detected only 4 h after germination (hag). A transcription factor related to biosynthesis of the secondary metabolite fumagillin, which can form hybrids with polyketides, was induced 2 hag, and polyketide synthase was observed 4 hag. The accumulation of ATP synthase, binding immunoglobulin protein (BiP), and catalase was validated by western blotting. In this study, we showed variations in protein expression during the early germination stages of fungus M. perniciosa. Proteins associated with fungal filamentation, and consequently with virulence, were detected in basidiospores 4 hag., for example, septin and kinesin. We discuss these results and propose a model of the germination of fungus M. perniciosa. This research can help elucidate the mechanisms underlying basic processes of host invasion and to develop strategies for control of the disease.

Combination of fluconazole with non-antifungal agents: a promising approach to cope with resistant Candida albicans infections and insight into new antifungal agent discovery.

PubMed

Liu, Shuyuan; Hou, Yinglong; Chen, Xu; Gao, Yuan; Li, Hui; Sun, Shujuan

2014-05-01

The past decades have witnessed a dramatic increase in invasive fungal infections, especially candidiasis. Despite the development of more effective new antifungal agents, fluconazole (FLC) is still widely used in the clinic because of its efficacy and low toxicity. However, as the number of patients treated with FLC has increased, FLC-resistant Candida albicans isolates emerge more frequently. In addition, biofilm-associated infections are commonly encountered and their resistance poses a great challenge to antifungal treatment. Various approaches have been proposed to increase the susceptibility of C. albicans to FLC in order to cope with treatment failures, among which is the combination of FLC with different classes of non-antifungal agents such as antibacterials, calcineurin inhibitors, heat shock protein 90 inhibitors, calcium homeostasis regulators and traditional Chinese medicine drugs. Interestingly, many of these combinations showed synergistic effects against C. albicans, especially resistant strains. The main mechanisms of these synergistic effects appear to be increasing the permeability of the membrane, reducing the efflux of antifungal drugs, interfering with intracellular ion homeostasis, inhibiting the activity of proteins and enzymes required for fungal survival, and inhibiting biofilm formation. These modes of action and the antifungal mechanisms of various compounds referenced in this paper highlight the idea that the reversal of fungal resistance can be achieved through various mechanisms. Studies examining drug interactions will hopefully provide new approaches against antifungal drug resistance as well as insight into antifungal agent discovery. Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Identification and characterization of haemofungin, a novel antifungal compound that inhibits the final step of haem biosynthesis.

PubMed

Ben Yaakov, Dafna; Rivkin, Anna; Mircus, Gabriel; Albert, Nathaniel; Dietl, Anna-Maria; Kovalerchick, Dimitry; Carmeli, Shmuel; Haas, Hubertus; Kontoyiannis, Dimitrios P; Osherov, Nir

2016-04-01

During recent decades, the number of invasive fungal infections among immunosuppressed patients has increased significantly, whereas the number of effective systemic antifungal drugs remains low and unsatisfactory. The aim of this study was to characterize a novel antifungal compound, CW-8/haemofungin, which we previously identified in a screen for compounds affecting fungal cell wall integrity. The in vitro characteristics of haemofungin were investigated by MIC evaluation against a panel of pathogenic and non-pathogenic fungi, bacteria and mammalian cells in culture. Haemofungin mode-of-action studies were performed by screening an Aspergillus nidulans overexpression genomic library for resistance-conferring plasmids and biochemical validation of the target. In vivo efficacy was tested in the Galleria mellonella and Drosophila melanogaster insect models of infection. We demonstrate that haemofungin causes swelling and lysis of growing fungal cells. It inhibits the growth of pathogenic Aspergillus, Candida, Fusarium and Rhizopus isolates at micromolar concentrations, while only weakly affecting the growth of mammalian cell lines. Genetic and biochemical analyses in A. nidulans and Aspergillus fumigatus indicate that haemofungin primarily inhibits ferrochelatase (HemH), the last enzyme in the haem biosynthetic pathway. Haemofungin was non-toxic and significantly reduced mortality rates of G. mellonella and D. melanogaster infected with A. fumigatus and Rhizopus oryzae, respectively. Further development and in vivo validation of haemofungin is warranted. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Secretome Analysis Identifies Potential Pathogenicity/Virulence Factors of Tilletia indica, a Quarantined Fungal Pathogen Inciting Karnal Bunt Disease in Wheat.

