Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases.

PubMed

Conti, Francesca; Lugo-Reyes, Saul Oswaldo; Blancas Galicia, Lizbeth; He, Jianxin; Aksu, Güzide; Borges de Oliveira, Edgar; Deswarte, Caroline; Hubeau, Marjorie; Karaca, Neslihan; de Suremain, Maylis; Guérin, Antoine; Baba, Laila Ait; Prando, Carolina; Guerrero, Gloria G; Emiroglu, Melike; Öz, Fatma Nur; Yamazaki Nakashimada, Marco Antonio; Gonzalez Serrano, Edith; Espinosa, Sara; Barlan, Isil; Pérez, Nestor; Regairaz, Lorena; Guidos Morales, Héctor Eduardo; Bezrodnik, Liliana; Di Giovanni, Daniela; Dbaibo, Ghassan; Ailal, Fatima; Galicchio, Miguel; Oleastro, Matias; Chemli, Jalel; Danielian, Silvia; Perez, Laura; Ortega, Maria Claudia; Soto Lavin, Susana; Hertecant, Joseph; Anal, Ozden; Kechout, Nadia; Al-Idrissi, Eman; ElGhazali, Gehad; Bondarenko, Anastasia; Chernyshova, Liudmyla; Ciznar, Peter; Herbigneaux, Rose-Marie; Diabate, Aminata; Ndaga, Stéphanie; Konte, Barik; Czarna, Ambre; Migaud, Mélanie; Pedraza-Sánchez, Sigifredo; Zaidi, Mussaret Bano; Vogt, Guillaume; Blanche, Stéphane; Benmustapha, Imen; Mansouri, Davood; Abel, Laurent; Boisson-Dupuis, Stéphanie; Mahlaoui, Nizar; Bousfiha, Ahmed Aziz; Picard, Capucine; Barbouche, Ridha; Al-Muhsen, Saleh; Espinosa-Rosales, Francisco J; Kütükçüler, Necil; Condino-Neto, Antonio; Casanova, Jean-Laurent; Bustamante, Jacinta

2016-07-01

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. Our objective was to assess the effect of mycobacterial disease in patients with CGD. We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Validation of qPCR Methods for the Detection of Mycobacterium in New World Animal Reservoirs.

PubMed

Housman, Genevieve; Malukiewicz, Joanna; Boere, Vanner; Grativol, Adriana D; Pereira, Luiz Cezar M; Silva, Ita de Oliveira; Ruiz-Miranda, Carlos R; Truman, Richard; Stone, Anne C

2015-11-01

Zoonotic pathogens that cause leprosy (Mycobacterium leprae) and tuberculosis (Mycobacterium tuberculosis complex, MTBC) continue to impact modern human populations. Therefore, methods able to survey mycobacterial infection in potential animal hosts are necessary for proper evaluation of human exposure threats. Here we tested for mycobacterial-specific single- and multi-copy loci using qPCR. In a trial study in which armadillos were artificially infected with M. leprae, these techniques were specific and sensitive to pathogen detection, while more traditional ELISAs were only specific. These assays were then employed in a case study to detect M. leprae as well as MTBC in wild marmosets. All marmosets were negative for M. leprae DNA, but 14 were positive for the mycobacterial rpoB gene assay. Targeted capture and sequencing of rpoB and other MTBC genes validated the presence of mycobacterial DNA in these samples and revealed that qPCR is useful for identifying mycobacterial-infected animal hosts.

Characterization of bovine gamma delta T cells phenotype during post-natal development and following Mycobacterium bovis vaccination or virulent infection

USDA-ARS?s Scientific Manuscript database

Bovine tuberculosis caused by Mycobacterium bovis is a globally significant veterinary health problem. Gamma delta T cells are known to participate in the immune control of mycobacterial infections. Data in human and non-human primates suggest that mycobacterial infection regulates memory/effector p...

[Prevalence and risk factors associated to tuberculosis and non-tuberculous mycobacterial infections in HIV-positive patients in Bogotá].

PubMed

Beltrán-León, Magda; Pérez-Llanos, Francy; Sánchez, Liliana; Parra-López, Carlos; Navarrete, Myriam; Sánchez, Ricardo; Awad, Carlos; Granada, Ana María; Quintero, Edgardo; Briceño, Óscar; Cruz, Óscar; Murcia, Martha Isabel

2018-03-15

Tuberculosis is one of the most widely distributed infectious diseases worldwide. It is the most common cause of mortality among AIDS patients. In Colombia, 12,918 tuberculosis cases were notified, and 926 deaths were reported in 2015. To determine the prevalence and risk factors associated to mycobacterial infections in HIVpositive patients in two public hospitals from Bogotá. A prospective and descriptive study was carried out by an active search for tuberculosis cases and non-tuberculous mycobacterial infections in HIV-positive patients. We considered demographic, social, clinical, and personal habits as variables. Statistical analyses were done using Stata 13™ software. Three hundred and fifty six patients were included, 81.2% were men and 18.8% were women; the mean age was 36.5 years. Tuberculosis infection had a frequency of 19.9% (95% CI: 15.9-24.5%) and non-tuberculous mycobacterial infection had a 3.9% frequency (95% CI: 2.16-6.5%). Bivariate analysis showed a statistically significant association between tuberculosis infection and CD4+ T cell counts (p=0.003), viral load (p=0.008), antiretroviral therapy (p=0.014), and body mass index (BMI) <18 kg/m2 (p=0.000). In non-tuberculous mycobacterial infections there was a statistically significantassociation with BMI (p=0.027) and CD4+ T cell counts (p=0.045). Factors associated with an impaired immune system caused by HIV infection are an important risk factor for developing tuberculosis. The lack of antiretroviral therapy and the BMI were also important risk factors for tuberculosis.

Nontuberculous Mycobacterial Infection after Fractionated CO2 Laser Resurfacing

PubMed Central

Culton, Donna A.; Miller, Becky A.; Miller, Melissa B.; MacKuen, Courteney; Groben, Pamela; White, Becky; Cox, Gary M.; Stout, Jason E.

2013-01-01

Nontuberculous mycobacteria are increasingly associated with cutaneous infections after cosmetic procedures. Fractionated CO2 resurfacing, a widely used technique for photorejuvenation, has been associated with a more favorable side effect profile than alternative procedures. We describe 2 cases of nontuberculous mycobacterial infection after treatment with a fractionated CO2 laser at a private clinic. Densely distributed erythematous papules and pustules developed within the treated area within 2 weeks of the laser procedure. Diagnosis was confirmed by histologic analysis and culture. Both infections responded to a 4-month course of a multidrug regimen. An environmental investigation of the clinic was performed, but no source of infection was found. The case isolates differed from each other and from isolates obtained from the clinic, suggesting that the infection was acquired by postprocedure exposure. Papules and pustules after fractionated CO2 resurfacing should raise the suspicion of nontuberculous mycobacterial infection. PMID:23628077

Nontuberculous mycobacterial skin infections: recognition and management.

PubMed

Elston, Dirk

2009-01-01

Mycobacterial organisms have re-emerged as an important cause of infectious disease worldwide. Both tuberculosis and nontuberculous mycobacterial infections remain endemic in many parts of the world and are becoming more common in patients with iatrogenic immunosuppression and HIV infection. The nontuberculous mycobacteria, often referred to as mycobacteria other than tuberculosis (MOT), are of special significance to the dermatologist because they often present in the skin, typically after exposure to an aqueous environment. Presentations range from indolent nodules with sporotrichoid spread to acute suppurative folliculitis and abscess formation. Infection with MOT should be considered whenever routine bacterial cultures are negative. Cultures should be obtained, but empiric therapy must often be started while cultures are pending. Some data suggest that clarithromycin may be the best initial empiric therapy.

A potential target gene for the host-directed therapy of mycobacterial infection in murine macrophages

PubMed Central

Bao, Zhang; Chen, Ran; Zhang, Pei; Lu, Shan; Chen, Xing; Yao, Yake; Jin, Xiaozheng; Sun, Yilan; Zhou, Jianying

2016-01-01

Mycobacterium tuberculosis (MTB), one of the major bacterial pathogens for lethal infectious diseases, is capable of surviving within the phagosomes of host alveolar macrophages; therefore, host genetic variations may alter the susceptibility to MTB. In this study, to identify host genes exploited by MTB during infection, genes were non-selectively inactivated using lentivirus-based antisense RNA methods in RAW264.7 macrophages, and the cells that survived virulent MTB infection were then screened. Following DNA sequencing of the surviving cell clones, 26 host genes affecting susceptibility to MTB were identified and their pathways were analyzed by bioinformatics analysis. In total, 9 of these genes were confirmed as positive regulators of collagen α-5(IV) chain (Col4a5) expression, a gene encoding a type IV collagen subunit present on the cell surface. The knockdown of Col4a5 consistently suppressed intracellular mycobacterial viability, promoting the survival of RAW264.7 macrophages following mycobacterial infection. Furthermore, Col4a5 deficiency lowered the pH levels of intracellular vesicles, including endosomes, lysosomes and phagosomes in the RAW264.7 cells. Finally, the knockdown of Col4a5 post-translationally increased microsomal vacuolar-type H+-ATPase activity in macrophages, leading to the acidification of intracellular vesicles. Our findings reveal a novel role for Col4a5 in the regulation of macrophage responses to mycobacterial infection and identify Col4a5 as a potential target for the host-directed anti-mycobacterial therapy. PMID:27432120

ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent Mycobacterium tuberculosis.

PubMed

Silva-Sánchez, Aarón; Meza-Pérez, Selene; Flores-Langarica, Adriana; Donis-Maturano, Luis; Estrada-García, Iris; Calderón-Amador, Juana; Hernández-Pando, Rogelio; Idoyaga, Juliana; Steinman, Ralph M; Flores-Romo, Leopoldo

2015-01-01

Airways infection with Mycobacterium tuberculosis (Mtb) is contained mostly by T cell responses, however, Mtb has developed evasion mechanisms which affect antigen presenting cell (APC) maturation/recruitment delaying the onset of Ag-specific T cell responses. Hypothetically, bypassing the natural infection routes by delivering antigens directly to APCs may overcome the pathogen's naturally evolved evasion mechanisms, thus facilitating the induction of protective immune responses. We generated a murine monoclonal fusion antibody (α-DEC-ESAT) to deliver Early Secretory Antigen Target (ESAT)-6 directly to DEC205+ APCs and to assess its in vivo effects on protection associated responses (IFN-γ production, in vivo CTL killing, and pulmonary mycobacterial load). Treatment with α-DEC-ESAT alone induced ESAT-6-specific IFN-γ producing CD4+ T cells and prime-boost immunization prior to Mtb infection resulted in early influx (d14 post-infection) and increased IFN-γ+ production by specific T cells in the lungs, compared to scarce IFN-γ production in control mice. In vivo CTL killing was quantified in relevant tissues upon transferring target cells loaded with mycobacterial antigens. During infection, α-DEC-ESAT-treated mice showed increased target cell killing in the lungs, where histology revealed cellular infiltrate and considerably reduced bacterial burden. Targeting the mycobacterial antigen ESAT-6 to DEC205+ APCs before infection expands specific T cell clones responsible for early T cell responses (IFN-γ production and CTL activity) and substantially reduces lung bacterial burden. Delivering mycobacterial antigens directly to APCs provides a unique approach to study in vivo the role of APCs and specific T cell responses to assess their potential anti-mycobacterial functions.

ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent Mycobacterium tuberculosis

PubMed Central

Silva-Sánchez, Aarón; Meza-Pérez, Selene; Flores-Langarica, Adriana; Donis-Maturano, Luis; Estrada-García, Iris; Calderón-Amador, Juana; Hernández-Pando, Rogelio; Idoyaga, Juliana; Flores-Romo, Leopoldo

2015-01-01

Airways infection with Mycobacterium tuberculosis (Mtb) is contained mostly by T cell responses, however, Mtb has developed evasion mechanisms which affect antigen presenting cell (APC) maturation/recruitment delaying the onset of Ag-specific T cell responses. Hypothetically, bypassing the natural infection routes by delivering antigens directly to APCs may overcome the pathogen’s naturally evolved evasion mechanisms, thus facilitating the induction of protective immune responses. We generated a murine monoclonal fusion antibody (α-DEC-ESAT) to deliver Early Secretory Antigen Target (ESAT)-6 directly to DEC205+ APCs and to assess its in vivo effects on protection associated responses (IFN-γ production, in vivo CTL killing, and pulmonary mycobacterial load). Treatment with α-DEC-ESAT alone induced ESAT-6-specific IFN-γ producing CD4+ T cells and prime-boost immunization prior to Mtb infection resulted in early influx (d14 post-infection) and increased IFN-γ+ production by specific T cells in the lungs, compared to scarce IFN-γ production in control mice. In vivo CTL killing was quantified in relevant tissues upon transferring target cells loaded with mycobacterial antigens. During infection, α-DEC-ESAT-treated mice showed increased target cell killing in the lungs, where histology revealed cellular infiltrate and considerably reduced bacterial burden. Targeting the mycobacterial antigen ESAT-6 to DEC205+ APCs before infection expands specific T cell clones responsible for early T cell responses (IFN-γ production and CTL activity) and substantially reduces lung bacterial burden. Delivering mycobacterial antigens directly to APCs provides a unique approach to study in vivo the role of APCs and specific T cell responses to assess their potential anti-mycobacterial functions. PMID:25915045

Differences between Mycobacterium-Host Cell Relationships in Latent Tuberculous Infection of Mice Ex Vivo and Mycobacterial Infection of Mouse Cells In Vitro

PubMed Central

Ufimtseva, Elena

2016-01-01

The search for factors that account for the reproduction and survival of mycobacteria, including vaccine strains, in host cells is the priority for studies on tuberculosis. A comparison of BCG-mycobacterial loads in granuloma cells obtained from bone marrow and spleens of mice with latent tuberculous infection and cells from mouse bone marrow and peritoneal macrophage cultures infected with the BCG vaccine in vitro has demonstrated that granuloma macrophages each normally contained a single BCG-Mycobacterium, while those acutely infected in vitro had increased mycobacterial loads and death rates. Mouse granuloma cells were observed to produce the IFNγ, IL-1α, GM-CSF, CD1d, CD25, CD31, СD35, and S100 proteins. None of these activation markers were found in mouse cell cultures infected in vitro or in intact macrophages. Lack of colocalization of lipoarabinomannan-labeled BCG-mycobacteria with the lysosomotropic LysoTracker dye in activated granuloma macrophages suggests that these macrophages were unable to destroy BCG-mycobacteria. However, activated mouse granuloma macrophages could control mycobacterial reproduction in cells both in vivo and in ex vivo culture. By contrast, a considerable increase in the number of BCG-mycobacteria was observed in mouse bone marrow and peritoneal macrophages after BCG infection in vitro, when no expression of the activation-related molecules was detected in these cells. PMID:27066505

Granulomatous encephalomyelitis and intestinal ganglionitis in a spectacled Amazon parrot (Amazona albifrons) infected with Mycobacterium genavense.

PubMed

Gomez, G; Saggese, M D; Weeks, B R; Hoppes, S M; Porter, B F

2011-01-01

An approximately 30-year-old male spectacled Amazon parrot (Amazona albifrons) was presented with a 2-week history of ataxia, head shaking, weight loss and seizures. Gross findings on necropsy examination included atrophy of the musculature, ruffled feathers and minimal epicardial and abdominal fat. Microscopically, there were perivascular cuffs of macrophages with fewer lymphocytes in the grey and white matter of the brain and spinal cord. These lesions were accompanied by gliosis and mild vacuolation of the white matter. In the small intestine, up to 70% of the intestinal ganglia were effaced by infiltrates of macrophages and fewer lymphocytes. The intestinal lamina propria contained multiple inflammatory aggregates of a similar nature. Ziehl-Neelsen staining revealed the presence of numerous bacilli within the cytoplasm of macrophages in the central nervous system (CNS) and enteric ganglia. Amplification of the DNAJ gene confirmed a mycobacterial infection and subsequent polymerase chain reaction (PCR) using a species-specific primer confirmed the aetiology as Mycobacterium genavense. Infection of the CNS with Mycobacterium spp. is uncommon and has not been previously reported in a parrot. This case is unusual in that the organism exhibited tropism for neural tissue. Copyright © 2010 Elsevier Ltd. All rights reserved.

Tubercular prosthetic joint infection: two case reports and literature review.

PubMed

Veloci, Sara; Mencarini, Jessica; Lagi, Filippo; Beltrami, Giovanni; Campanacci, Domenico Andrea; Bartoloni, Alessandro; Bartalesi, Filippo

2018-02-01

Tubercular prosthetic joint infection (TB-PJI) is an uncommon complication. Lack of evidence of systemic tuberculosis and clinical suspicion could bring a delay in the time of the diagnosis. The aims of this study are to underline the importance of awareness and suspicion of mycobacterial infection in the differential diagnosis in PJI and to evaluate the appropriateness of different therapeutic options. Case report and literature review. We report two cases of TB-PJI after total knee arthroplasty in Caucasian patients without prior history of tubercular disease or exposure. In both cases, the diagnosis was obtained years after the onset of symptoms. Despite that, both patients improved during antitubercular treatment (a four-drug regimen consisting of rifampicin, isoniazid, ethambutol, and pyrazinamide for 2 months, followed by rifampicin and isoniazid). Moreover, after an 18-month course of treatment, there was no need for surgical therapy. The result of the literature review allows us to identify 64 cases of TB-PJI. Many differences in both medical and surgical management have been found, among those reviewed cases. Considering our experience and the literature review, we recommend considering a conservative approach (debridement and adequate antituberculous chemotherapy) as a suitable and safe option.

N-acetyl-cysteine exhibits potent anti-mycobacterial activity in addition to its known anti-oxidative functions.

PubMed

Amaral, Eduardo P; Conceição, Elisabete L; Costa, Diego L; Rocha, Michael S; Marinho, Jamocyr M; Cordeiro-Santos, Marcelo; D'Império-Lima, Maria Regina; Barbosa, Theolis; Sher, Alan; Andrade, Bruno B

2016-10-28

Mycobacterium tuberculosis infection is thought to induce oxidative stress. N-acetyl-cysteine (NAC) is widely used in patients with chronic pulmonary diseases including tuberculosis due to its mucolytic and anti-oxidant activities. Here, we tested whether NAC exerts a direct antibiotic activity against mycobacteria. Oxidative stress status in plasma was compared between pulmonary TB (PTB) patients and those with latent M. tuberculosis infection (LTBI) or healthy uninfected individuals. Lipid peroxidation, DNA oxidation and cell death, as well as accumulation of reactive oxygen species (ROS) were measured in cultures of primary human monocyte-derived macrophages infected with M. tuberculosis and treated or not with NAC. M. tuberculosis, M. avium and M. bovis BCG cultures were also exposed to different doses of NAC with or without medium pH adjustment to control for acidity. The anti-mycobacterial effect of NAC was assessed in M. tuberculosis infected human THP-1 cells and bone marrow-derived macrophages from mice lacking a fully functional NADPH oxidase system. The capacity of NAC to control M. tuberculosis infection was further tested in vivo in a mouse (C57BL/6) model. PTB patients exhibited elevated levels of oxidation products and a reduction of anti-oxidants compared with LTBI cases or uninfected controls. NAC treatment in M. tuberculosis-infected human macrophages resulted in a decrease of oxidative stress and cell death evoked by mycobacteria. Importantly, we observed a dose-dependent reduction in metabolic activity and in vitro growth of NAC treated M. tuberculosis, M. avium and M. bovis BCG. Furthermore, anti-mycobacterial activity in infected macrophages was shown to be independent of the effects of NAC on the host NADPH oxidase system in vitro. Short-term NAC treatment of M. tuberculosis infected mice in vivo resulted in a significant reduction of mycobacterial loads in the lungs. NAC exhibits potent anti-mycobacterial effects and may limit M. tuberculosis infection and disease both through suppression of the host oxidative response and through direct antimicrobial activity.

Cutaneous sarcoidosis in Asians: a report of 25 patients from Singapore.

PubMed

Chong, W-S; Tan, H-H; Tan, S-H

2005-03-01

Sarcoidosis is a systemic noncaseating granulomatous disorder of unknown origin involving multiple organ systems. There has been no report so far to describe the epidemiological pattern of cutaneous involvement in sarcoidosis in South-East Asia with diverse ethnic groups. A retrospective study examining the clinicopathological features of all patients diagnosed with sarcoidosis at a tertiary dermatology centre in Singapore from 1980 to 2003 was conducted. Cutaneous sarcoidosis was diagnosed in 25 patients: 13 were Indian, 11 were Chinese and one was Eurasian. Cutaneous manifestations included papules, nodules, plaques and scarring alopecia. Extracutaneous involvement of lymph nodes (four patients), lungs (eight patients) and eyes (two patients) was seen. Eight patients had abnormal chest radiographic findings. Histopathological examination of skin lesions revealed noncaseating, epithelioid granulomatous infiltration in the dermis without evidence of mycobacterial infection, deep fungal infection or polarizable birefringent material. Treatment modalities included corticosteroids, hydroxychloroquine, isotretinoin, methotrexate and surgical excision. Five patients had complete resolution of the cutaneous lesions. Cutaneous sarcoidosis is rare in Asia and indeed in Singapore. Extracutaneous involvement is not uncommon and a thorough clinical evaluation should be undertaken.

Animal Models of Mycobacteria Infection

PubMed Central

Ordway, Diane J.; Orme, Ian M.

2011-01-01

This unit describes the infection of mice and guinea pigs with mycobacteria via various routes, as well as necropsy methods for the determination of mycobacterial loads within target organs. Additionally, methods for cultivating mycobacteria and preparing stocks are described. The protocols outlined are primarily used for M. tuberculosis, but can also be used for the study of other non-tuberculosis mycobacterial species. PMID:18432756

Adenoviral vector-mediated GM-CSF gene transfer improves anti-mycobacterial immunity in mice - role of regulatory T cells.

PubMed

Singpiel, Alena; Kramer, Julia; Maus, Regina; Stolper, Jennifer; Bittersohl, Lara Friederike; Gauldie, Jack; Kolb, Martin; Welte, Tobias; Sparwasser, Tim; Maus, Ulrich A

2018-03-01

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor involved in differentiation, survival and activation of myeloid and non-myeloid cells with important implications for lung antibacterial immunity. Here we examined the effect of pulmonary adenoviral vector-mediated delivery of GM-CSF (AdGM-CSF) on anti-mycobacterial immunity in M. bovis BCG infected mice. Exposure of M. bovis BCG infected mice to AdGM-CSF either applied on 6h, or 6h and 7days post-infection substantially increased alveolar recruitment of iNOS and IL-12 expressing macrophages, and significantly increased accumulation of IFNγ pos T cells and particularly regulatory T cells (Tregs). This was accompanied by significantly reduced mycobacterial loads in the lungs of mice. Importantly, diphtheria toxin-induced depletion of Tregs did not influence mycobacterial loads, but accentuated immunopathology in AdGM-CSF-exposed mice infected with M. bovis BCG. Together, the data demonstrate that AdGM-CSF therapy improves lung protective immunity against M. bovis BCG infection in mice independent of co-recruited Tregs, which however critically contribute to limit lung immunopathology in BCG-infected mice. These data may be relevant to the development of immunomodulatory strategies to limit immunopathology-based lung injury in tuberculosis in humans. Copyright © 2017 Elsevier GmbH. All rights reserved.

Usefulness of Chinese Herbal Medicines as Host-Directed Therapeutics against Mycobacterial Infections: A Review.

PubMed

Tomioka, Haruaki

2017-01-01

The high incidence of tuberculosis (TB) in developing countries, the resurgence of TB in industrialized countries, and the worldwide increase in the prevalence of Mycobacterium avium complex infections have prompted the quest for new antimycobacterial drugs. However, the development of such chemotherapeutics is currently making very slow progress. It therefore appears that devising improved administration protocols for clinical treatment against intractable mycobacteriosis using existing chemotherapeutics is more practical than awaiting the development of novel antimycobacterial drugs. The modulation of host immune responses using immunoadjunctive agents may increase the efficacy of antimicrobial treatment against mycobacteriosis. Particularly, the mild and long-term up-regulation of host immune reactions against mycobacterial pathogens using Chinese herbal medicines (CHMs) may be beneficial for immunoadjunctive therapy. This review focuses on the current status and future prospects regarding the development of CHMs that can be useful for the clinical control of intractable mycobacterial infections.

The epidemiologic relationship between tuberculosis and non-tuberculous mycobacterial disease: a systematic review.

PubMed

Brode, S K; Daley, C L; Marras, T K

2014-11-01

Tuberculosis (TB) rates are decreasing in many areas, while non-tuberculous mycobacteria (NTM) infection rates are increasing. The relationship between the epidemiology of TB and NTM infections is not well understood. To understand the epidemiologic relationship between TB and NTM disease worldwide. A systematic review of Medline (1946-2014) was conducted to identify studies that reported temporal trends in NTM disease incidence. TB rates for each geographic area included were then retrieved. Linear regression models were fitted to calculate slopes describing changes over time. There were 22 studies reporting trends in rates of NTM disease, representing 16 geographic areas over four continents: 75% of areas had climbing incidence rates, while 12.5% had stable rates and 12.5% had declining rates. Most studies (81%) showed declining TB incidence rates. The proportion of incident mycobacterial disease caused by NTM was shown to be rising in almost every geographic area (94%). We found an increase in the proportion of mycobacterial disease caused by NTM in many parts of the world due to a simultaneous reduction in TB and increase in NTM disease. Research into the interaction between mycobacterial infections may help explain this inverse relationship.

Husbandry stress exacerbates mycobacterial infections in adult zebrafish, Danio rerio (Hamilton)

USGS Publications Warehouse

Ramsay, J.M.; Watral, Virginia G.; Schreck, C.B.; Kent, M.L.

2009-01-01

Mycobacteria are significant pathogens of laboratory zebrafish, Danio rerio (Hamilton). Stress is often implicated in clinical disease and morbidity associated with mycobacterial infections but has yet to be examined with zebrafish. The aim of this study was to examine the effects of husbandry stressors on zebrafish infected with mycobacteria. Adult zebrafish were exposed to Mycobacterium marinum or Mycobacterium chelonae, two species that have been associated with disease in zebrafish. Infected fish and controls were then subjected to chronic crowding and handling stressors and examined over an 8-week period. Whole-body cortisol was significantly elevated in stressed fish compared to non-stressed fish. Fish infected with M. marinum ATCC 927 and subjected to husbandry stressors had 14% cumulative mortality while no mortality occurred among infected fish not subjected to husbandry stressors. Stressed fish, infected with M. chelonae H1E2 from zebrafish, were 15-fold more likely to be infected than non-stressed fish at week 8 post-injection. Sub-acute, diffuse infections were more common among stressed fish infected with M. marinum or M. chelonae than non-stressed fish. This is the first study to demonstrate an effect of stress and elevated cortisol on the morbidity, prevalence, clinical disease and histological presentation associated with mycobacterial infections in zebrafish. Minimizing husbandry stress may be effective at reducing the severity of outbreaks of clinical mycobacteriosis in zebrafish facilities. ?? 2009 Blackwell Publishing Ltd.

Mycobacterial blood culture as the only means of diagnosis of disseminated tuberculosis in advanced HIV infection.

PubMed

Mathuram, Alice Joan; Michael, Joy Sarojini; Turaka, Vijay Prakash; Jasmine, Sudha; Carey, Ronald; Ramya, I

2018-04-01

The diagnosis of disseminated tuberculosis (TB) in advanced HIV infection is often delayed because of difficulty in obtaining suitable specimens for culture. A total of 32 such patients from South India with positive mycobacterial blood cultures were studied over ten years. Almost all (90%) had a febrile illness and the majority (68.7%) had clinical lung involvement, but only 27.3% had positive sputum smears. Liver biopsy yielded a positive diagnosis in only 1/7. Cytopenia was almost universal (96.9%). Bone marrow cultures were, however, positive in 54.8%, of whom one-quarter grew atypical mycobacteria. Mycobacterial blood culture is therefore a useful adjunct test to diagnose TB in advanced HIV.

Hand Infections

MedlinePlus

... drainage or pus should be sent for laboratory testing to determine the type of bacteria causing the infection and the appropriate antibiotic for treatment. CAUSES Atypical Mycobacterial Infections Rarely, a ...

Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF.

PubMed

Olleros, Maria L; Chavez-Galan, Leslie; Segueni, Noria; Bourigault, Marie L; Vesin, Dominique; Kruglov, Andrey A; Drutskaya, Marina S; Bisig, Ruth; Ehlers, Stefan; Aly, Sahar; Walter, Kerstin; Kuprash, Dmitry V; Chouchkova, Miliana; Kozlov, Sergei V; Erard, François; Ryffel, Bernard; Quesniaux, Valérie F J; Nedospasov, Sergei A; Garcia, Irene

2015-09-01

Tumor necrosis factor (TNF) is an important cytokine for host defense against pathogens but is also associated with the development of human immunopathologies. TNF blockade effectively ameliorates many chronic inflammatory conditions but compromises host immunity to tuberculosis. The search for novel, more specific human TNF blockers requires the development of a reliable animal model. We used a novel mouse model with complete replacement of the mouse TNF gene by its human ortholog (human TNF [huTNF] knock-in [KI] mice) to determine resistance to Mycobacterium bovis BCG and M. tuberculosis infections and to investigate whether TNF inhibitors in clinical use reduce host immunity. Our results show that macrophages from huTNF KI mice responded to BCG and lipopolysaccharide similarly to wild-type macrophages by NF-κB activation and cytokine production. While TNF-deficient mice rapidly succumbed to mycobacterial infection, huTNF KI mice survived, controlling the bacterial burden and activating bactericidal mechanisms. Administration of TNF-neutralizing biologics disrupted the control of mycobacterial infection in huTNF KI mice, leading to an increased bacterial burden and hyperinflammation. Thus, our findings demonstrate that human TNF can functionally replace murine TNF in vivo, providing mycobacterial resistance that could be compromised by TNF neutralization. This new animal model will be helpful for the testing of specific biologics neutralizing human TNF. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Studies of transmission of mycobacterial infections in Chinook salmon

USGS Publications Warehouse

Ross, A.J.; Johnson, H.E.

1962-01-01

THE INCLUSION OF VISCERA AND CARCASSES OF TUBERCULOUS ADULT SALMON IN THE DIET OF JUVENILE SALMONIDS is considered to be the major source of mycobacterial infections in hatchery-reared fish (Wood and Ordal, 1958; Ross, Earp, and Wood, 1959). In considering additional modes of infection, we speculated about transovarian transmission or a mechanical process arising from contamination of the ova at the egg-taking stage with subsequent entry of the bacteria into the egg at the time of fertilization. This paper is a report on observations made during an experiment designed to test the latter theories.

Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway.

PubMed

Fineran, Paul; Lloyd-Evans, Emyr; Lack, Nathan A; Platt, Nick; Davis, Lianne C; Morgan, Anthony J; Höglinger, Doris; Tatituri, Raju Venkata V; Clark, Simon; Williams, Ian M; Tynan, Patricia; Al Eisa, Nada; Nazarova, Evgeniya; Williams, Ann; Galione, Antony; Ory, Daniel S; Besra, Gurdyal S; Russell, David G; Brenner, Michael B; Sim, Edith; Platt, Frances M

2016-11-18

Tuberculosis remains a major global health concern. The ability to prevent phagosome-lysosome fusion is a key mechanism by which intracellular mycobacteria, including Mycobacterium tuberculosis , achieve long-term persistence within host cells. The mechanisms underpinning this key intracellular pro-survival strategy remain incompletely understood. Host macrophages infected with persistent mycobacteria share phenotypic similarities with cells taken from patients suffering from Niemann-Pick Disease Type C (NPC), a rare lysosomal storage disease in which endocytic trafficking defects and lipid accumulation within the lysosome lead to cell dysfunction and cell death. We investigated whether these shared phenotypes reflected an underlying mechanistic connection between mycobacterial intracellular persistence and the host cell pathway dysfunctional in NPC. The induction of NPC phenotypes in macrophages from wild-type mice or obtained from healthy human donors was assessed via infection with mycobacteria and subsequent measurement of lipid levels and intracellular calcium homeostasis. The effect of NPC therapeutics on intracellular mycobacterial load was also assessed. Macrophages infected with persistent intracellular mycobacteria phenocopied NPC cells, exhibiting accumulation of multiple lipid types, reduced lysosomal Ca 2+ levels, and defects in intracellular trafficking. These NPC phenotypes could also be induced using only lipids/glycomycolates from the mycobacterial cell wall. These data suggest that persistent intracellular mycobacteria inhibit the NPC pathway, likely via inhibition of the NPC1 protein, and subsequently induce altered acidic store Ca 2+ homeostasis. Reduced lysosomal calcium levels may provide a mechanistic explanation for the reduced levels of phagosome-lysosome fusion in mycobacterial infection. Treatments capable of correcting defects in NPC mutant cells via modulation of host cell calcium were of benefit in promoting clearance of mycobacteria from infected host cells. These findings provide a novel mechanistic explanation for mycobacterial intracellular persistence, and suggest that targeting interactions between the mycobacteria and host cell pathways may provide a novel avenue for development of anti-TB therapies.

Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway

PubMed Central

Fineran, Paul; Lloyd-Evans, Emyr; Lack, Nathan A.; Platt, Nick; Davis, Lianne C.; Morgan, Anthony J.; Höglinger, Doris; Tatituri, Raju Venkata V.; Clark, Simon; Williams, Ian M.; Tynan, Patricia; Al Eisa, Nada; Nazarova, Evgeniya; Williams, Ann; Galione, Antony; Ory, Daniel S.; Besra, Gurdyal S.; Russell, David G.; Brenner, Michael B.; Sim, Edith; Platt, Frances M.