PubMed

Pandey, Vishakha; Singh, Manoj; Pandey, Dinesh; Marla, Soma; Kumar, Anil

2018-04-01

Tilletia indica is a smut fungus that incites Karnal bunt in wheat. It has been considered as quarantine pest in more than 70 countries. Despite its quarantine significance, there is meager knowledge regarding the molecular mechanisms of disease pathogenesis. Moreover, various disease management strategies have proven futile. Development of effective disease management strategy requires identification of pathogenicity/virulence factors. With this aim, the present study was conducted to compare the secretomes of T. indica isolates, that is, highly (TiK) and low (TiP) virulent isolates. About 120 and 95 protein spots were detected reproducibly in TiK and TiP secretome gel images. Nineteen protein spots, which were consistently observed as upregulated/differential in the secretome of TiK isolate, were selected for their identification by MALDI-TOF/TOF. Identified proteins exhibited homology with fungal proteins playing important role in fungal adhesion, penetration, invasion, protection against host-derived reactive oxygen species, production of virulence factors, cellular signaling, and degradation of host cell wall proteins and antifungal proteins. These results were complemented with T. indica genome sequence leading to identification of candidate pathogenicity/virulence factors homologs that were further subjected to sequence- and structure-based functional annotation. Thus, present study reports the first comparative secretome analysis of T. indica for identification of pathogenicity/virulence factors. This would provide insights into pathogenic mechanisms of T. indica and aid in devising effective disease management strategies. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Population genomic analyses of the brown root-rot pathogen, Phellinus noxius, examine potential invasive spread among Pacific islands

Treesearch

Jane E. Stewart; Mee-Sook Kim; Louise Shuey; Norio Sahashi; Yuko Ota; Robert L. Schlub; Phil G. Cannon; Ned B. Klopfenstein

2016-01-01

Phellinus noxius (Corner) G. H. Cunn is a vastly destructive, fast-growing fungal pathogen that affects a wide range of woody hosts in pan-tropical areas, including Asia, Australia, Africa, and Oceania (Ann et al. 2002; Figure 1) . This pathogen causes brown root-rot disease on cacao, coffee, and rubber, as well as diverse fruit, nut, ornamental, and other...

Phytotoxic activity against Bromus tectorum for secondary metabolites of a seed-pathogenic Fusarium strain belonging to the F. tricinctum species complex

Treesearch

Marco Masi; Susan Meyer; Gennaro Pescitelli; Alessio Cimmino; Suzette Clement; Beth Peacock; Antonio Evidente

2017-01-01

The winter annual grass Bromus tectorum (cheatgrass) has become highly invasive in semiarid ecosystems of western North America. In these areas, a natural phenomenon, complete cheatgrass stand failure (‘die-off’), is apparently caused by a complex interaction among soilborne fungal pathogens. Several Fusarium strains belonging to the Fusarium tricinctum species complex...

Invasive rhino-orbito-cerebral mucormycosis in a diabetic patient – the need for prompt treatment

PubMed Central

Chow, Vanessa; Khan, Sheema; Balogun, Adeola; Mitchell, David; Mühlschlegel, Fritz A.