2017-01-01

Background. Tuberculosis remains a major global health concern. The ability to prevent phagosome-lysosome fusion is a key mechanism by which intracellular mycobacteria, including Mycobacterium tuberculosis, achieve long-term persistence within host cells. The mechanisms underpinning this key intracellular pro-survival strategy remain incompletely understood. Host macrophages infected with intracellular mycobacteria share phenotypic similarities with cells taken from patients suffering from Niemann-Pick Disease Type C (NPC), a rare lysosomal storage disease in which endocytic trafficking defects and lipid accumulation within the lysosome lead to cell dysfunction and cell death. We investigated whether these shared phenotypes reflected an underlying mechanistic connection between mycobacterial intracellular persistence and the host cell pathway dysfunctional in NPC.  Methods. The induction of NPC phenotypes in macrophages from wild-type mice or obtained from healthy human donors was assessed via infection with mycobacteria and subsequent measurement of lipid levels and intracellular calcium homeostasis. The effect of NPC therapeutics on intracellular mycobacterial load was also assessed.  Results. Macrophages infected with intracellular mycobacteria phenocopied NPC cells, exhibiting accumulation of multiple lipid types, reduced lysosomal Ca 2+ levels, and defects in intracellular trafficking. These NPC phenotypes could also be induced using only lipids/glycomycolates from the mycobacterial cell wall. These data suggest that intracellular mycobacteria inhibit the NPC pathway, likely via inhibition of the NPC1 protein, and subsequently induce altered acidic store Ca 2+ homeostasis. Reduced lysosomal calcium levels may provide a mechanistic explanation for the reduced levels of phagosome-lysosome fusion in mycobacterial infection. Treatments capable of correcting defects in NPC mutant cells via modulation of host cell calcium were of benefit in promoting clearance of mycobacteria from infected host cells.  Conclusion. These findings provide a novel mechanistic explanation for mycobacterial intracellular persistence, and suggest that targeting interactions between the mycobacteria and host cell pathways may provide a novel avenue for development of anti-TB therapies. PMID:28008422

Intracerebral Mycobacterium bovis bacilli Calmette-Guerin infection-induced immune responses in the CNS 1

PubMed Central

Lee, JangEun; Ling, Changying; Kosmalski, Michelle M.; Hulseberg, Paul; Schreiber, Heidi A.; Sandor, Matyas; Fabry, Zsuzsanna

2010-01-01

To study whether cerebral mycobacterial infection induces granuloma and protective immunity similar to systemic infection, we intracerebrally infected mice with Mycobacterium bovis bacilli Calmette-Guerin. Granuloma and IFN-γ+CD4+ T cell responses are induced in the central nervous system (CNS) similar to periphery, but the presence of IFN-γIL-17 double-positive CD4+ T cells is unique to the CNS. The major CNS source of TNF-α is microglia, with modest production by CD4+ T cells and macrophage. Protective immunity is accompanied by accumulation of Foxp3+CD4+ T cells and PD-L2+ dendritic cells, suggesting that both inflammatory and anti-inflammatory responses develop in the CNS following mycobacterial infection. PMID:19535154

Health Impacts of Environmental Mycobacteria†

PubMed Central

Primm, Todd P.; Lucero, Christie A.; Falkinham, Joseph O.

2004-01-01

Environmental mycobacteria are emerging pathogens causing opportunistic infections in humans and animals. The health impacts of human-mycobacterial interactions are complex and likely much broader than currently recognized. Environmental mycobacteria preferentially survive chlorination in municipal water, using it as a vector to infect humans. Widespread chlorination of water has likely selected more resistant environmental mycobacteria species and potentially explains the shift from M. scrofulaceum to M. avium as a cause of cervical lymphadenitis in children. Thus, human activities have affected mycobacterial ecology. While the slow growth and hydrophobicity of environmental mycobacteria appear to be disadvantages, the unique cell wall architecture also grants high biocide and antibiotic resistance, while hydrophobicity facilitates nutrient acquisition, biofilm formation, and spread by aerosolization. The remarkable stress tolerance of environmental mycobacteria is the major reason they are human pathogens. Environmental mycobacteria invade protozoans, exhibiting parasitic and symbiotic relationships. The molecular mechanisms of mycobacterial intracellular pathogenesis in animals likely evolved from similar mechanisms facilitating survival in protozoans. In addition to outright infection, environmental mycobacteria may also play a role in chronic bowl diseases, allergies, immunity to other pulmonary infections, and the efficacy of bacillus Calmette-Guerin vaccination. PMID:14726457

Health impacts of environmental mycobacteria.

PubMed

Primm, Todd P; Lucero, Christie A; Falkinham, Joseph O

2004-01-01

Environmental mycobacteria are emerging pathogens causing opportunistic infections in humans and animals. The health impacts of human-mycobacterial interactions are complex and likely much broader than currently recognized. Environmental mycobacteria preferentially survive chlorination in municipal water, using it as a vector to infect humans. Widespread chlorination of water has likely selected more resistant environmental mycobacteria species and potentially explains the shift from M. scrofulaceum to M. avium as a cause of cervical lymphadenitis in children. Thus, human activities have affected mycobacterial ecology. While the slow growth and hydrophobicity of environmental mycobacteria appear to be disadvantages, the unique cell wall architecture also grants high biocide and antibiotic resistance, while hydrophobicity facilitates nutrient acquisition, biofilm formation, and spread by aerosolization. The remarkable stress tolerance of environmental mycobacteria is the major reason they are human pathogens. Environmental mycobacteria invade protozoans, exhibiting parasitic and symbiotic relationships. The molecular mechanisms of mycobacterial intracellular pathogenesis in animals likely evolved from similar mechanisms facilitating survival in protozoans. In addition to outright infection, environmental mycobacteria may also play a role in chronic bowl diseases, allergies, immunity to other pulmonary infections, and the efficacy of bacillus Calmette-Guerin vaccination.

Production of matrix metalloproteinases in response to mycobacterial infection.

PubMed

Quiding-Järbrink, M; Smith, D A; Bancroft, G J

2001-09-01

Matrix metalloproteinases (MMPs) constitute a large family of enzymes with specificity for the various proteins of the extracellular matrix which are implicated in tissue remodeling processes and chronic inflammatory conditions. To investigate the role of MMPs in immunity to mycobacterial infections, we incubated murine peritoneal macrophages with viable Mycobacterium bovis BCG or Mycobacterium tuberculosis H37Rv and assayed MMP activity in the supernatants by zymography. Resting macrophages secreted only small amounts of MMP-9 (gelatinase B), but secretion increased dramatically in a dose-dependent manner in response to either BCG or M. tuberculosis in vitro. Incubation with mycobacteria also induced increased MMP-2 (gelatinase A) activity. Neutralization of tumor necrosis alpha (TNF-alpha), and to a lesser extent interleukin 18 (IL-18), substantially reduced MMP production in response to mycobacteria. Exogenous addition of TNF-alpha or IL-18 induced macrophages to express MMPs, even in the absence of bacteria. The immunoregulatory cytokines gamma interferon (IFN-gamma), IL-4, and IL-10 all suppressed BCG-induced MMP production, but through different mechanisms. IFN-gamma treatment increased macrophage secretion of TNF-alpha but still reduced their MMP activity. Conversely, IL-4 and IL-10 seemed to act by reducing the amount of TNF-alpha available to the macrophages. Finally, infection of BALB/c or severe combined immunodeficiency (SCID) mice with either BCG or M. tuberculosis induced substantial increases in MMP-9 activity in infected tissues. In conclusion, we show that mycobacterial infection induces MMP-9 activity both in vitro and in vivo and that this is regulated by TNF-alpha, IL-18, and IFN-gamma. These findings indicate a possible contribution of MMPs to tissue remodeling processes that occur in mycobacterial infections.

Macrophage-Inducible C-Type Lectin Mincle-Expressing Dendritic Cells Contribute to Control of Splenic Mycobacterium bovis BCG Infection in Mice

PubMed Central

Behler, Friederike; Maus, Regina; Bohling, Jennifer; Knippenberg, Sarah; Kirchhof, Gabriele; Nagata, Masahiro; Jonigk, Danny; Izykowski, Nicole; Mägel, Lavinia; Welte, Tobias; Yamasaki, Sho

2014-01-01

The macrophage-inducible C-type lectin Mincle has recently been identified to be a pattern recognition receptor sensing mycobacterial infection via recognition of the mycobacterial cell wall component trehalose-6′,6-dimycolate (TDM). However, its role in systemic mycobacterial infections has not been examined so far. Mincle-knockout (KO) mice were infected intravenously with Mycobacterium bovis BCG to mimic the systemic spread of mycobacteria under defined experimental conditions. After intravenous infection with M. bovis BCG, Mincle-KO mice responded with significantly higher numbers of mycobacterial CFU in spleen and liver, while reduced granuloma formation was observed only in the spleen. At the same time, reduced Th1 cytokine production and decreased numbers of gamma interferon-producing T cells were observed in the spleens of Mincle-KO mice relative to the numbers in the spleens of wild-type (WT) mice. The effect of adoptive transfer of defined WT leukocyte subsets generated from bone marrow cells of zDC+/DTR mice (which bear the human diphtheria toxin receptor [DTR] under the control of the classical dendritic cell-specific zinc finger transcription factor zDC) to specifically deplete Mincle-expressing classical dendritic cells (cDCs) but not macrophages after diphtheria toxin application on the numbers of splenic and hepatic CFU and T cell subsets was then determined. Adoptive transfer experiments revealed that Mincle-expressing splenic cDCs rather than Mincle-expressing macrophages contributed to the reconstitution of attenuated splenic antimycobacterial immune responses in Mincle-KO mice after intravenous challenge with BCG. Collectively, we show that expression of Mincle, particularly by cDCs, contributes to the control of splenic M. bovis BCG infection in mice. PMID:25332121

Onchocerciasis modulates the immune response to mycobacterial antigens

PubMed Central

Stewart, G R; Boussinesq, M; Coulson, T; Elson, L; Nutman, T; Bradley, J E

1999-01-01

Chronic helminth infection induces a type-2 cellular immune response. In contrast to this, mycobacterial infections commonly induce a type-1 immune response which is considered protective. Type-2 responses and diminished type-1 responses to mycobacteria have been previously correlated with active infection states such as pulmonary tuberculosis and lepromatous leprosy. The present study examines the immune responses of children exposed to both the helminth parasite Onchocerca volvulus and the mycobacterial infections, Mycobacterium tuberculosis and M. leprae. Proliferation of peripheral blood mononuclear cells (PBMC) and production of IL-4 in response to both helminth and mycobacterial antigen (PPD) decreased dramatically with increasing microfilarial (MF) density. Although interferon-gamma (IFN-γ) production strongly correlated with cellular proliferation, it was surprisingly not related to MF density for either antigen. IL-4 production in response to helminth antigen and PPD increased with ascending children's age. IFN-γ and cellular proliferation to PPD were not related to age, but in response to helminth antigen were significantly higher in children of age 9–12 years than children of either the younger age group (5–8 years) or the older group (13–16 years). Thus, there was a MF density-related down-regulation of cellular responsiveness and age-related skewing toward type 2 which was paralleled in response to both the helminth antigen and PPD. This parasite-induced immunomodulation of the response to mycobacteria correlates with a previous report of doubled incidence of lepromatous leprosy in onchocerciasis hyperendemic regions. Moreover, this demonstration that helminth infection in humans can modulate the immune response to a concurrent infection or immunological challenge is of critical importance to future vaccination strategies. PMID:10469056

Determination of antibiotic resistance and high-performance liquid chromatography profiles for Mycobacterium species.

PubMed

Toka Özer, Türkan; Yula, Erkan; Doğan, Metin; Baskın, Hüseyin

2018-04-27

Incidence of mycobacterial infections has been increasing. However, diagnosis and treatment of mycobacterial infections can be difficult. The aim of this study was to investigate high-performance liquid chromatography (HPLC) analysis of the mycolic acids for rapid identification and dendrogram cluster analysis of mycobacterium species. Clinical specimens received for mycobacterial culture and antimicrobial susceptibility test were processed by standard laboratory protocols. Positive cultures were analyzed with HPLC method. Mycolic acid analysis with HPLC was used for diagnosis of tuberculosis and other mycobacterial infections. These reports were compared with Sherlock Library mycobacterial species, and the similarity index was analyzed. This value was formed by a software in multidimensional space that was the calculation of the average distance between the nearest library profile and unknown profile. The ninety-two samples were identified as M. tuberculosis. (similarity index between 0.593 and 0.994). One of the other strains was identified as M. avium intracellulare (strain No. 82) (SI = 0.906); one of them was identified as M. interjectum (strain no. 89) (SI = 0.644). Total 94 samples were identified, and dendrogram was applied to these samples. Profile A (10.6%), profile B (59.6%), profile C (11.7%), profile D (3.2%), and other profiles as single different profiles were identified. Rates for each as 1% (89, 94, 1, 82, 26, 42, 32, 41, 100, 43, 47, 44, 40, 35). High-performance liquid chromatography is a useful, rapid, reliable, and practical method for diagnosis of mycobacterium species. © 2018 Wiley Periodicals, Inc.

Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections.

PubMed

Hetzel, Miriam; Mucci, Adele; Blank, Patrick; Nguyen, Ariane Hai Ha; Schiller, Jan; Halle, Olga; Kühnel, Mark-Philipp; Billig, Sandra; Meineke, Robert; Brand, Daniel; Herder, Vanessa; Baumgärtner, Wolfgang; Bange, Franz-Christoph; Goethe, Ralph; Jonigk, Danny; Förster, Reinhold; Gentner, Bernhard; Casanova, Jean-Laurent; Bustamante, Jacinta; Schambach, Axel; Kalinke, Ulrich; Lachmann, Nico

2018-02-01

Mendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by severe infections caused by weakly virulent mycobacteria. Biallelic null mutations in genes encoding interferon gamma receptor 1 or 2 ( IFNGR1 or IFNGR2 ) result in a life-threatening disease phenotype in early childhood. Recombinant interferon γ (IFN-γ) therapy is inefficient, and hematopoietic stem cell transplantation has a poor prognosis. Thus, we developed a hematopoietic stem cell (HSC) gene therapy approach using lentiviral vectors that express Ifnγr1 either constitutively or myeloid specifically. Transduction of mouse Ifnγr1 -/- HSCs led to stable IFNγR1 expression on macrophages, which rescued their cellular responses to IFN-γ. As a consequence, genetically corrected HSC-derived macrophages were able to suppress T-cell activation and showed restored antimycobacterial activity against Mycobacterium avium and Mycobacterium bovis Bacille Calmette-Guérin (BCG) in vitro. Transplantation of genetically corrected HSCs into Ifnγr1 -/- mice before BCG infection prevented manifestations of severe BCG disease and maintained lung and spleen organ integrity, which was accompanied by a reduced mycobacterial burden in lung and spleen and a prolonged overall survival in animals that received a transplant. In summary, we demonstrate an HSC-based gene therapy approach for IFNγR1 deficiency, which protects mice from severe mycobacterial infections, thereby laying the foundation for a new therapeutic intervention in corresponding human patients. © 2018 by The American Society of Hematology.

Enhanced gamma interferon responses of mouse spleen cells following immunotherapy for tuberculosis relapse.

PubMed

Gil, Olga; Vilaplana, Cristina; Guirado, Evelyn; Díaz, Jorge; Cáceres, Neus; Singh, Mahavir; Cardona, Pere-Joan

2008-11-01

Gamma interferon responses of spleen cells in mice were examined during postchemotherapy relapse of intraperitoneally induced latent tuberculous infection. The mycobacterial extract RUTI, which prevented the relapse, significantly enhanced the immune responses to secreted and structural recombinant mycobacterial antigens, suggesting that RUTI-mediated protection was mediated by activated T cells.

Striking the right immunological balance prevents progression of tuberculosis.

PubMed

Vyas, Shachi Pranjal; Goswami, Ritobrata

2017-12-01

Tuberculosis (TB) caused by infection with Mycobacterium tuberculosis (Mtb) is a major burden for human health worldwide. Current standard treatments for TB require prolonged administration of antimycobacterial drugs leading to exaggerated inflammation and tissue damage. This can result in the reactivation of latent TB culminating in TB progression. Thus, there is an unmet need to develop therapies that would shorten the duration of anti-TB treatment and to induce optimal protective immune responses to control the spread of mycobacterial infection with minimal lung pathology. Granulomata is the hallmark structure formed by the organized accumulation of immune cells including macrophages, natural killer cells, dendritic cells, neutrophils, T cells, and B cells to the site of Mtb infection. It safeguards the host by containing Mtb in latent form. However, granulomata can undergo caseation and contribute to the reactivation of latent TB, if the immune responses developed to fight mycobacterial infection are not properly controlled. Thus, an optimal balance between innate and adaptive immune cells might play a vital role in containing mycobacteria in latent form for prolonged periods and prevent the spread of Mtb infection from one individual to another. Optimal and well-regulated immune responses against Mycobacterium tuberculosis may help to prevent the reactivation of latent TB. Moreover, therapies targeting balanced immune responses could help to improve treatment outcomes among latently infected TB patients and thereby limit the dissemination of mycobacterial infection.

Detection and Characterization of Infections and Infection Susceptibility

ClinicalTrials.gov

2018-06-26

Immune Disorders; Chronic Granulomatous Disease; Genetic Immunological Deficiencies; Hyperimmunoglobulin-E Recurrent Infection Syndrome; Recurrent Infections; Unknown Immune Deficiency; GATA2 Deficiency (MonoMAC); Nontuberculous Mycobacterial Infections; Hyper IgE (Job s) Syndrome; Leukocyte Adhesion Deficiency; Susceptibility to Disseminated Infections; Primary Immune Deficiency Disease (PIDD)

Mycobacterial lesions in fish, amphibians, reptiles, rodents, lagomorphs, and ferrets with reference to animal models.

PubMed

Reavill, Drury R; Schmidt, Robert E

2012-01-01

Mycobacteriosis is a serious disease across many animal species. Approximately more than 120 species are currently recognized in the genus Mycobacterium. This article describes the zoonotic potential of mycobacteria and mycobacteriosis in fish, amphibians, rodents, rabbits, and ferrets. It considers clinical signs; histology; molecular methods of identification, such as polymerase chain reaction and DNA sequencing; routes of infection; and disease progression. Studying the disease in animals may aid in understanding the pathogenesis of mycobacterial infections in humans and identify better therapy and preventative options such as vaccines.

Mycobacterium genavense infections in non-HIV immunocompromised hosts: a systematic review.

PubMed

Mahmood, Maryam; Ajmal, Saira; Abu Saleh, Omar M; Bryson, Alexandra; Marcelin, Jasmine R; Wilson, John W

2018-05-01

Mycobacterium genavense is a non-tuberculous mycobacterium which can rarely cause disease in non-HIV immunocompromised hosts. We describe our experience with this unusual infection and perform a systematic review of the literature to describe the features of M. genavense infection in non-HIV immunocompromised hosts. All cases of Mycobacterium genavense infection in non-HIV patients at our institution were reviewed. In addition, we conducted a systematic review of the literature to identify previously published cases of M. genavense infections in non-HIV hosts. Two cases of M. genavense were identified at our center; a 51-year-old renal transplant recipient with a prosthetic knee joint infection and a 66-year-old woman with idiopathic CD4 lymphocytopenia with gastrointestinal tract disease. The systematic review identified 44 cases of M. genavense infection in non-HIV hosts. The most common underlying conditions were solid organ transplantation (40%), sarcoidosis (14%) and hematopoietic stem cell transplantation (7%). Disease most commonly involved the gastrointestinal tract, spleen, liver or bone marrow. Diagnosis was challenging with PCR required for identification in nearly all cases. Over one-third of patients died, which may reflect the combination of infection and underlying comorbidities. Overall cure was achieved in 61% with a mean duration of antimycobacterial therapy of 15.5 months (range 10-24). M. genavense infection is a rare mycobacterial infection in non-HIV immunocompromised hosts. It should be suspected in immunocompromised patients presenting with disseminated mycobacterial infection, acid fast bacilli on smear or histopathologic examination, with poor or no growth in mycobacterial cultures.

Mycobacterial culture

MedlinePlus

... test to look for the bacteria that cause tuberculosis and other infections caused by similar bacteria. How ... order this test if you have signs of tuberculosis or a related infection. Normal Results If there ...

Mycobacterial Infections

MedlinePlus

... many different kinds. The most common one causes tuberculosis. Another one causes leprosy. Still others cause infections ... aren't "typical" because they don't cause tuberculosis. But they can still harm people, especially people ...

Generation of transgenic cattle expressing human β-defensin 3 as an approach to reducing susceptibility to Mycobacterium bovis infection.

PubMed

Su, Feng; Wang, Yongsheng; Liu, Guanghui; Ru, Kun; Liu, Xin; Yu, Yuan; Liu, Jun; Wu, Yongyan; Quan, Fusheng; Guo, Zekun; Zhang, Yong

2016-03-01

Bovine tuberculosis results from infection with Mycobacterium bovis, a member of the Mycobacterium tuberculosis family. Worldwide, M. bovis infections result in economic losses in the livestock industry; cattle production is especially hard-hit by this disease. Generating M. bovis-resistant cattle may potentially mitigate the impact of this disease by reducing M. bovis infections. In this study, we used transgenic somatic cell nuclear transfer to generate cattle expressing the gene encoding human β-defensin 3 (HBD3), which confers resistance to mycobacteria in vitro. We first generated alveolar epithelial cells expressing HBD3 under the control of the bovine MUC1 promoter, and confirmed that these cells secreted HBD3 and possessed anti-mycobacterial capacity. We then generated and identified transgenic cattle by somatic cell nuclear transfer. The cleavage and blastocyst formation rates of genetically modified embryos provided evidence that monoclonal transgenic bovine fetal fibroblast cells have an integral reprogramming ability that is similar to that of normal cells. Five genetically modified cows were generated, and their anti-mycobacterial capacities were evaluated. Alveolar epithelial cells and macrophages from these cattle expressed higher levels of HBD3 protein compared with non-transgenic cells and possessed effective anti-mycobacterial capacity. These results suggest that the overall risk of M. bovis infection in transgenic cattle is efficiently reduced, and support the development of genetically modified animals as an effective tool to reduce M. bovis infection. © 2016 Federation of European Biochemical Societies.

Efficacy of BACTEC TB in the rapid confirmatory diagnosis of mycobacterial infections. A Lebanese tertiary care center experience.

PubMed

Itani, Lina Y; Cherry, Mohamad A; Araj, George F

2005-01-01

Rapid detection of Mycobacterium tuberculosis (MTB), especially multidrug-resistant strains, is of importance for prompt clinical management and initiation of public health control measures. Culture remains the "gold" standard in the confirmatory laboratory diagnosis of mycobacterial infections. The reliability of the automated radiometric BACTEC 460 TB (BACTEC) system for the rapid detection of mycobacteria in clinical specimens was evaluated and compared to the conventional culture on Lowenstein-Jensen (LJ) medium. All clinical specimens submitted for mycobacterial culture were processed and simultaneously cultured on both BACTEC broth medium and LJ solid medium. Acid-fast bacilli (AFB) smears were also performed on the sediments. Differentiation of mycobacterial isolates as MTB or Mycobacterium sp. other than tuberculosis (MOTT) was based on the BACTEC NAP test. All positive culture findings recovered between January 1997 and December 2003 were analyzed in this study. A total of 3300 specimens were tested of which 355 (10.7%) yielded positive cultures consisting of 233 (65.6%) MTB and 122 (34.4%) MOTT. The percentages of AFB smear-positive were 45% and 49% in clinical specimens yielding MTB & MOTT, respectively. Though several types of specimens were cultured, most isolates (72% of MTB & 91% of MOTT) were recovered from respiratory specimens. Overall, the BACTEC showed significantly higher mycobacteria recovery rate (91%) than LJ (77%). In terms of times to detection, BACTEC showed significantly shorter detection time of isolates than LJ for the overall (mean 9.6 days for BACTEC vs. 22.8 days for LJ) and for each category of AFB smear finding. The detection time is shortened for BACTEC with the increasing grade of smear positivity. BACTEC is substantially more sensitive, efficient and rapid than LJ in the laboratory diagnosis of mycobacterial infections. This system also provides rapid differentiation of MTB from MOTT and susceptibility test results on MTB. However, the simultaneous use of BACTEC and LJ is recommended to provide maximum optimal recovery of isolates from clinical specimens. The time-saving in BACTEC provides an excellent facility for physicians in patient management and to public health personnel for prompt initiation of infection control measures.

Recurrent mycobacterial osteomyelitis. Report of a case due to Mycobacterium avium-intracellulare-scrofulaceum complex and BCG vaccination.

PubMed

Solheim, L F; Kjelsberg, F

1982-01-01

A 28-year-old man suffering from recurrent mycobacterial osteomyelitis during several years is reported. Eight years old he had a Mycobacterium scrofulaceum infection in his right calcaneus. A serious infection with multiple foci of osteomyelitis occurred after BCG vaccination at the age of 14 years and 11 years later multifocal lesions of osteomyelitis due to Mycobacterium avium-intracellulare-scrofulaceum complex appeared. The special clinical problems due to the relative or complete resistence of these organisms to antituberculous drugs are emphasized. The mainstays of treatment are surgical revision and drainage with prolonged and intensive multiple drug therapy.

Severe Disseminated Mycobacterium avium Infection in a Patient with a Positive Serum Autoantibody to Interferon-γ

PubMed Central

Ikeda, Hiroshi; Nakamura, Kiwamu; Ikenori, Mei; Saito, Takahiro; Nagamine, Keisuke; Inoue, Minoru; Sakagami, Takuro; Suzuki, Hiroko; Usui, Mariko; Kanemitsu, Keiji; Matsumoto, Akinori; Shinbo, Takuro

2016-01-01

We herein report a case of disseminated Mycobacterium avium infection that involved both optic nerves, the conjunctiva, the right lower lung, and multiple skin lesions, including a thoracic nodule. The patient was a 65-year-old man without any significant medical history. The pathogen was detected in the patient's eye discharge, sputum, bronchial lavage fluid, and thoracic nodule. Anti-mycobacterial chemotherapy, including clarithromycin, rifampicin, and ethambutol, was administered, and the thoracic nodule was resected. An autoantibody to interferon-γ was detected in the patient's serum. Bilateral swelling of his optic nerves and facial dermatitis improved after initiating anti-mycobacterial chemotherapy. PMID:27746449

Macrophage sphingolipids are essential for the entry of mycobacteria.

PubMed

Viswanathan, Gopinath; Jafurulla, Md; Kumar, G Aditya; Raghunand, Tirumalai R; Chattopadhyay, Amitabha

2018-07-01

Mycobacteria are intracellular pathogens that can invade and survive within host macrophages. Mycobacterial infections remain a major cause of mortality and morbidity worldwide, with serious concerns of emergence of multi and extensively drug-resistant tuberculosis. While significant advances have been made in identifying mycobacterial virulence determinants, the detailed molecular mechanism of internalization of mycobacteria into host cells remains poorly understood. Although several studies have highlighted the crucial role of sphingolipids in mycobacterial growth, persistence and establishment of infection, the role of sphingolipids in the entry of mycobacteria into host cells is not known. In this work, we explored the role of host membrane sphingolipids in the entry of Mycobacterium smegmatis into J774A.1 macrophages. Our results show that metabolic depletion of sphingolipids in host macrophages results in a significant reduction in the entry of M. smegmatis. Importantly, the entry of Escherichia coli into host macrophages under similar conditions remained invariant, implying the specificity of the requirement of sphingolipids in mycobacterial entry. To the best of our knowledge, our results constitute the first report demonstrating the role of host macrophage sphingolipids in the entry of mycobacteria. Our results could help in the development of novel therapeutic strategies targeting sphingolipid-mediated entry of mycobacteria into host cells. Copyright © 2018 Elsevier B.V. All rights reserved.

Opportunities for Improved Serodiagnosis of Human Tuberculosis, Bovine Tuberculosis, and Paratuberculosis

PubMed Central

Wadhwa, Ashutosh; Hickling, Graham J.; Eda, Shigetoshi

2012-01-01

Mycobacterial infections—tuberculosis (TB), bovine tuberculosis (bTB), and Johne's disease (JD)—are major infectious diseases of both human and animals. Methods presently in use for diagnosis of mycobacterial infections include bacterial culture, nucleic acid amplification, tuberculin skin test, interferon-γ assay, and serology. Serological tests have several advantages over other methods, including short turn-around time, relatively simple procedures, and low cost. However, current serodiagnostic methods for TB, bTB and JD exhibit low sensitivity and/or specificity. Recent studies that have aimed to develop improved serodiagnostic tests have mostly focused on identifying useful species-specific protein antigens. A review of recent attempts to improve diagnostic test performance indicates that the use of multiple antigens can improve the accuracy of serodiagnosis of these mycobacterial diseases. Mycobacteria also produce a variety of species-specific nonprotein molecules; however, only a few such molecules (e.g., cord factor and lipoarabinomannan) have so far been evaluated for their effectiveness as diagnostic antigens. For TB and bTB, there has been recent progress in developing laboratory-free diagnostic methods. New technologies such as microfluidics and “Lab-on-Chip” are examples of promising new technologies that can underpin development of laboratory-free diagnostic devices for these mycobacterial infections. PMID:22720192

Methodological and Clinical Aspects of the Molecular Epidemiology of Mycobacterium tuberculosis and Other Mycobacteria

PubMed Central

Minias, Alina; van Ingen, Jakko; Rastogi, Nalin; Brzostek, Anna; Żaczek, Anna; Dziadek, Jarosław

2016-01-01

SUMMARY Molecular typing has revolutionized epidemiological studies of infectious diseases, including those of a mycobacterial etiology. With the advent of fingerprinting techniques, many traditional concepts regarding transmission, infectivity, or pathogenicity of mycobacterial bacilli have been revisited, and their conventional interpretations have been challenged. Since the mid-1990s, when the first typing methods were introduced, a plethora of other modalities have been proposed. So-called molecular epidemiology has become an essential subdiscipline of modern mycobacteriology. It serves as a resource for understanding the key issues in the epidemiology of tuberculosis and other mycobacterial diseases. Among these issues are disclosing sources of infection, quantifying recent transmission, identifying transmission links, discerning reinfection from relapse, tracking the geographic distribution and clonal expansion of specific strains, and exploring the genetic mechanisms underlying specific phenotypic traits, including virulence, organ tropism, transmissibility, or drug resistance. Since genotyping continues to unravel the biology of mycobacteria, it offers enormous promise in the fight against and prevention of the diseases caused by these pathogens. In this review, molecular typing methods for Mycobacterium tuberculosis and nontuberculous mycobacteria elaborated over the last 2 decades are summarized. The relevance of these methods to the epidemiological investigation, diagnosis, evolution, and control of mycobacterial diseases is discussed. PMID:26912567

Paradoxical response preceding control of Scedosporium apiospermum mycetoma with posaconazole treatment.

PubMed

Béraud, Guillaume; Desbois, Nicole; Coyo, Caroline; Quist, Danièle; Rozé, Benoit; Savorit, Luc; Cabié, André

2015-01-01

Mycetoma is a chronic granulomatous infection that is difficult to treat, notably when due to fungi such as Scedosporium apiospermum. Recent antifungal agents could be an option, but cases are rarely reported, and none with posaconazole. Paradoxical responses, defined as initial clinical worsening despite appropriate treatment, are common in tuberculosis but rare in deep mycoses in non-immunocompromised hosts. Hence, paradoxical responses in context other than mycobacterial infection in an immunocompromised host could provide insights into the pathophysiology and the optimal strategy for treatment. We report the first case of a mycetoma caused by S. apiospermum with bone involvement treated with posaconazole, and the paradoxical response observed at the beginning of the treatment. As with mycobacterial infections, a paradoxical response in deep mycosis could represent the earliest marker of therapeutic efficacy.

Face mask sampling for the detection of Mycobacterium tuberculosis in expelled aerosols.

PubMed

Williams, Caroline M L; Cheah, Eddy S G; Malkin, Joanne; Patel, Hemu; Otu, Jacob; Mlaga, Kodjovi; Sutherland, Jayne S; Antonio, Martin; Perera, Nelun; Woltmann, Gerrit; Haldar, Pranabashis; Garton, Natalie J; Barer, Michael R

2014-01-01

Although tuberculosis is transmitted by the airborne route, direct information on the natural output of bacilli into air by source cases is very limited. We sought to address this through sampling of expelled aerosols in face masks that were subsequently analyzed for mycobacterial contamination. In series 1, 17 smear microscopy positive patients wore standard surgical face masks once or twice for periods between 10 minutes and 5 hours; mycobacterial contamination was detected using a bacteriophage assay. In series 2, 19 patients with suspected tuberculosis were studied in Leicester UK and 10 patients with at least one positive smear were studied in The Gambia. These subjects wore one FFP30 mask modified to contain a gelatin filter for one hour; this was subsequently analyzed by the Xpert MTB/RIF system. In series 1, the bacteriophage assay detected live mycobacteria in 11/17 patients with wearing times between 10 and 120 minutes. Variation was seen in mask positivity and the level of contamination detected in multiple samples from the same patient. Two patients had non-tuberculous mycobacterial infections. In series 2, 13/20 patients with pulmonary tuberculosis produced positive masks and 0/9 patients with extrapulmonary or non-tuberculous diagnoses were mask positive. Overall, 65% of patients with confirmed pulmonary mycobacterial infection gave positive masks and this included 3/6 patients who received diagnostic bronchoalveolar lavages. Mask sampling provides a simple means of assessing mycobacterial output in non-sputum expectorant. The approach shows potential for application to the study of airborne transmission and to diagnosis.

Face Mask Sampling for the Detection of Mycobacterium tuberculosis in Expelled Aerosols

PubMed Central

Malkin, Joanne; Patel, Hemu; Otu, Jacob; Mlaga, Kodjovi; Sutherland, Jayne S.; Antonio, Martin; Perera, Nelun; Woltmann, Gerrit; Haldar, Pranabashis; Garton, Natalie J.; Barer, Michael R.

2014-01-01

Background Although tuberculosis is transmitted by the airborne route, direct information on the natural output of bacilli into air by source cases is very limited. We sought to address this through sampling of expelled aerosols in face masks that were subsequently analyzed for mycobacterial contamination. Methods In series 1, 17 smear microscopy positive patients wore standard surgical face masks once or twice for periods between 10 minutes and 5 hours; mycobacterial contamination was detected using a bacteriophage assay. In series 2, 19 patients with suspected tuberculosis were studied in Leicester UK and 10 patients with at least one positive smear were studied in The Gambia. These subjects wore one FFP30 mask modified to contain a gelatin filter for one hour; this was subsequently analyzed by the Xpert MTB/RIF system. Results In series 1, the bacteriophage assay detected live mycobacteria in 11/17 patients with wearing times between 10 and 120 minutes. Variation was seen in mask positivity and the level of contamination detected in multiple samples from the same patient. Two patients had non-tuberculous mycobacterial infections. In series 2, 13/20 patients with pulmonary tuberculosis produced positive masks and 0/9 patients with extrapulmonary or non-tuberculous diagnoses were mask positive. Overall, 65% of patients with confirmed pulmonary mycobacterial infection gave positive masks and this included 3/6 patients who received diagnostic bronchoalveolar lavages. Conclusion Mask sampling provides a simple means of assessing mycobacterial output in non-sputum expectorant. The approach shows potential for application to the study of airborne transmission and to diagnosis. PMID:25122163

Host-directed strategies using lipid nanoparticles to reduce mycobacteria survival

NASA Astrophysics Data System (ADS)

Pereira, L.; Diogo, J.; Mateus, R.; Pimentel, M.; Videira, M.