2014-01-01

Mucormycosis is a rare life threatening fungal infection predominately seen in immunocompromised or diabetic patients. The following case is of a known type II diabetic patient who presented with sepsis and sudden unilateral loss of vision secondary to infective rhino-orbito-cerebral mucormycosis. Treatment of the condition required extensive surgical intervention and medical management for a life saving outcome. PMID:25750854

Experimental evidence of a pathogen invasion threshold

PubMed Central

Krkošek, Martin

2018-01-01

Host density thresholds to pathogen invasion separate regions of parameter space corresponding to endemic and disease-free states. The host density threshold is a central concept in theoretical epidemiology and a common target of human and wildlife disease control programmes, but there is mixed evidence supporting the existence of thresholds, especially in wildlife populations or for pathogens with complex transmission modes (e.g. environmental transmission). Here, we demonstrate the existence of a host density threshold for an environmentally transmitted pathogen by combining an epidemiological model with a microcosm experiment. Experimental epidemics consisted of replicate populations of naive crustacean zooplankton (Daphnia dentifera) hosts across a range of host densities (20–640 hosts l−1) that were exposed to an environmentally transmitted fungal pathogen (Metschnikowia bicuspidata). Epidemiological model simulations, parametrized independently of the experiment, qualitatively predicted experimental pathogen invasion thresholds. Variability in parameter estimates did not strongly influence outcomes, though systematic changes to key parameters have the potential to shift pathogen invasion thresholds. In summary, we provide one of the first clear experimental demonstrations of pathogen invasion thresholds in a replicated experimental system, and provide evidence that such thresholds may be predictable using independently constructed epidemiological models. PMID:29410876

Oral Samples as Non-Invasive Proxies for Assessing the Composition of the Rumen Microbial Community.

PubMed

Tapio, Ilma; Shingfield, Kevin J; McKain, Nest; Bonin, Aurélie; Fischer, Daniel; Bayat, Ali R; Vilkki, Johanna; Taberlet, Pierre; Snelling, Timothy J; Wallace, R John

2016-01-01

Microbial community analysis was carried out on ruminal digesta obtained directly via rumen fistula and buccal fluid, regurgitated digesta (bolus) and faeces of dairy cattle to assess if non-invasive samples could be used as proxies for ruminal digesta. Samples were collected from five cows receiving grass silage based diets containing no additional lipid or four different lipid supplements in a 5 x 5 Latin square design. Extracted DNA was analysed by qPCR and by sequencing 16S and 18S rRNA genes or the fungal ITS1 amplicons. Faeces contained few protozoa, and bacterial, fungal and archaeal communities were substantially different to ruminal digesta. Buccal and bolus samples gave much more similar profiles to ruminal digesta, although fewer archaea were detected in buccal and bolus samples. Bolus samples overall were most similar to ruminal samples. The differences between both buccal and bolus samples and ruminal digesta were consistent across all treatments. It can be concluded that either proxy sample type could be used as a predictor of the rumen microbial community, thereby enabling more convenient large-scale animal sampling for phenotyping and possible use in future animal breeding programs aimed at selecting cattle with a lower environmental footprint.

Antifungal defense of probiotic Lactobacillus rhamnosus GG is mediated by blocking adhesion and nutrient depletion

PubMed Central

Braunsdorf, Christina; Grumaz, Christian; Müller, Christoph; Lorenz, Stefan; Stevens, Philip; Wagener, Jeanette; Hebecker, Betty; Hube, Bernhard; Bracher, Franz; Sohn, Kai; Schaller, Martin