2015-02-01

Antibiotic-resistant infections and the stagnations in the development of new drugs have increased the demand for new therapeutic approaches against Mycobacterium tuberculosis. Innovative systems that are able to target and eradicate the bacteria in the infected host cells may represent a therapeutic breakthrough while avoiding latency. The development of nanosystems aiming a controlled and targeted intracellular drug release, have proved to increase cytosolic therapeutic concentration while reducing undesired side effects. This work's main goal was to develop a host-directed strategy against mycobacterial infection through the design of a biocompatible nanocarrier for phage-derived protein delivery, using M. smegmatis as model. Since mycobacterial pathogenicity is strongly supported by the presence of lipids in the cell wall, their degradation induces bacterial destruction through cell wall hydrolysis. Phage-based lipolytic enzymes such as, LysB a mycolylarabinogalactan esterase, represent an appealing therapeutic approach. The herein proposed Ms6 LysB-containing lipid nanocarrier (SLN_LysB) explores the known advantages of nanomedicine-based systems for phagocytic cells selectively targeting thus allowing LysB intracellular accumulation and a more pronounced mycobacterial infection eradication. Adsorption efficiency value indicates the potential of this system as a protein nanocarrier. Moreover, promising outcomes were obtained in host-infected macrophages treated with SLN_LysB. The results show that the herein proposed strategy was more effective in inhibiting the growth of M. smegmatis than free LysB, which might be related to the nanocarrier internalization. Acting as effective protein nanocarriers, the protein-guided delivery in the infected phagocytic cells allows it to exert its hydrolytic action on the lipid layer of the Mycobacterium.

Mycobacterium intracellulare infection of the shoulder and spine in a patient with steroid-treated systemic Lupus erythematosus

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

Zvetina, J.R.; Rubinstein, H.; Demos, T.C.

1982-05-01

Atypical mycobacterial infections of bone are rare. A patient with systemic lupus erythematosus treated with steroids developed an M. intracellulare infection of the shoulder and spine. These infections are insidious and diagnosis is difficult. Marked involvement of one joint, large effusion, or aspirated small synovial fragments suggest an atypical tuberculous joint infection.

Comparative Proteomics Identifies Host Immune System Proteins Affected by Infection with Mycobacterium bovis

PubMed Central

López, Vladimir; Villar, Margarita; Queirós, João; Vicente, Joaquín; Mateos-Hernández, Lourdes; Díez-Delgado, Iratxe; Contreras, Marinela; Alves, Paulo C.; Alberdi, Pilar; Gortázar, Christian; de la Fuente, José

2016-01-01

Mycobacteria of the Mycobacterium tuberculosis complex (MTBC) greatly impact human and animal health worldwide. The mycobacterial life cycle is complex, and the mechanisms resulting in pathogen infection and survival in host cells are not fully understood. Eurasian wild boar (Sus scrofa) are natural reservoir hosts for MTBC and a model for mycobacterial infection and tuberculosis (TB). In the wild boar TB model, mycobacterial infection affects the expression of innate and adaptive immune response genes in mandibular lymph nodes and oropharyngeal tonsils, and biomarkers have been proposed as correlates with resistance to natural infection. However, the mechanisms used by mycobacteria to manipulate host immune response are not fully characterized. Our hypothesis is that the immune system proteins under-represented in infected animals, when compared to uninfected controls, are used by mycobacteria to guarantee pathogen infection and transmission. To address this hypothesis, a comparative proteomics approach was used to compare host response between uninfected (TB-) and M. bovis-infected young (TB+) and adult animals with different infection status [TB lesions localized in the head (TB+) or affecting multiple organs (TB++)]. The results identified host immune system proteins that play an important role in host response to mycobacteria. Calcium binding protein A9, Heme peroxidase, Lactotransferrin, Cathelicidin and Peptidoglycan-recognition protein were under-represented in TB+ animals when compared to uninfected TB- controls, but protein levels were higher as infection progressed in TB++ animals when compared to TB- and/or TB+ adult wild boar. MHCI was the only protein over-represented in TB+ adult wild boar when compared to uninfected TB- controls. The results reported here suggest that M. bovis manipulates host immune response by reducing the production of immune system proteins. However, as infection progresses, wild boar immune response recovers to limit pathogen multiplication and promote survival, facilitating pathogen transmission. PMID:27027307

Uncommon opportunistic fungal infections of oral cavity: A review

PubMed Central

Deepa, AG; Nair, Bindu J; Sivakumar, TT; Joseph, Anna P

2014-01-01

The majority of opportunistic oral mucosal fungal infections are due to Candida albicans and Aspergillus fumigatus species. Mucor and Cryptococcus also have a major role in causing oral infections, whereas Geotrichum, Fusarium, Rhodotorula, Saccharomyces and Penicillium marneffei are uncommon pathogens in the oral cavity. The broad spectrum of clinical presentation includes pseudo-membranes, abscesses, ulcers, pustules and extensive tissue necrosis involving bone. This review discusses various uncommon opportunistic fungal infections affecting the oral cavity including their morphology, clinical features and diagnostic methods. PMID:25328305

Interaction between mycobacteria and mucus on a human respiratory tissue organ culture model with an air interface.

PubMed

Middleton, A M; Chadwick, M V; Nicholson, A G; Wilson, R; Thornton, D J; Kirkham, S; Sheehan, J K

2004-01-01

Mycobacteria adhere specifically to extracellular matrix (ECM) and mucus with a fibrous, but not globular, appearance, in organ cultures of human respiratory mucosa examined by scanning electron microscopy. Previously, light microscopy sections made of tissue infected for 7 days demonstrated mycobacteria associated with mucus on the organ culture surface, and within submucosal glands in areas of damaged epithelium. The authors have now investigated the interactions between Mycobacterium avium complex (MAC), Mycobacterium tuberculosis (MTB), and Mycobacterium smegmatis (MS) and mucus by preincubating bacteria with purified mucins MUC5AC and MUC5B prior to inoculation onto the organ culture mucosal surface. They have also measured mucin production by the organ culture after mycobacterial infection. Mucus did not cause clumping of mycobacteria. There was a significant (P=.03) increase in the amount of fibrous mucus, but not globular mucus, observed on tissue inoculated with mucins compared to controls. The number of bacteria adhering to ECM was markedly reduced after incubation with mucins, which could indicate a protective effect. Mycobacterial infection did not increase mucin production by the organ culture. Mycobacterial adherence to mucins may play a role in the pathogenicity of mycobacteria in diseases such as cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease (COPD), in which there are changes in mucus composition and clearance.

Validation of a CD1b tetramer assay for studies of human mycobacterial infection or vaccination.

PubMed

Layton, Erik D; Yu, Krystle K Q; Smith, Malisa T; Scriba, Thomas J; De Rosa, Stephen C; Seshadri, Chetan

2018-07-01

CD1 tetramers loaded with lipid antigens facilitate the identification of rare lipid-antigen specific T cells present in human blood and tissue. Because CD1 proteins are structurally non-polymorphic, these tetramers can be applied to genetically diverse human populations, unlike MHC-I and MHC-II tetramers. However, there are no standardized assays to quantify and characterize lipid antigen-specific T cells present within clinical samples. We incorporated CD1b tetramers loaded with the mycobacterial lipid glucose monomycolate (GMM) into a multi-parameter flow cytometry assay. Using a GMM-specific T-cell line, we demonstrate that the assay is linear, reproducible, repeatable, precise, accurate, and has a limit of detection of approximately 0.007%. Having formally validated this assay, we performed a cross-sectional study of healthy U.S. controls and South African adolescents with and without latent tuberculosis infection (LTBI). We show that GMM-specific T cells are specifically detected in South African subjects with LTBI and not in U.S. healthy controls. This assay can be expanded to include additional tetramers or phenotypic markers to characterize GMM-specific T cells in studies of mycobacterial infection, disease, or vaccination. Copyright © 2018 Elsevier B.V. All rights reserved.

Susceptibility to mycobacterial disease due to mutations in IL-12Rβ1 in three Iranian patients.

PubMed

Alinejad Dizaj, Maryam; Mortaz, Esmaeil; Mahdaviani, Seyed Alireza; Mansouri, Davood; Mehrian, Payam; Verhard, Els M; Varahram, Mohammad; Babaie, Delara; Adcock, Ian M; Garssen, Johan; van de Vosse, Esther; Velayati, Aliakbar

2018-06-01

In the last decade, autosomal recessive interleukin-12 receptor β1 (IL-12Rβ1) deficiency, the most common cause of Mendelian susceptibility to mycobacterial disease (MSMD), has been diagnosed in a few children and adults with severe tuberculosis in Iran. Here, we report three cases referred to the Immunology, Asthma and Allergy ward at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD) at Masih Daneshvari Hospital from 2012 to 2017 with Mycobacterium tuberculosis and non-tuberculous mycobacteria infections due to defects in IL-12Rβ1 but with different clinical manifestations. All three were homozygous for either an IL-12Rβ1 missense or nonsense mutation that caused the IL-12Rβ1 protein not to be expressed on the cell membrane and completely abolished the cellular response to recombinant IL-12. Our findings suggest that the presence of IL-12Rβ1 deficiency should be determined in children with mycobacterial infections at least in countries with a high prevalence of parental consanguinity and in areas endemic for TB like Iran.

Whole-genome analysis of mycobacteria from birds at the San Diego Zoo.

PubMed

Pfeiffer, Wayne; Braun, Josephine; Burchell, Jennifer; Witte, Carmel L; Rideout, Bruce A

2017-01-01

Mycobacteria isolated from more than 100 birds diagnosed with avian mycobacteriosis at the San Diego Zoo and its Safari Park were cultured postmortem and had their whole genomes sequenced. Computational workflows were developed and applied to identify the mycobacterial species in each DNA sample, to find single-nucleotide polymorphisms (SNPs) between samples of the same species, to further differentiate SNPs between as many as three different genotypes within a single sample, and to identify which samples are closely clustered genomically. Nine species of mycobacteria were found in 123 samples from 105 birds. The most common species were Mycobacterium avium and Mycobacterium genavense, which were in 49 and 48 birds, respectively. Most birds contained only a single mycobacterial species, but two birds contained a mixture of two species. The M. avium samples represent diverse strains of M. avium avium and M. avium hominissuis, with many pairs of samples differing by hundreds or thousands of SNPs across their common genome. By contrast, the M. genavense samples are much closer genomically; samples from 46 of 48 birds differ from each other by less than 110 SNPs. Some birds contained two, three, or even four genotypes of the same bacterial species. Such infections were found in 4 of 49 birds (8%) with M. avium and in 11 of 48 birds (23%) with M. genavense. Most were mixed infections, in which the bird was infected by multiple mycobacterial strains, but three infections with two genotypes differing by ≤ 10 SNPs were likely the result of within-host evolution. The samples from 31 birds with M. avium can be grouped into nine clusters within which any sample is ≤ 12 SNPs from at least one other sample in the cluster. Similarly, the samples from 40 birds with M. genavense can be grouped into ten such clusters. Information about these genomic clusters is being used in an ongoing, companion study of mycobacterial transmission to help inform management of bird collections.

Whole-genome analysis of mycobacteria from birds at the San Diego Zoo

PubMed Central

Pfeiffer, Wayne; Braun, Josephine; Burchell, Jennifer; Witte, Carmel L.; Rideout, Bruce A.

2017-01-01

Methods Mycobacteria isolated from more than 100 birds diagnosed with avian mycobacteriosis at the San Diego Zoo and its Safari Park were cultured postmortem and had their whole genomes sequenced. Computational workflows were developed and applied to identify the mycobacterial species in each DNA sample, to find single-nucleotide polymorphisms (SNPs) between samples of the same species, to further differentiate SNPs between as many as three different genotypes within a single sample, and to identify which samples are closely clustered genomically. Results Nine species of mycobacteria were found in 123 samples from 105 birds. The most common species were Mycobacterium avium and Mycobacterium genavense, which were in 49 and 48 birds, respectively. Most birds contained only a single mycobacterial species, but two birds contained a mixture of two species. The M. avium samples represent diverse strains of M. avium avium and M. avium hominissuis, with many pairs of samples differing by hundreds or thousands of SNPs across their common genome. By contrast, the M. genavense samples are much closer genomically; samples from 46 of 48 birds differ from each other by less than 110 SNPs. Some birds contained two, three, or even four genotypes of the same bacterial species. Such infections were found in 4 of 49 birds (8%) with M. avium and in 11 of 48 birds (23%) with M. genavense. Most were mixed infections, in which the bird was infected by multiple mycobacterial strains, but three infections with two genotypes differing by ≤ 10 SNPs were likely the result of within-host evolution. The samples from 31 birds with M. avium can be grouped into nine clusters within which any sample is ≤ 12 SNPs from at least one other sample in the cluster. Similarly, the samples from 40 birds with M. genavense can be grouped into ten such clusters. Information about these genomic clusters is being used in an ongoing, companion study of mycobacterial transmission to help inform management of bird collections. PMID:28267758

Mycobacterial growth inhibition is associated with trained innate immunity.

PubMed

Joosten, Simone A; van Meijgaarden, Krista E; Arend, Sandra M; Prins, Corine; Oftung, Fredrik; Korsvold, Gro Ellen; Kik, Sandra V; Arts, Rob Jw; van Crevel, Reinout; Netea, Mihai G; Ottenhoff, Tom Hm

2018-05-01

The lack of defined correlates of protection hampers development of vaccines against tuberculosis (TB). In vitro mycobacterial outgrowth assays are thought to better capture the complexity of the human host/Mycobacterium tuberculosis (Mtb) interaction. Here, we used a mycobacterial growth inhibition assay (MGIA) based on peripheral blood mononuclear cells to investigate the capacity to control outgrowth of bacille Calmette-Guérin (BCG). Interestingly, strong control of BCG outgrowth was observed almost exclusively in individuals with recent exposure to Mtb, but not in (long-term) latent TB infection, and only modestly in BCG vaccinees. Mechanistically, control of mycobacterial outgrowth strongly correlated with the presence of a CD14dim monocyte population, but also required the presence of T cells. The nonclassical monocytes produced CXCL10, and CXCR3 receptor blockade inhibited the capacity to control BCG outgrowth. Expression of CXCR3 splice variants was altered in recently Mtb-exposed individuals. Cytokines previously associated with trained immunity were detected in MGIA supernatants, and CXCL9, CXCL10, and CXCL11 represent new markers of trained immunity. These data indicate that CXCR3 ligands are associated with trained immunity and are critical factors in controlling mycobacterial outgrowth. In conclusion, control of mycobacterial outgrowth early after exposure to Mtb is the result of trained immunity mediated by a CXCL10-producing nonclassical CD14dim monocyte subset.

Sclerotiorin inhibits protein kinase G from Mycobacterium tuberculosis and impairs mycobacterial growth in macrophages.

PubMed

Chen, Dongni; Ma, Shuangshuang; He, Lei; Yuan, Peibo; She, Zhigang; Lu, Yongjun

2017-03-01

As a eukaryotic-like Ser/Thr protein kinase, Mycobacterium tuberculosis virulent effector protein kinase G (PknG) mediates mycobacterial survival by regulating bacterial cell metabolic processes and preventing phagosome-lysosome fusion in host macrophages. Targeting PknG is an effective strategy for development of anti-tuberculosis (TB) drugs. In the study, we found that sclerotiorin, derived from marine fungi from the South China Sea, exhibited moderately strong inhibitory effects on recombinant PknG, with an IC 50 value of 76.5 μM, and acted as a non-competitive inhibitor. The dissociation constant (K D ) of sclerotiorin determined by MST was 11.4 μM, demonstrating a moderate binding strength between them. Sclerotiorin could substantially impair the mycobacterial survival in infected macrophages while the macrophage viability remained unaffected, though it did not inhibit the mycobacterial growth in culture. When sclerotiorin was used in combination with rifampicin, intracellular mycobacterial growth decreased as sclerotiorin concentration increased. Docking analysis suggested a binding mechanism of inhibition with performing interactions with the P-loop and catalytic loop of PknG. In summary, we reported that sclerotiorin had moderately strong PknG inhibitory activity, but no cytotoxicity, and it could substantially decrease the mycobacterial growth inside macrophages, suggesting that sclerotiorin has potential to supplement antibiotic therapy for TB. Copyright © 2017 Elsevier Ltd. All rights reserved.

Factors associated with pastoral community knowledge and occurrence of mycobacterial infections in Human-Animal Interface areas of Nakasongola and Mubende districts, Uganda

PubMed Central

2010-01-01

Background Nontuberculous mycobacteria (NTM) are emerging opportunistic pathogens whose role in human and animal disease is increasingly being recognized. Major concerns are their role as opportunistic pathogens in HIV/AIDS infections. The role of open natural water sources as source and livestock/wildlife as reservoirs of infections to man are well documented. This presents a health challenge to the pastoral systems in Africa that rely mostly on open natural water sources to meet livestock and human needs. Recent study in the pastoral areas of Uganda showed infections with same genotypes of NTM in pastoralists and their livestock. The aim of this study was to determine the environmental, animal husbandry and socio-demographic factors associated with occurrence and the pastoral community knowledge of mycobacterial infections at the human-environment-livestock/wildlife interface (HELI) areas in pastoral ecosystems of Uganda. Methods Two hundred and fifty three (253) individuals were subjected to a questionnaire survey across the study districts of Nakasongola and Mubende. Data were analyzed using descriptive statistics and multivariable logistic regression analysis. Results Humans sharing of the water sources with wild animals from the forest compared to savannah ecosystem (OR = 3.3), the tribe of herding pastoral community (OR = 7.9), number of rooms present in household (3-5 vs. 1-2 rooms) (OR = 3.3) were the socio-demographic factors that influenced the level of knowledge on mycobacterial infections among the pastoral communities. Tribe (OR = 6.4), use of spring vs. stream water for domestic use (OR = 4.5), presence of sediments in household water receptacle (OR = 2.32), non separation of water containers for drinking and domestic use (OR = 2.46), sharing of drinking water sources with wild animals (OR = 2.1), duration of involvement of >5 yrs in cattle keeping (OR = 3.7) and distance of household to animal night shelters (>20 meters) (OR = 3.8) were significant socio-demographic factors associated with the risk of occurrence of mycobacterioses among the pastoral communities in Uganda. Conclusion The socio-demographic, environmental and household related factors influence the risk of occurrence as well as pastoralists' knowledge of mycobacterial infections in the pastoral households at the human-environment-livestock/wildlife pastoral interface areas of Uganda. PMID:20698978

Introducing the new BTS Guideline: Management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).

PubMed

Haworth, Charles S; Floto, R Andres

2017-11-01

The new BTS Guidelines for the management of non-tuberculous mycobacterial pulmonary disease combine the best available evidence with expert consensus to generate a set of pragmatic Guidelines, published as a supplement to this issue of Thorax, to assist in the management of these challenging infections. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Mycobacterium tuberculosis-triggered Hippo pathway orchestrates CXCL1/2 expression to modulate host immune responses.

PubMed

Boro, Monoranjan; Singh, Vikas; Balaji, Kithiganahalli Narayanaswamy

2016-11-24

Mycobacterium tuberculosis (Mtb) pathogenesis encompasses a plethora of finely regulated alterations within the host which eventually coin the outcome of infection. Chemokines are important components in directing immune cell recruitment to the site of infection, and shaping the disease progression. Here, we demonstrate that Hippo (mammalian sterile 20-like 1 and 2 kinases, MST1/2, in mammals), is activated during mycobacterial infection in a toll-like receptor (TLR) 2-interleukin receptor-1 associated kinases (IRAK1/4)-dependent manner. Mtb-triggered Hippo signaling modulates the expression and secretion of chemokines (CXCL1 and CXCL2); as silencing MST1/2 compromised the ability of Mtb to furnish the same. Further insight into the mechanism of Hippo-mediated regulation of chemokines revealed the role for a non-canonical Hippo effector interferon (IFN) regulatory factor (IRF) 3 in the process and marked the effect to be independent of LATS1. Alongside their ability to guide directed recruitment of immune cells, we have uncovered a paracrine role for Hippo-mediated secretion of CXCL1 and CXCL2 in the production of anti-microbial peptides (beta-defensins), iNOS, NOX2 and pro-inflammatory molecules during mycobacterial infection of the host. This study highlights the involvement of TLR2-IRAK1/4-MST1/2-IRF3 axis in Mtb-triggered modulation of chemokines and identifies Hippo signaling as a novel regulator of host-mycobacterial interactions.

Intestinal lymphangiectasia: an undescribed cause of malabsorption and incomplete immunological recovery in HIV-infected patients.

PubMed

Marco-Lattur, Maria D; Payeras, Antoni; Campins, Antoni A; Pons, Jaume; Cifuentes, Carmen; Riera, Melcior

2011-02-01

Although paradoxical virological and immunological response after HAART has been well studied, intestinal lymphangiectasia (IL) in HIV-1 infected patients has not previously described. To describe HIV patients who developed IL. Clinical Case series. 4 patients with HIV and IL diagnosis based on clinical, endoscopic and pathological findings. All four cases had prior mycobacterial infections with abdominal lymph node involvement and a very low CD4 cell count nadir. They developed intestinal lymphangiectasia despite appropriate virological suppression with HAART and repeatedly negative mycobacterial cultures. Two patients were clinically symptomatic with oedemas, ascites, diarrhoea, asthenia, weight loss; but the other two were diagnosed with malabsorption as a result of laboratory findings, with hypoproteinemia and hypoalbuminemia. Three of them were diagnosed by video capsule endoscopy. IL should be considered in HIV-1 infected patients who present with clinical or biochemical malabsorption parameters when there is no immunological recovery while on HAART. Copyright © 2010 Elsevier España, S.L. All rights reserved.

Tuberculosis masked by immunodeficiency: a review of two cases diagnosed with chronic granulomatous disease.

PubMed

Nacaroğlu, Hikmet Tekin; Bahçeci Erdem, Semiha; Gülez, Nesrin; Ünsal Karkıner, Canan Şule; Devrim, İlker; Genel, Ferah; Köker, Mustafa Yavuz; Can, Demet

2017-03-01

Chronic granulomatous disease (CGD) is a genetically heterogeneous primary immunodeficiency that is characterized by recurrent and life-threatening infections resulting from defects in phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system and granuloma formation due to increased inflammatory response. The most commonly involved organs are the lungs, skin, lymph nodes, and liver due to infection. It may present with recurrent pneumonia, hilar lymphadenopathy, empyema, abscess, reticulonodular patterns, and granulomas due to lung involvement. In recent years, mycobacterial disease susceptibility has been reported in CGD cases. This article presents two male cases, one of whom is aged 18 months and the other is aged 5 years, who were diagnosed with CGD and tuberculosis during examination due to extended pneumonia. This report is presented because CGD should be considered not only in the presence of skin abscesses and Aspergillus infections, but also in the differential diagnosis for cases with BCG-itis and/or tuberculosis. It should be kept in mind that mycobacterial infections can occur during the course of the disease.

Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration

PubMed Central

Berg, Russell D.; Levitte, Steven; O’Sullivan, Mary P.; O’Leary, Seónadh M.; Cambier, C.J.; Cameron, James; Takaki, Kevin K.; Moens, Cecilia B.; Tobin, David M.; Keane, Joseph; Ramakrishnan, Lalita

2016-01-01

Summary A zebrafish genetic screen for determinants of susceptibility to Mycobacterium marinum identified a hypersusceptible mutant deficient in lysosomal cysteine cathepsins that manifests hallmarks of human lysosomal storage diseases. Under homeostatic conditions, mutant macrophages accumulate undigested lysosomal material, which disrupts endocytic recycling and impairs their migration to, and thus engulfment of, dying cells. This causes a buildup of unengulfed cell debris. During mycobacterial infection, macrophages with lysosomal storage cannot migrate toward infected macrophages undergoing apoptosis in the tuberculous granuloma. The unengulfed apoptotic macrophages undergo secondary necrosis, causing granuloma breakdown and increased mycobacterial growth. Macrophage lysosomal storage similarly impairs migration to newly infecting mycobacteria. This phenotype is recapitulated in human smokers, who are at increased risk for tuberculosis. A majority of their alveolar macrophages exhibit lysosomal accumulations of tobacco smoke particulates and do not migrate to Mycobacterium tuberculosis. The incapacitation of highly microbicidal first-responding macrophages may contribute to smokers’ susceptibility to tuberculosis. PMID:27015311

Modeling tuberculosis pathogenesis through ex vivo lung tissue infection.

PubMed

Carranza-Rosales, Pilar; Carranza-Torres, Irma Edith; Guzmán-Delgado, Nancy Elena; Lozano-Garza, Gerardo; Villarreal-Treviño, Licet; Molina-Torres, Carmen; Villarreal, Javier Vargas; Vera-Cabrera, Lucio; Castro-Garza, Jorge

2017-12-01

Tuberculosis (TB) is one of the top 10 causes of death worldwide. Several in vitro and in vivo experimental models have been used to study TB pathogenesis and induction of immune response during Mycobacterium tuberculosis infection. Precision cut lung tissue slices (PCLTS) is an experimental model, in which all the usual cell types of the organ are found, the tissue architecture and the interactions amongst the different cells are maintained. PCLTS in good physiological conditions, monitored by MTT assay and histology, were infected with either virulent Mycobacterium tuberculosis strain H37Rv or the TB vaccine strain Mycobacterium bovis BCG. Histological analysis showed that bacilli infecting lung tissue slices were observed in the alveolar septa, alveolar light spaces, near to type II pneumocytes, and inside macrophages. Mycobacterial infection of PCLTS induced TNF-α production, which is consistent with previous M. tuberculosis in vitro and in vivo studies. This is the first report of using PCLTS as a system to study M. tuberculosis infection. The PCLTS model provides a useful tool to evaluate the innate immune responses and other aspects during the early stages of mycobacterial infection. Copyright © 2017. Published by Elsevier Ltd.

Total hip replacement infected with Mycobacterium tuberculosis complicated by Addison disease and psoas muscle abscess: a case report.

PubMed

De Nardo, Pasquale; Corpolongo, Angela; Conte, Aristide; Gentilotti, Elisa; Narciso, Pasquale

2012-01-10

Prosthetic joint infection due to Mycobacterium tuberculosis is occasionally encountered in clinical practice. To the best of our knowledge, this is the first report of a prosthetic joint infection due to Mycobacterium tuberculosis complicated by psoas abscesses and secondary Addison disease. A 67-year-old immunocompetent Caucasian woman underwent total left hip arthroplasty because of osteoarthritis. After 18 months, she underwent arthroplasty revision for a possible prosthetic infection. Periprosthetic tissue specimens for bacteria were negative, and empirical antibiotic therapy was unsuccessful. She was then admitted to our department because of complications arising 22 months after arthroplasty. A physical examination revealed a sinus tract overlying her left hip and skin and mucosal pigmentation. Her levels of C-reactive protein, basal cortisol, adrenocorticotropic hormone, and sodium were out of normal range. Results of the tuberculin skin test and QuantiFERON-TB Gold test were positive. Computed tomography revealed a periprosthetic abscess and the inclusion of the left psoas muscle. Results of microbiological tests were negative, but polymerase chain reaction of a specimen taken from the hip fistula was positive for Mycobacterium tuberculosis. Our patient's condition was diagnosed as prosthetic joint infection and muscle psoas abscess due to Mycobacterium tuberculosis and secondary Addison disease. She underwent standard treatment with rifampicin, ethambutol, isoniazid, and pyrazinamide associated with hydrocortisone and fludrocortisone. At 15 months from the beginning of therapy, she was in good clinical condition and free of symptoms. Prosthetic joint infection with Mycobacterium tuberculosis is uncommon. A differential diagnosis of tuberculosis should be considered when dealing with prosthetic joint infection, especially when repeated smears and histology examination from infected joints are negative. Clinical outcomes of prosthetic joint infection by Mycobacterium tuberculosis are unpredictable, especially given the limited literature in this field and the uncertainty of whether medical treatment alone can eradicate the infection without prosthesis removal. Furthermore, this case report raises interesting issues such as the necessity of a follow-up evaluation after treatment based on clinical conditions, the utility of a more standardized length of treatment for periprosthetic tuberculous infection, and the importance of a high diffusion capacity of anti-mycobacterial agents in order to eradicate the infection.

Rapid-Growing Mycobacteria Infections in Medical Tourists: Our Experience and Literature Review.

PubMed

Singh, Mansher; Dugdale, Caitlin M; Solomon, Isaac H; Huang, Anne; Montgomery, Mary W; Pomahac, Bohdan; Yawetz, Sigal; Maguire, James H; Talbot, Simon G

2016-09-01

"Medical tourism" has gained popularity over the past few decades. This is particularly common with patients seeking elective cosmetic surgery in the developing world. However, the risk of severe and unusual infectious complications appears to be higher than for patients undergoing similar procedures in the United States. The authors describe their experience with atypical mycobacterial infections in cosmetic surgical patients returning to the United States postoperatively. A review of patient medical records presenting with infectious complications after cosmetic surgery between January 2010 and July 2015 was performed. Patients presenting with mycobacterial infections following cosmetic surgery were reviewed in detail. An extensive literature review was performed for rapid-growing mycobacteria (RGM) related to cosmetic procedures. Between January 2010 and July 2015, three patients presented to our institution with culture-proven Mycobacterium abscessus at the sites of recent cosmetic surgery. All had surgery performed in the developing world. The mean age of these patients was 36 years (range, 29-44 years). There was a delay of up to 16 weeks between the initial presentation and correct diagnosis. All patients were treated with surgical drainage and combination antibiotics with complete resolution. We present series of patients with mycobacterial infections after cosmetic surgery in the developing world. This may be related to the endemic nature of these bacteria and/or inadequate sterilization or sterile technique. Due to low domestic incidence of these infections, diagnosis may be difficult and/or delayed. Consulting physicians should have a low threshold to consider atypical etiologies in such scenarios. 5 Therapeutic. © 2016 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.

Effects of Ascent to High Altitude on Human Antimycobacterial Immunity

PubMed Central

Aldridge, Robert W.; Siedner, Mark J.; Necochea, Alejandro; Leybell, Inna; Valencia, Teresa; Herrera, Beatriz; Wiles, Siouxsie; Friedland, Jon S.; Gilman, Robert H.; Evans, Carlton A.

2013-01-01

Background Tuberculosis infection, disease and mortality are all less common at high than low altitude and ascent to high altitude was historically recommended for treatment. The immunological and mycobacterial mechanisms underlying the association between altitude and tuberculosis are unclear. We studied the effects of altitude on mycobacteria and antimycobacterial immunity. Methods Antimycobacterial immunity was assayed in 15 healthy adults residing at low altitude before and after they ascended to 3400 meters; and in 47 long-term high-altitude residents. Antimycobacterial immunity was assessed as the extent to which participants’ whole blood supported or restricted growth of genetically modified luminescent Bacille Calmette-Guérin (BCG) mycobacteria during 96 hours incubation. We developed a simplified whole blood assay that could be used by a technician in a low-technology setting. We used this to compare mycobacterial growth in participants’ whole blood versus positive-control culture broth and versus negative-control plasma. Results Measurements of mycobacterial luminescence predicted the number of mycobacterial colonies cultured six weeks later. At low altitude, mycobacteria grew in blood at similar rates to positive-control culture broth whereas ascent to high altitude was associated with restriction (p≤0.002) of mycobacterial growth to be 4-times less than in culture broth. At low altitude, mycobacteria grew in blood 25-times more than negative-control plasma whereas ascent to high altitude was associated with restriction (p≤0.01) of mycobacterial growth to be only 6-times more than in plasma. There was no evidence of differences in antimycobacterial immunity at high altitude between people who had recently ascended to high altitude versus long-term high-altitude residents. Conclusions An assay of luminescent mycobacterial growth in whole blood was adapted and found to be feasible in low-resource settings. This demonstrated that ascent to or residence at high altitude was associated with decreased mycobacterial growth in whole blood relative to controls, consistent with altitude-related augmentation of antimycobacterial cellular immunity. PMID:24058530

WC1+ gamma delta T cells from cattle naturally infected with Mycobacterium avium subsp. paratuberculosis respond differentially to stimulation with PPD-J.

USDA-ARS?s Scientific Manuscript database

A role for gamma delta T cells in protection against mycobacterial infections including Johne’s disease (JD) has been suggested. In neonatal calves where the risk to infection with Mycobacterium avium subsp. paratuberculosis (MAP) is high, the majority of circulating CD3+ lymphocytes are gamma delta...

The assessment of changes to the nontuberculous mycobacterial metabolome in response to anti-TB drugs.

PubMed

Drapal, Margit; Wheeler, Paul R; Fraser, Paul D

2018-06-26

Mycobacterium species can cause a range of nontuberculous infections of healthy and immunocompromised people as well as infect people during and after surgical procedures. The similarity of nontuberculous mycobacteria (NTM) to the tuberculosis bacilli (TB) could ultimately enable the use of anti-TB drugs for the genus. Hence, three NTM (M. smegmatis, M. phlei and M. avium) were cultured under different lab conditions, causing two mycobacterial phenotypes (active and dormant), and treated with isoniazid (INH) and ethambutol (EMB) independently or in combination. Metabolite profiling was applied to facilitate the investigation and characterisation of intracellular targets affected by the antibiotics. Aliquots of the cell culture were taken over the treatment period and the metabolite profile of the cells analysed by GC/MS. Comparative analysis of the metabolite levels to untreated mycobacteria confirmed the successful action of the antibiotics on the metabolism of all three species. Furthermore, single metabolites and metabolite pathways affected by the antibiotics could be identified and included, besides the known target sites for INH and EMB on mycobacterial cells, changes in e.g. nucleotide and saccharide levels. The combined treatment highlighted the property of EMB to enhance the effects of INH even under hypoxic culture conditions.

1 Ubiquitination as a mechanism to transport soluble mycobacterial and eukaryotic proteins to exosomes

PubMed Central

Smith, Victoria L.; Jackson, Liam; Schorey, Jeffrey S.

2015-01-01

Exosomes are extracellular vesicles of endocytic origin, which function in intercellular communication. Our previous studies indicate that exosomes released from M. tuberculosis infected macrophages contain soluble mycobacterial proteins. However, it was unclear how these secreted proteins were targeted to exosomes. In this study we determined that exosome production by the murine macrophage cell line RAW264.7 requires the endosomal sorting complexes required for transport (ESCRT) and that trafficking of mycobacterial proteins from phagocytosed bacilli to exosomes was dependent on protein ubiquitination. Moreover, soluble mycobacterial proteins when added exogenously to RAW264.7 or human HEK 293 cells were endocytosed, ubiquitinated and released via exosomes. This suggested that endocytosed proteins could be recycled from cells through exosomes. This hypothesis was supported using the tumor–associated protein He4 which when endocytosed by RAW264.7 or HEK 293 cells was transported to exosomes in an ubiquitin-dependent manner. Our data suggest that ubiquitination is a modification sufficient for trafficking soluble proteins within the phagocytic/endocytic network to exosomes. PMID:26246139

Does disseminated nontuberculous mycobacterial disease cause false-positive Determine B-LAM lateral flow assay results? A retrospective review.