2017-01-01

Candida albicans is an inhabitant of mucosal surfaces in healthy individuals but also the most common cause of fungal nosocomial blood stream infections, associated with high morbidity and mortality. As such life-threatening infections often disseminate from superficial mucosal infections we aimed to study the use of probiotic Lactobacillus rhamnosus GG (LGG) in prevention of mucosal C. albicans infections. Here, we demonstrate that LGG protects oral epithelial tissue from damage caused by C. albicans in our in vitro model of oral candidiasis. Furthermore, we provide insights into the mechanisms behind this protection and dissect direct and indirect effects of LGG on C. albicans pathogenicity. C. albicans viability was not affected by LGG. Instead, transcriptional profiling using RNA-Seq indicated dramatic metabolic reprogramming of C. albicans. Additionally, LGG had a significant impact on major virulence attributes, including adhesion, invasion, and hyphal extension, whose reduction, consequently, prevented epithelial damage. This was accompanied by glucose depletion and repression of ergosterol synthesis, caused by LGG, but also due to blocked adhesion sites. Therefore, LGG protects oral epithelia against C. albicans infection by preventing fungal adhesion, invasion and damage, driven, at least in parts, by metabolic reprogramming due to nutrient limitation caused by LGG. PMID:29023454

Oral Samples as Non-Invasive Proxies for Assessing the Composition of the Rumen Microbial Community

PubMed Central

Tapio, Ilma; Shingfield, Kevin J.; McKain, Nest; Bonin, Aurélie; Fischer, Daniel; Bayat, Ali R.; Vilkki, Johanna; Taberlet, Pierre; Snelling, Timothy J.; Wallace, R. John

2016-01-01

Microbial community analysis was carried out on ruminal digesta obtained directly via rumen fistula and buccal fluid, regurgitated digesta (bolus) and faeces of dairy cattle to assess if non-invasive samples could be used as proxies for ruminal digesta. Samples were collected from five cows receiving grass silage based diets containing no additional lipid or four different lipid supplements in a 5 x 5 Latin square design. Extracted DNA was analysed by qPCR and by sequencing 16S and 18S rRNA genes or the fungal ITS1 amplicons. Faeces contained few protozoa, and bacterial, fungal and archaeal communities were substantially different to ruminal digesta. Buccal and bolus samples gave much more similar profiles to ruminal digesta, although fewer archaea were detected in buccal and bolus samples. Bolus samples overall were most similar to ruminal samples. The differences between both buccal and bolus samples and ruminal digesta were consistent across all treatments. It can be concluded that either proxy sample type could be used as a predictor of the rumen microbial community, thereby enabling more convenient large-scale animal sampling for phenotyping and possible use in future animal breeding programs aimed at selecting cattle with a lower environmental footprint. PMID:26986467

Glucose-6-phosphate dehydrogenase deficiency and risk of invasive fungal disease in patients with acute myeloid leukemia.

PubMed

Sanna, Marco; Caocci, Giovanni; Ledda, Antonio; Orrù, Federica; Fozza, Claudio; Deias, Paola; Tidore, Gianni; Dore, Fausto; La Nasa, Giorgio

2017-11-01

Invasive fungal diseases (IFD) are still a leading cause of morbidity and mortality in patients with acute myeloid leukemia (AML). Glucose-6-phosphate dehydrogenase is an enzyme that leads to the production of NADPH, required to destroy microorganisms in the respiratory burst reaction of white blood cells. We evaluated the role of G6PD deficiency in susceptibility of IFD in 108 AML patients undergoing intensive chemotherapy. In all, 28 patients harbored G6PD deficiency (G6PD-), whereas 80 were normal (G6PD +). Incidence of IFD was significantly higher in G6PD- patients compared to G6PD + patients (35.7% vs. 5%, p = .0002, OR = 10, 95% CI = 2.96-37.5). Higher risk of mold infections (17.9% vs. 5%, p = .048, OR = 4.1, 95% CI = 1.0-16.6) and Candida sepsis (17.9% vs. 0%, p = .0009, OR = 37.68, 95% CI =2.0-707.1) was observed in G6PD - patients. The evaluation of G6PD activity may help to identify AML patients at higher risk of IFD, allowing to design more intensive surveillance and therapeutic strategies.

Epigenetic regulation of development and pathogenesis in fungal plant pathogens.