PubMed

Nel, Jeremy S; Lippincott, Christopher K; Berhanu, Rebecca; Spencer, David C; Sanne, Ian M; Ive, Prudence

2017-06-02

We retrospectively reviewed the Determine TB-LAM lateral flow assay (LF-LAM) results among HIV-infected patients with disseminated nontuberculous mycobacterial (NTM) disease. LF-LAM was positive in 19/21 patients without evidence of tuberculosis coinfection. Although tuberculosis-NTM coinfection may have been underdiagnosed, our results suggest that disseminated NTM disease may cause false-positive LF-LAM results. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

[Reccurent mycobacterial diseases in patients with impaired axis IL-12/INF-gamma].

PubMed

Strach, Magdalena; Nalepa, Piotr; Sulicka-Grodzicka, Joanna; Kierzkowska, Izabella; Siedlar, Maciej; Grodzicki, Tomasz

2013-01-01

Mycobacteria is a large group of pathogens that are common in environment, in soil and tap water. Although mycobacteria [non tuberculosis mycobacteria] can inhabit body surface without causing any disease in the circumstances of primary or secondary immunodeficiency can cause clinically significant organ or systemic damage. Defect of IL-12/INFgamma axis is an example of primary immunodeficiency that predispose to mycobacterial infections while protection against other microorganisms is not damaged. We present review of known defects of IL-12/IFNgamma axis and brief presentation of our own experience.

Investigation of 4-amino-5-alkynylpyrimidine-2(1H)-ones as anti-mycobacterial agents.

PubMed

Garg, Gaurav; Pande, Milind; Agrawal, Ambika; Li, Jie; Kumar, Rakesh

2016-04-15

In vitro anti-mycobacterial activities of novel 4-amino-5-alkynylpyrimidine-2(1H)-ones were investigated. 4-Amino-5-heptynylpyrimidine-2(1H)-one (3) and 4-amino-5-(2-phenylethynyl)pyrimidine-2(1H)-one (7) displayed potent in vitro activity against Mycobacterium bovis and Mycobacterium tuberculosis. Compounds 3 and 7 were also assessed for their in vivo activity in BALB/c mice infected with M. tuberculosis (H37Ra). Both compounds showed promising in vivo efficacy at a dose of 25 mg/kg for 2 weeks. Importantly, compounds 3 and 7 interacted synergistically with the front-line anti-tuberculosis drug isoniazid in vitro and in vivo. These results suggest that this class of compounds has strong anti-mycobacterial potential. Copyright © 2016 Elsevier Ltd. All rights reserved.

Disseminated Tuberculosis and Chronic Mucocutaneous Candidiasis in a Patient with a Gain-of-Function Mutation in Signal Transduction and Activator of Transcription 1.

PubMed

Pedraza-Sánchez, Sigifredo; Lezana-Fernández, Jose Luis; Gonzalez, Yolanda; Martínez-Robles, Luis; Ventura-Ayala, María Laura; Sadowinski-Pine, Stanislaw; Nava-Frías, Margarita; Moreno-Espinosa, Sarbelio; Casanova, Jean-Laurent; Puel, Anne; Boisson-Dupuis, Stephanie; Torres, Martha

2017-01-01

In humans, recessive loss-of-function mutations in STAT1 are associated with mycobacterial and viral infections, whereas gain-of-function (GOF) mutations in STAT1 are associated with a type of primary immunodeficiency related mainly, but not exclusively, to chronic mucocutaneous candidiasis (CMC). We studied and established a molecular diagnosis in a pediatric patient with mycobacterial infections, associated with CMC. The patient, daughter of a non-consanguineous mestizo Mexican family, had axillary adenitis secondary to BCG vaccination and was cured with resection of the abscess at 1-year old. At the age of 4 years, she had a supraclavicular abscess with acid-fast-staining bacilli identified in the soft tissue and bone, with clinical signs of disseminated infection and a positive Gene-X-pert test, which responded to anti-mycobacterial drugs. Laboratory tests of the IL-12/interferon gamma (IFN-γ) circuit showed a higher production of IL-12p70 in the whole blood from the patient compared to healthy controls, when stimulated with BCG and BCG + IFN-γ. The whole blood of the patient produced 35% less IFN-γ compared to controls assessed by ELISA and flow cytometry, but IL-17 producing T cells from patient were almost absent in PBMC stimulated with PMA plus ionomycin. Signal transduction and activator of transcription 1 (STAT1) was hyperphosphorylated at tyrosine 701 in response to IFN-γ and -α, as demonstrated by flow cytometry and Western blotting in fresh blood mononuclear cells and in Epstein-Barr virus lymphoblastoid cell lines (EBV-LCLs); phosphorylation of STAT1 in EBV-LCLs from the patient was resistant to inhibition by staurosporine but sensitive to ruxolitinib, a Jak phosphorylation inhibitor. Genomic DNA sequencing showed a de novo mutation in STAT1 in cells from the patient, absent in her parents and brother; a known T385M missense mutation in the DNA-binding domain of the transcription factor was identified, and it is a GOF mutation. Therefore, GOF mutations in STAT1 can induce susceptibility not only to fungal but also to mycobacterial infections by mechanisms to be determined.

Disseminated Tuberculosis and Chronic Mucocutaneous Candidiasis in a Patient with a Gain-of-Function Mutation in Signal Transduction and Activator of Transcription 1

PubMed Central

Pedraza-Sánchez, Sigifredo; Lezana-Fernández, Jose Luis; Gonzalez, Yolanda; Martínez-Robles, Luis; Ventura-Ayala, María Laura; Sadowinski-Pine, Stanislaw; Nava-Frías, Margarita; Moreno-Espinosa, Sarbelio; Casanova, Jean-Laurent; Puel, Anne; Boisson-Dupuis, Stephanie; Torres, Martha

2017-01-01

In humans, recessive loss-of-function mutations in STAT1 are associated with mycobacterial and viral infections, whereas gain-of-function (GOF) mutations in STAT1 are associated with a type of primary immunodeficiency related mainly, but not exclusively, to chronic mucocutaneous candidiasis (CMC). We studied and established a molecular diagnosis in a pediatric patient with mycobacterial infections, associated with CMC. The patient, daughter of a non-consanguineous mestizo Mexican family, had axillary adenitis secondary to BCG vaccination and was cured with resection of the abscess at 1-year old. At the age of 4 years, she had a supraclavicular abscess with acid-fast-staining bacilli identified in the soft tissue and bone, with clinical signs of disseminated infection and a positive Gene-X-pert test, which responded to anti-mycobacterial drugs. Laboratory tests of the IL-12/interferon gamma (IFN-γ) circuit showed a higher production of IL-12p70 in the whole blood from the patient compared to healthy controls, when stimulated with BCG and BCG + IFN-γ. The whole blood of the patient produced 35% less IFN-γ compared to controls assessed by ELISA and flow cytometry, but IL-17 producing T cells from patient were almost absent in PBMC stimulated with PMA plus ionomycin. Signal transduction and activator of transcription 1 (STAT1) was hyperphosphorylated at tyrosine 701 in response to IFN-γ and -α, as demonstrated by flow cytometry and Western blotting in fresh blood mononuclear cells and in Epstein-Barr virus lymphoblastoid cell lines (EBV-LCLs); phosphorylation of STAT1 in EBV-LCLs from the patient was resistant to inhibition by staurosporine but sensitive to ruxolitinib, a Jak phosphorylation inhibitor. Genomic DNA sequencing showed a de novo mutation in STAT1 in cells from the patient, absent in her parents and brother; a known T385M missense mutation in the DNA-binding domain of the transcription factor was identified, and it is a GOF mutation. Therefore, GOF mutations in STAT1 can induce susceptibility not only to fungal but also to mycobacterial infections by mechanisms to be determined. PMID:29270166

Disseminated infection with Mycobacterium tilburgii in a male immunocompromised patient.

PubMed

Temmerman, Sarah; Vandekerckhove, Linos; Sermijn, Erica; Vogelaers, Dirk; Claeys, Geert; Vaneechoutte, Mario; Cools, Piet; Callens, Steven

2014-05-01

Mycobacterium tilburgii is a nonculturable nontuberculous mycobacterium identifiable only by molecular methods. We report a case of disseminated M. tilburgii infection illustrating the importance of 16S rRNA gene sequencing to determine the responsible mycobacterial pathogen and the difficulties in tailoring antimycobacterial treatment in the absence of a culturable organism.

Mycobacterial lipolytic enzymes: a gold mine for tuberculosis research.

PubMed

Dedieu, L; Serveau-Avesque, C; Kremer, L; Canaan, S

2013-01-01

Tuberculosis (TB) is one of the deadliest infectious diseases worldwide with a strong impact in developing countries. Mycobacterium tuberculosis, the etiological agent of TB, has a high capacity to evade the host immune system and establish a chronic, asymptomatic and latent infection. In a latent TB infection, persistent bacilli are present in a non-replicating dormant state within host granulomas. During reactivation, bacilli start replicating again leading to an active TB infection that can be highly contagious. Mycobacterial lipids and lipolytic enzymes are thought to play important physiological roles during dormancy and reactivation. The role of lipolytic enzymes in the physiology of M. tuberculosis and physiopathology of the disease will be discussed in this review, with an emphasis on the secreted or cell wall-associated, surface exposed lipolytic enzymes characterized to date. Studies on the localization, enzymatic activity and immunological properties of these enzymes highlighted their possible usefulness as new diagnostic markers in the fight against TB. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

The Warburg effect in mycobacterial granulomas is dependent on the recruitment and activation of macrophages by interferon-γ

PubMed Central

Appelberg, Rui; Moreira, Diana; Barreira-Silva, Palmira; Borges, Margarida; Silva, Letícia; Dinis-Oliveira, Ricardo Jorge; Resende, Mariana; Correia-Neves, Margarida; Jordan, Michael B; Ferreira, Nuno C; Abrunhosa, Antero J; Silvestre, Ricardo

2015-01-01

Granulomas are the hallmark of mycobacterial disease. Here, we demonstrate that both the cell recruitment and the increased glucose consumption in granulomatous infiltrates during Mycobacterium avium infection are highly dependent on interferon-γ (IFN-γ). Mycobacterium avium-infected mice lacking IFN-γ signalling failed to developed significant inflammatory infiltrations and lacked the characteristic uptake of the glucose analogue fluorine-18-fluorodeoxyglucose (FDG). To assess the role of macrophages in glucose uptake we infected mice with a selective impairment of IFN-γ signalling in the macrophage lineage (MIIG mice). Although only a partial reduction of the granulomatous areas was observed in infected MIIG mice, the insensitivity of macrophages to IFN-γ reduced the accumulation of FDG. In vivo, ex vivo and in vitro assays showed that macrophage activated by IFN-γ displayed increased rates of glucose uptake and in vitro studies showed also that they had increased lactate production and increased expression of key glycolytic enzymes. Overall, our results show that the activation of macrophages by IFN-γ is responsible for the Warburg effect observed in organs infected with M. avium. PMID:25807843

Isolation of nontuberculous mycobacteria from soil using Middlebrook 7H10 agar with increased malachite green concentration.

PubMed

Hu, Yuli; Yu, Xinglong; Zhao, Dun; Li, Runcheng; Liu, Yang; Ge, Meng; Hu, Huican

2017-12-01

Environmental exposure is considered to be responsible for nontuberculous mycobacterial infections in humans. To facilitate the isolation of mycobacteria from soil, Middlebrook 7H10 agar was optimized as an enhanced selective medium by increasing the concentration of malachite green. A series of modified Middlebrook 7H10 agar media with malachite green concentrations ranging from 2.5 to 2500 mg/L was evaluated using 20 soil samples decontaminated with 3% sodium dodecyl sulfate plus 2% NaOH for 30 min. Among these modified Middlebrook 7H10 media, the medium with malachite green at a concentration of 250 mg/L, i.e., at the same concentration as in Löwenstein-Jensen medium, was the most effective in terms of the number of plates with mycobacterial growth. This medium was further evaluated with 116 soil samples. The results showed that 87.1% (101/116) of the samples produced mycobacterial growth, and 15 samples (12.9%) produced no mycobacterial growth. Of the plates inoculated with the soil samples, each in duplicate, 5.2% (12/232) showed late contamination. In total, 19 mycobacterial species were isolated, including seven (36.8%) rapidly growing mycobacteria and 12 (63.2%) slowly growing mycobacteria. Our results demonstrate that the modified Middlebrook 7H10 agar with 250 mg/L malachite green is useful for the primary isolation of nontuberculous mycobacteria from soil.

First insights into the genetic diversity of Mycobacterium tuberculosis isolates from HIV-infected Mexican patients and mutations causing multidrug resistance

PubMed Central

2010-01-01

Background The prevalence of infections with Mycobacterium tuberculosis (MTb) and nontuberculous mycobacteria (NTM) species in HIV-infected patients in Mexico is unknown. The aims of this study were to determine the frequency of MTb and NTM species in HIV-infected patients from Mexico City, to evaluate the genotypic diversity of the Mycobacterium tuberculosis complex strains, to determine their drug resistance profiles by colorimetric microplate Alamar Blue assay (MABA), and finally, to detect mutations present in katG, rpoB and inhA genes, resulting in isoniazid (INH) and rifampin (RIF) resistance. Results Of the 67 mycobacterial strains isolated, 48 were identified as MTb, 9 as M. bovis, 9 as M. avium and 1 as M. intracellulare. IS6110-RFLP of 48 MTb strains showed 27 profiles. Spoligotyping of the 48 MTb strains yielded 21 patterns, and 9 M. bovis strains produced 7 patterns. Eleven new spoligotypes patterns were found. A total of 40 patterns were produced from the 48 MTb strains when MIRU-VNTR was performed. Nineteen (39.6%) MTb strains were resistant to one or more drugs. One (2.1%) multidrug-resistant (MDR) strain was identified. A novel mutation was identified in a RIF-resistant strain, GAG → TCG (Glu → Ser) at codon 469 of rpoB gene. Conclusions This is the first molecular analysis of mycobacteria isolated from HIV-infected patients in Mexico, which describe the prevalence of different mycobacterial species in this population. A high genetic diversity of MTb strains was identified. New spoligotypes and MIRU-VNTR patterns as well as a novel mutation associated to RIF-resistance were found. This information will facilitate the tracking of different mycobacterial species in HIV-infected individuals, and monitoring the spread of these microorganisms, leading to more appropriate measures for tuberculosis control. PMID:20236539

Priming of innate antimycobacterial immunity by heat-killed Listeria monocytogenes induces sterilizing response in the adult zebrafish tuberculosis model

PubMed Central

Luukinen, Hanna; Vanha-aho, Leena-Maija; Svorjova, Aleksandra; Kantanen, Laura; Järvinen, Sampsa; Dufour, Eric; Rämet, Mika; Hytönen, Vesa Pekka

2018-01-01

ABSTRACT Mycobacterium tuberculosis remains one of the most problematic infectious agents, owing to its highly developed mechanisms to evade host immune responses combined with the increasing emergence of antibiotic resistance. Host-directed therapies aiming to optimize immune responses to improve bacterial eradication or to limit excessive inflammation are a new strategy for the treatment of tuberculosis. In this study, we have established a zebrafish-Mycobacterium marinum natural host-pathogen model system to study induced protective immune responses in mycobacterial infection. We show that priming adult zebrafish with heat-killed Listeria monocytogenes (HKLm) at 1 day prior to M. marinum infection leads to significantly decreased mycobacterial loads in the infected zebrafish. Using rag1−/− fish, we show that the protective immunity conferred by HKLm priming can be induced through innate immunity alone. At 24 h post-infection, HKLm priming leads to a significant increase in the expression levels of macrophage-expressed gene 1 (mpeg1), tumor necrosis factor α (tnfa) and nitric oxide synthase 2b (nos2b), whereas superoxide dismutase 2 (sod2) expression is downregulated, implying that HKLm priming increases the number of macrophages and boosts intracellular killing mechanisms. The protective effects of HKLm are abolished when the injected material is pretreated with nucleases or proteinase K. Importantly, HKLm priming significantly increases the frequency of clearance of M. marinum infection by evoking sterilizing immunity (25 vs 3.7%, P=0.0021). In this study, immune priming is successfully used to induce sterilizing immunity against mycobacterial infection. This model provides a promising new platform for elucidating the mechanisms underlying sterilizing immunity and to develop host-directed treatment or prevention strategies against tuberculosis. This article has an associated First Person interview with the first author of the paper. PMID:29208761

Fighting mycobacterial infections by antibiotics, phytochemicals and vaccines.

PubMed

Bamberger, Denise; Jantzer, Nora; Leidner, Katharina; Arend, Joachim; Efferth, Thomas

2011-07-01

Buruli ulcer is a neglected disease caused by Mycobacterium ulcerans and represents the world's third most common mycobacterial infection. It produces the polyketide toxins, mycolactones A, B, C and D, which induce apoptosis and necrosis. Clinical symptoms are subcutaneous nodules, papules, plaques and ulcerating oedemae, which can enlarge and destroy nerves and blood vessels and even invade bones by lymphatic or haematogenous spread (osteomyelitis). Patients usually do not suffer from pain or systematic inflammation. Surgery is the treatment of choice, although recurrence is common and wide surgical excisions including healthy tissues result in significant morbidity. Antibiotic therapy with rifamycins, aminoglycosides, macrolides and quinolones also improves cure rates. Still less exploited treatment options are phytochemicals from medicinal plants used in affected countries. Vaccination against Buruli ulcer is still in its infancy. Copyright © 2010. Published by Elsevier SAS.

[Granular Cell Tumor of the Lung - a Visual Diagnosis on Bronchoscopy?