PubMed

Dubey, Akanksha; Jeon, Junhyun

2017-08-01

Evidently, epigenetics is at forefront in explaining the mechanisms underlying the success of human pathogens and in the identification of pathogen-induced modifications within host plants. However, there is a lack of studies highlighting the role of epigenetics in the modulation of the growth and pathogenicity of fungal plant pathogens. In this review, we attempt to highlight and discuss the role of epigenetics in the regulation of the growth and pathogenicity of fungal phytopathogens using Magnaporthe oryzae, a devastating fungal plant pathogen, as a model system. With the perspective of wide application in the understanding of the development, pathogenesis and control of other fungal pathogens, we attempt to provide a synthesized view of the epigenetic studies conducted on M. oryzae to date. First, we discuss the mechanisms of epigenetic modifications in M. oryzae and their impact on fungal development and pathogenicity. Second, we highlight the unexplored epigenetic mechanisms and areas of research that should be considered in the near future to construct a holistic view of epigenetic functioning in M. oryzae and other fungal plant pathogens. Importantly, the development of a complete understanding of the modulation of epigenetic regulation in fungal pathogens can help in the identification of target points to combat fungal pathogenesis. © 2016 BSPP AND JOHN WILEY & SONS LTD.

Isavuconazole Population Pharmacokinetic Analysis Using Nonparametric Estimation in Patients with Invasive Fungal Disease (Results from the VITAL Study)

PubMed Central

Kovanda, Laura L.; Desai, Amit V.; Lu, Qiaoyang; Townsend, Robert W.; Akhtar, Shahzad; Bonate, Peter

2016-01-01

Isavuconazonium sulfate (Cresemba; Astellas Pharma Inc.), a water-soluble prodrug of the triazole antifungal agent isavuconazole, is available for the treatment of invasive aspergillosis (IA) and invasive mucormycosis. A population pharmacokinetic (PPK) model was constructed using nonparametric estimation to compare the pharmacokinetic (PK) behaviors of isavuconazole in patients treated in the phase 3 VITAL open-label clinical trial, which evaluated the efficacy and safety of the drug for treatment of renally impaired IA patients and patients with invasive fungal disease (IFD) caused by emerging molds, yeasts, and dimorphic fungi. Covariates examined were body mass index (BMI), weight, race, impact of estimated glomerular filtration rate (eGFR) on clearance (CL), and impact of weight on volume. PK parameters were compared based on IFD type and other patient characteristics. Simulations were performed to describe the MICs covered by the clinical dosing regimen. Concentrations (n = 458) from 136 patients were used to construct a 2-compartment model (first-order absorption compartment and central compartment). Weight-related covariates affected clearance, but eGFR did not. PK parameters and intersubject variability of CL were similar across different IFD groups and populations. Target attainment analyses demonstrated that the clinical dosing regimen would be sufficient for total drug area under the concentration-time curve (AUC)/MIC targets ranging from 50.5 for Aspergillus spp. (up to the CLSI MIC of 0.5 mg/liter) to 270 and 5,053 for Candida albicans (up to MICs of 0.125 and 0.004 mg/liter, respectively) and 312 for non-albicans Candida spp. (up to a MIC of 0.125 mg/liter). The estimations for Candida spp. were exploratory considering that no patients with Candida infections were included in the current analyses. (The VITAL trial is registered at ClinicalTrials.gov under number NCT00634049.) PMID:27185799

Amphotericin B lipid complex as prophylaxis of invasive fungal infections in patients with acute myelogenous leukemia and myelodysplastic syndrome undergoing induction chemotherapy.

PubMed

Mattiuzzi, Gloria N; Kantarjian, Hagop; Faderl, Stefan; Lim, JoAnn; Kontoyiannis, Dimitrios; Thomas, Deborah; Wierda, William; Raad, Isaam; Garcia-Manero, Guillermo; Zhou, Xian; Ferrajoli, Alexandra; Bekele, Nebiyou; Estey, Elihu

2004-02-01

The optimal antifungal prophylactic regimen for patients with acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing induction chemotherapy has yet to be identified. A prospective historical control study evaluated the efficacy and safety of amphotericin B lipid complex (ABLC) in this patient population. Newly diagnosed patients with AML or high-risk MDS who were undergoing induction chemotherapy received prophylactic ABLC 2.5 mg/kg intravenously 3 times weekly. This treatment group was compared with a historical control group that had similar baseline characteristics and received prophylactic liposomal amphotericin B (L-AmB) 3 mg/kg 3 times weekly. The primary endpoint was the incidence of documented or suspected fungal infections during and up to 4 weeks after cessation of prophylaxis. Reported adverse events were used to assess tolerability. The overall efficacy of antifungal prophylaxis was similar in patients who received ABLC and patients who received L-AmB (P=0.95). Among 131 ABLC-treated patients and 70 L-AmB-treated patients who were assessed for efficacy and safety, 49% of patients in each group completed therapy without developing a documented or suspected fungal infection. Documented fungal infections occurred in 5% of ABLC-treated patients and in 4% of L-AmB-treated patients. Alternative antifungal strategies were required because of persistent fever or pneumonia of unknown pathogen in 28% and 32% of ABLC-treated and L-AmB-treated patients, respectively. Grade 3 and 4 adverse events, therapy discontinuations due to adverse events, and survival rates also were similar between treatment groups. ABLC and L-AmB appeared to have similar efficacy and were tolerated well as antifungal prophylaxis in patients with AML and high-risk MDS who were undergoing induction chemotherapy. Copyright 2003 American Cancer Society.

The Absence of NOD1 Enhances Killing of Aspergillus fumigatus Through Modulation of Dectin-1 Expression.

PubMed

Gresnigt, Mark S; Jaeger, Martin; Subbarao Malireddi, R K; Rasid, Orhan; Jouvion, Grégory; Fitting, Catherine; Melchers, Willem J G; Kanneganti, Thirumala-Devi; Carvalho, Agostinho; Ibrahim-Granet, Oumaima; van de Veerdonk, Frank L

2017-01-01

One of the major life-threatening infections for which severely immunocompromised patients are at risk is invasive aspergillosis (IA). Despite the current treatment options, the increasing antifungal resistance and poor outcome highlight the need for novel therapeutic strategies to improve outcome of patients with IA. In the current study, we investigated whether and how the intracellular pattern recognition receptor NOD1 is involved in host defense against Aspergillus fumigatus . When exploring the role of NOD1 in an experimental mouse model, we found that Nod1 -/- mice were protected against IA and demonstrated reduced fungal outgrowth in the lungs. We found that macrophages derived from bone marrow of Nod1 -/- mice were more efficiently inducing reactive oxygen species and cytokines in response to Aspergillus . Most strikingly, these cells were highly potent in killing A. fumigatus compared with wild-type cells. In line, human macrophages in which NOD1 was silenced demonstrated augmented Aspergillus killing and NOD1 stimulation decreased fungal killing. The differentially altered killing capacity of NOD1 silencing versus NOD1 activation was associated with alterations in dectin-1 expression, with activation of NOD1 reducing dectin-1 expression. Furthermore, we were able to demonstrate that Nod1 -/- mice have elevated dectin-1 expression in the lung and bone marrow, and silencing of NOD1 gene expression in human macrophages increases dectin-1 expression. The enhanced dectin-1 expression may be the mechanism of enhanced fungal killing of Nod1 -/- cells and human cells in which NOD1 was silenced, since blockade of dectin-1 reversed the augmented killing in these cells. Collectively, our data demonstrate that NOD1 receptor plays an inhibitory role in the host defense against Aspergillus . This provides a rationale to develop novel immunotherapeutic strategies for treatment of aspergillosis that target the NOD1 receptor, to enhance the efficiency of host immune cells to clear the infection by increasing fungal killing and cytokine responses.

Spartina alterniflora invasion alters soil microbial community composition and microbial respiration following invasion chronosequence in a coastal wetland of China

PubMed Central

Yang, Wen; Jeelani, Nasreen; Leng, Xin; Cheng, Xiaoli; An, Shuqing

2016-01-01

The role of exotic plants in regulating soil microbial community structure and activity following invasion chronosequence remains unclear. We investigated soil microbial community structure and microbial respiration following Spartina alterniflora invasion in a chronosequence of 6-, 10-, 17-, and 20-year-old by comparing with bare flat in a coastal wetland of China. S. alterniflora invasion significantly increased soil moisture and salinity, the concentrations of soil water-soluble organic carbon and microbial biomass carbon (MBC), the quantities of total and various types of phospholipid fatty acids (PLFAs), the fungal:bacterial PLFAs ratio and cumulative microbial respiration compared with bare flat. The highest MBC, gram-negative bacterial and saturated straight-chain PLFAs were found in 10-year-old S. alterniflora soil, while the greatest total PLFAs, bacterial and gram-positive bacterial PLFAs were found in 10- and 17-year-old S. alterniflora soils. The monounsaturated:branched PLFAs ratio declined, and cumulative microbial respiration on a per-unit-PLFAs increased following S. alterniflora invasion in the chronosequence. Our results suggest that S. alterniflora invasion significantly increased the biomass of soil various microbial groups and microbial respiration compared to bare flat soil by increasing soil available substrate, and modifying soil physiochemical properties. Soil microbial community reached the most enriched condition in the 10-year-old S. alterniflora community. PMID:27241173

Evaluation of hirst-type spore trap to monitor environmental fungal load in hospital

PubMed Central

Gustin, Marie-Paule; Cassier, Pierre; Loeffert, Sophie Tiphaine; Thibaudon, Michel; Bénet, Thomas; Vanhems, Philippe

2017-01-01

The main purpose was to validate the use of outdoor-indoor volumetric impaction sampler with Hirst-type spore traps (HTSTs) to continuously monitor fungal load in order to prevent invasive fungal infections during major structural work in hospital settings. For 4 weeks, outdoor fungal loads were quantified continuously by 3 HTSTs. Indoor air was sampled by both HTST and viable impaction sampler. Results were expressed as particles/m3 (HTST) or colony-forming units (CFU)/m3 (biocollector). Paired comparisons by day were made with Wilcoxon’s paired signed-rank test or paired Student’s t-test as appropriate. Paired airborne spore levels were correlated 2 by 2, after log-transformation with Pearson’s cross-correlation. Concordance was calculated with kappa coefficient (κ). Median total fungal loads (TFLs) sampled by the 3 outdoor HTSTs were 3,025.0, 3,287.5 and 3,625.0 particles/m3 (P = 0.6, 0.6 and 0.3).—Concordance between Aspergillaceae fungal loads (AFLs, including Aspergillus spp. + Penicillium spp.) was low (κ = 0.2). A low positive correlation was found between TFLs sampled with outdoor HTST and indoor HTST with applying a 4-hour time lag, r = 0.30, 95% CI (0.23–0.43), P<0.001. In indoor air, Aspergillus spp. were detected by the viable impaction sampler on 63.1% of the samples, whereas AFLs were found by HTST-I on only 3.6% of the samples. Concordance between Aspergillus spp. loads and AFLs sampled with the 2 methods was very low (κ = 0.1). This study showed a 4-hour time lag between increase of outdoor and indoor TFLs, possibly due to insulation and aeraulic flow of the building. Outdoor HTSTs may permit to quickly identify (after 48 hours) time periods with high outdoor fungal loads. An identified drawback is that a too low sample area read did not seem to enable detection of Aspergillaceae spores efficiently. Indoor HTSTs may not be recommended at this time, and outdoor HTSTs need further study. Air sampling by viable impaction sampler remains the reference tool for quantifying fungal contamination of indoor air in hospitals. PMID:28486534

Evaluation of hirst-type spore trap to monitor environmental fungal load in hospital.

PubMed

Dananché, Cédric; Gustin, Marie-Paule; Cassier, Pierre; Loeffert, Sophie Tiphaine; Thibaudon, Michel; Bénet, Thomas; Vanhems, Philippe

2017-01-01

The main purpose was to validate the use of outdoor-indoor volumetric impaction sampler with Hirst-type spore traps (HTSTs) to continuously monitor fungal load in order to prevent invasive fungal infections during major structural work in hospital settings. For 4 weeks, outdoor fungal loads were quantified continuously by 3 HTSTs. Indoor air was sampled by both HTST and viable impaction sampler. Results were expressed as particles/m3 (HTST) or colony-forming units (CFU)/m3 (biocollector). Paired comparisons by day were made with Wilcoxon's paired signed-rank test or paired Student's t-test as appropriate. Paired airborne spore levels were correlated 2 by 2, after log-transformation with Pearson's cross-correlation. Concordance was calculated with kappa coefficient (κ). Median total fungal loads (TFLs) sampled by the 3 outdoor HTSTs were 3,025.0, 3,287.5 and 3,625.0 particles/m3 (P = 0.6, 0.6 and 0.3).-Concordance between Aspergillaceae fungal loads (AFLs, including Aspergillus spp. + Penicillium spp.) was low (κ = 0.2). A low positive correlation was found between TFLs sampled with outdoor HTST and indoor HTST with applying a 4-hour time lag, r = 0.30, 95% CI (0.23-0.43), P<0.001. In indoor air, Aspergillus spp. were detected by the viable impaction sampler on 63.1% of the samples, whereas AFLs were found by HTST-I on only 3.6% of the samples. Concordance between Aspergillus spp. loads and AFLs sampled with the 2 methods was very low (κ = 0.1). This study showed a 4-hour time lag between increase of outdoor and indoor TFLs, possibly due to insulation and aeraulic flow of the building. Outdoor HTSTs may permit to quickly identify (after 48 hours) time periods with high outdoor fungal loads. An identified drawback is that a too low sample area read did not seem to enable detection of Aspergillaceae spores efficiently. Indoor HTSTs may not be recommended at this time, and outdoor HTSTs need further study. Air sampling by viable impaction sampler remains the reference tool for quantifying fungal contamination of indoor air in hospitals.

Human Monoclonal Antibody-Based Therapy in the Treatment of Invasive Candidiasis

PubMed Central

Bugli, Francesca; Cacaci, Margherita; Martini, Cecilia; Torelli, Riccardo; Posteraro, Brunella; Sanguinetti, Maurizio; Paroni Sterbini, Francesco

2013-01-01

Invasive candidiasis (IC) represents the leading fungal infection of humans causing life-threatening disease in immunosuppressed and neutropenic individuals including also the intensive care unit patients. Despite progress in recent years in drugs development for the treatment of IC, morbidity and mortality rates still remain very high. Historically, cell-mediated immunity and innate immunity are considered to be the most important lines of defense against candidiasis. Nevertheless recent evidence demonstrates that antibodies with defined specificities could act with different degrees showing protection against systemic and mucosal candidiasis. Mycograb is a human recombinant monoclonal antibody against heat shock protein 90 (Hsp90) that was revealed to have synergy when combined with fluconazole, caspofungin, and amphotericin B against a broad spectrum of Candida species. Furthermore, recent studies have established an important role for Hsp90 in mediating Candida resistance to echinocandins, giving to this antibody molecule even more attractive biological properties. In response to the failure of marketing authorization by the CHMP (Committee for Medicinal Products for Human Use) a new formulation of Mycograb, named Mycograb C28Y variant, with an amino acid substitution was developed in recent years. First data on Mycograb C28Y variant indicate that this monoclonal antibody lacked efficacy in a murine candidiasis model. PMID:23878583