PubMed

Keymel, S; Büter, S; Krüger, S

2018-05-22

A 38 years old patient presented with a progressive reduction of his general condition and weight loss. Chest imaging revealed consolidations and cavities suggesting a mycobacterial infection. For further diagnosis, a bronchoscopy was performed. In fact, a nontuberculous mycobacterial infection was found. As an incidental finding, we saw a white polypoid tumor in the middle lobe bronchus. The histology of this tumor revealed a granular cell tumor (GCT). The GCT is a rare tumor entity which occurs at different anatomical locations. In the lungs, the GCT may become symptomatic as it can cause bronchial obstruction. In chest imaging, it can manifest as infiltration, atelectasis or nodule. Likewise, GCT can be found as an incidental finding in bronchoscopy. First choice treatment is surgical resection of the tumor. © Georg Thieme Verlag KG Stuttgart · New York.

Monosodium Urate Crystals Promote Innate Anti-Mycobacterial Immunity and Improve BCG Efficacy as a Vaccine against Tuberculosis

PubMed Central

Taus, Francesco; Santucci, Marilina B.; Greco, Emanuela; Morandi, Matteo; Palucci, Ivana; Mariotti, Sabrina; Poerio, Noemi; Nisini, Roberto; Delogu, Giovanni; Fraziano, Maurizio

2015-01-01

A safer and more effective anti-Tuberculosis vaccine is still an urgent need. We probed the effects of monosodium urate crystals (MSU) on innate immunity to improve the Bacille Calmette-Guerin (BCG) vaccination. Results showed that in vitro MSU cause an enduring macrophage stimulation of the anti-mycobacterial response, measured as intracellular killing, ROS production and phagolysosome maturation. The contribution of MSU to anti-mycobacterial activity was also shown in vivo. Mice vaccinated in the presence of MSU showed a lower number of BCG in lymph nodes draining the vaccine inoculation site, in comparison to mice vaccinated without MSU. Lastly, we showed that MSU improved the efficacy of BCG vaccination in mice infected with Mycobacterium tuberculosis (MTB), measured in terms of lung and spleen MTB burden. These results demonstrate that the use of MSU as adjuvant may represent a novel strategy to enhance the efficacy of BCG vaccination. PMID:26023779

Auditing smear microscopy results according to time to detection using the BACTEC™ MGIT™ TB system.

PubMed

Elsaghier, A A F

2015-09-01

Smear microscopy is a rapid method for the identification of the most infectious patients with mycobacterial infection. Suboptimal smear microscopy may significantly compromise or delay patient isolation and contact tracing. A stringent method for auditing mycobacterial smear results is thus needed. This article proposes an auditing tool based on time to detection (TTD) of culture-positive samples using the automated BACTEC™ MGIT™ 960 TB system. In our study, sputum samples subjected to liquefaction and concentration before staining with a TTD of ≤ 13 days using the BACTEC system should be positive on smear microscopy.

Enhanced effect of BCG vaccine against pulmonary Mycobacterium tuberculosis infection in mice with lung Th17 response to mycobacterial heparin-binding hemagglutinin adhesin antigen.

PubMed

Fukui, Masayuki; Shinjo, Kikuko; Umemura, Masayuki; Shigeno, Satoko; Harakuni, Tetsuya; Arakawa, Takeshi; Matsuzaki, Goro

2015-12-01

Although the BCG vaccine can prevent tuberculosis (TB) in infants, its ability to prevent adult pulmonary TB is reportedly limited. Therefore, development of a novel effective vaccine against pulmonary TB has become an international research priority. We have previously reported that intranasal vaccination of mice with a mycobacterial heparin-binding hemagglutinin adhesin (HBHA) plus mucosal adjuvant cholera toxin (CT) enhances production of IFN-γ and anti-HBHA antibody and suppresses extrapulmonary bacterial dissemination after intranasal infection with BCG. In the present study, the effects of intranasal HBHA + CT vaccine on murine pulmonary Mycobacterium tuberculosis (Mtb) infection were examined. Intranasal HBHA + CT vaccination alone failed to reduce the bacterial burden in the infected lung. However, a combination vaccine consisting of s.c. BCG priming and an intranasal HBHA + CT booster significantly enhanced protective immunity against pulmonary Mtb infection on day 14 compared with BCG vaccine alone. Further, it was found that intranasal HBHA + CT vaccine enhanced not only IFN-γ but also IL-17A production by HBHA-specific T cells in the lung after pulmonary Mtb infection. Therefore, this combination vaccine may be a good candidate for a new vaccine strategy against pulmonary TB. © 2015 The Societies and Wiley Publishing Asia Pty Ltd.

Specific recognition of mycobacterial protein and peptide antigens by gamma-delta T cell subsets following infection with virulent Mycobacterium bovis

USDA-ARS?s Scientific Manuscript database

Promoting effective immunity to Mycobacterium tuberculosis complex pathogens is a challenge that is of interest to the fields of human and veterinary medicine alike. We report that gamma delta T cells from virulent Mycobacterium bovis-infected cattle respond specifically and directly to complex, pro...

A case of chronic otitis media caused by Mycobacterium abscessus.

PubMed

Sugimoto, Hisashi; Ito, Makoto; Hatano, Miyako; Nakanishi, Yosuke; Maruyama, Yumiko; Yoshizaki, Tomokazu

2010-10-01

Although it appears very uncommon in adult COM, Mycobacterium abscessus should be considered as a possible cause of a chronically draining ear. Multi-antibiotic chemotherapy including high-dose clarithromycin can effectively treat adult COM cased by M. abscessus. The first case report of adult chronic otitis media (COM) caused by M. abscessus is described here. A 61-year-old woman presented persistent otorrhea for 2 months, despite treatment with standard antimicrobial drugs. Physical examination revealed a small perforation of the tympanic membrane and edematous middle ear mucosa. Mycobacterial cultures and PCR yielded non-tuberculous mycobacteria (NTM); M. abscessus. Intravenous panipenem/betamipron and amikacin and oral clarithromycin were administered for 36 days. Computed tomography of the temporal bone showed improved aeration in the tympanic cavity, but soft tissue shadow remained unchanged in the mastoid 31 days after starting medication. She therefore underwent tympano-mastoidectomy at 36 days. At surgery, inflammation remained in the middle ear, and edematous pale mucosal tissue was noted around the stapes and ossicular chain. Histopathologic examination showed inflammation and granulation tissue, but no caseating necrosis or acid-fast bacilli. After surgery the symptoms resolved and remained well without evidence of infection recurrence 12 months after the operation. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Transgenic tomato expressing interleukin-12 has a therapeutic effect in a murine model of progressive pulmonary tuberculosis

PubMed Central

Elías-López, A L; Marquina, B; Gutiérrez-Ortega, A; Aguilar, D; Gomez-Lim, M; Hernández-Pando, R

2008-01-01

Host control of mycobacterial infection, in both human and mouse models, has been shown to be associated with the production of interferon (IFN)-γ by CD4+ T cells. Interleukin (IL)-12 is known to be a crucial cytokine in the differentiation of IFN-γ-producing T helper 1 (Th1) cells. To determine whether continuous administration of IL-12 expressed in transgenic tomato (TT–IL-12) has therapeutic efficacy in a murine model of pulmonary tuberculosis, BALB/c mice were infected with either Mycobacterium tuberculosis H37Rv strain or a multi-drug-resistant clinical isolate (MDR) and treated with a daily oral dose of TT-IL12 crude fruit extracts. For the early H37Rv infection, TT–IL-12 administration was started 1 day before infection and continued for 60 days. In the H37Rv or MDR late infection, treatment was started 60 days after infection and continued for another 60 days. In both phases of infection, TT–IL-12 administration resulted in a reduction of bacterial loads and tissue damage compared with wild-type tomato (non-TT). The Th1 response was increased and the Th2 response was reduced. In the late infection, a long-term treatment with TT–IL-12 was necessary. We demonstrate that TT–IL-12 increases resistance to infection and reduces lung tissue damage during early and late drug-sensitive and drug-resistant mycobacterial infection. PMID:18727633

Fulminant infection by uncommon organisms in animal bite wounds.

PubMed

Dutta, J K

1998-10-01

In 1995 and 1996, 215 patients exposed to different species of animals were treated at the Amarnath Polyclinic, Balasore, in India. Among them were two children infected by uncommon organisms, i.e., Capnocytophaga canimorsus and Pasteurella multocida; the patients recovered with appropriate antibiotic therapy.

The Protein Interactome of Mycobacteriophage Giles Predicts Functions for Unknown Proteins.

PubMed

Mehla, Jitender; Dedrick, Rebekah M; Caufield, J Harry; Siefring, Rachel; Mair, Megan; Johnson, Allison; Hatfull, Graham F; Uetz, Peter

2015-08-01

Mycobacteriophages are viruses that infect mycobacterial hosts and are prevalent in the environment. Nearly 700 mycobacteriophage genomes have been completely sequenced, revealing considerable diversity and genetic novelty. Here, we have determined the protein complement of mycobacteriophage Giles by mass spectrometry and mapped its genome-wide protein interactome to help elucidate the roles of its 77 predicted proteins, 50% of which have no known function. About 22,000 individual yeast two-hybrid (Y2H) tests with four different Y2H vectors, followed by filtering and retest screens, resulted in 324 reproducible protein-protein interactions, including 171 (136 nonredundant) high-confidence interactions. The complete set of high-confidence interactions among Giles proteins reveals new mechanistic details and predicts functions for unknown proteins. The Giles interactome is the first for any mycobacteriophage and one of just five known phage interactomes so far. Our results will help in understanding mycobacteriophage biology and aid in development of new genetic and therapeutic tools to understand Mycobacterium tuberculosis. Mycobacterium tuberculosis causes over 9 million new cases of tuberculosis each year. Mycobacteriophages, viruses of mycobacterial hosts, hold considerable potential to understand phage diversity, evolution, and mycobacterial biology, aiding in the development of therapeutic tools to control mycobacterial infections. The mycobacteriophage Giles protein-protein interaction network allows us to predict functions for unknown proteins and shed light on major biological processes in phage biology. For example, Giles gp76, a protein of unknown function, is found to associate with phage packaging and maturation. The functions of mycobacteriophage-derived proteins may suggest novel therapeutic approaches for tuberculosis. Our ORFeome clone set of Giles proteins and the interactome data will be useful resources for phage interactomics. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Rare Orbital Infections ~ State of the Art ~ Part II

PubMed Central

Hamed-Azzam, Shirin; AlHashash, Islam; Briscoe, Daniel; Rose, Geoffrey E; Verity, David H.

2018-01-01

Infections of the orbit and periorbita are relatively frequent. Identifying unusual organisms is crucial because they can cause severe local and systemic morbidity, despite their rarity. Opportunistic infections of the orbit should be considered mainly in debilitated or immunocompromised patients. The key to successful management includes a high index of suspicion, prompt diagnosis, and addressing the underlying systemic disease. This review summarizes unusual infectious processes of the orbit, including mycobacterial, fungal, and parasitic infections, as well as their pathophysiology, symptoms, signs, and treatment. PMID:29719648

Fulminant infection by uncommon organisms in animal bite wounds.

PubMed Central

Dutta, J. K.

1998-01-01

In 1995 and 1996, 215 patients exposed to different species of animals were treated at the Amarnath Polyclinic, Balasore, in India. Among them were two children infected by uncommon organisms, i.e., Capnocytophaga canimorsus and Pasteurella multocida; the patients recovered with appropriate antibiotic therapy. PMID:10211359

Pulmonary Nontuberculous Mycobacterial Disease

PubMed Central

Kim, Richard D.; Greenberg, David E.; Ehrmantraut, Mary E.; Guide, Shireen V.; Ding, Li; Shea, Yvonne; Brown, Margaret R.; Chernick, Milica; Steagall, Wendy K.; Glasgow, Connie G.; Lin, JingPing; Jolley, Clara; Sorbara, Lynn; Raffeld, Mark; Hill, Suvimol; Avila, Nilo; Sachdev, Vandana; Barnhart, Lisa A.; Anderson, Victoria L.; Claypool, Reginald; Hilligoss, Dianne M.; Garofalo, Mary; Fitzgerald, Alan; Anaya-O'Brien, Sandra; Darnell, Dirk; DeCastro, Rosamma; Menning, Heather M.; Ricklefs, Stacy M.; Porcella, Stephen F.; Olivier, Kenneth N.; Moss, Joel; Holland, Steven M.

2008-01-01

Rationale: Pulmonary nontuberculous mycobacterial (PNTM) disease is increasing, but predisposing features have been elusive. Objectives: To prospectively determine the morphotype, immunophenotype, and cystic fibrosis transmembrane conductance regulator genotype in a large cohort with PNTM. Methods: We prospectively enrolled 63 patients with PNTM infection, each of whom had computerized tomography, echocardiogram, pulmonary function, and flow cytometry of peripheral blood. In vitro cytokine production in response to mitogen, LPS, and cytokines was performed. Anthropometric measurements were compared with National Health and Nutrition Examination Survey (NHANES) age- and ethnicity-matched female control subjects extracted from the NHANES 2001–2002 dataset. Measurements and Main Results: Patients were 59.9 (±9.8 yr [SD]) old, and 5.4 (±7.9 yr) from diagnosis to enrollment. Patients were 95% female, 91% white, and 68% lifetime nonsmokers. A total of 46 were infected with Mycobacterium avium complex, M. xenopi, or M. kansasii; 17 were infected with rapidly growing mycobacteria. Female patients were significantly taller (164.7 vs. 161.0 cm; P < 0.001) and thinner (body mass index, 21.1 vs. 28.2; P < 0.001) than matched NHANES control subjects, and thinner (body mass index, 21.1 vs. 26.8; P = 0.002) than patients with disseminated nontuberculous mycobacterial infection. A total of 51% of patients had scoliosis, 11% pectus excavatum, and 9% mitral valve prolapse, all significantly more than reference populations. Stimulated cytokine production was similar to that of healthy control subjects, including the IFN-γ/IL-12 pathway. CD4+, CD8+, B, and natural killer cell numbers were normal. A total of 36% of patients had mutations in the cystic fibrosis transmembrane conductance regulator gene. Conclusions: Patients with PNTM infection are taller and leaner than control subjects, with high rates of scoliosis, pectus excavatum, mitral valve prolapse, and cystic fibrosis transmembrane conductance regulator mutations, but without recognized immune defects. PMID:18703788

Environmental risks for nontuberculous mycobacteria. Individual exposures and climatic factors in the cystic fibrosis population.

PubMed

Prevots, D Rebecca; Adjemian, Jennifer; Fernandez, Aisling G; Knowles, Michael R; Olivier, Kenneth N

2014-09-01

Persons with cystic fibrosis are at high risk of pulmonary nontuberculous mycobacterial infection, with a national prevalence estimated at 13%. The risk of nontuberculous mycobacteria associated with specific environmental exposures, and the correlation with climatic conditions in this population has not been described. To describe the association of pulmonary nontuberculous mycobacteria with individual exposures to water and soil aerosols, and the population associations of these infections with climatic factors. We conducted a nested case-control study within a cohort study of pulmonary nontuberculous mycobacteria prevalence at 21 geographically diverse national cystic fibrosis centers. Incident nontuberculous mycobacterial infection cases (at least one prior negative culture followed by one positive culture) were age- and sex-matched to culture-negative controls. Exposures to water and soil were assessed by administering a standardized questionnaire. Cohort prevalence at each of the 21 centers was correlated with climatic conditions in the same area through linear regression modeling. Overall, 48 cases and 85 control subjects were enrolled. Indoor swimming was associated with incident infection (adjusted odds ratio, 5.9, 95% confidence interval, 1.3-26.1), although only nine cases (19%) and five control subjects (6%) reported indoor swimming in the 4 months prior to infection. Exposure to showering and municipal water supply was common among both cases and control subjects: 77% of cases and 76% of control subjects reported showering at least daily. In linear regression, average annual atmospheric water vapor content was significantly predictive of center prevalence (P = 0.0019), with R(2) = 0.40. Atmospheric conditions explain more of the variation in disease prevalence than individual behaviors. The risk of specific exposures may vary by geographic region due to differences in conditions favoring mycobacterial growth and survival. However, because exposure to these organisms is ubiquitous and behaviors are similar among persons with and without pulmonary nontuberculous mycobacteria, genetic susceptibility beyond cystic fibrosis is likely to be important for disease development. Common individual risk factors in high-risk populations remain to be identified.

Direct Detection and Identification of Mycobacterium tuberculosis and Mycobacterium bovis in Bovine Samples by a Novel Nested PCR Assay: Correlation with Conventional Techniques

PubMed Central

Mishra, A.; Singhal, A.; Chauhan, D. S.; Katoch, V. M.; Srivastava, K.; Thakral, S. S.; Bharadwaj, S. S.; Sreenivas, V.; Prasad, H. K.

2005-01-01

Mycobacterium tuberculosis and M. bovis infect animals and humans. Their epidemiologies in developed and developing countries differ, owing to differences in the implementation of preventive measures (World Health Organization, 1999). Identification and differentiation of these closely related mycobacterial species would help to determine the source, reservoirs of infection, and disease burden due to diverse mycobacterial pathogens. The utility of the hupB gene (Rv2986c in M. tuberculosis, or Mb3010c in M. bovis) to differentiate M. tuberculosis and M. bovis was evaluated by a PCR-restriction fragment length polymorphism (RFLP) assay with 56 characterized bovine isolates (S. Prabhakar et al., J. Clin. Microbiol. 42:2724-2732, 2004). The degree of concordance between the PCR-RFLP assay and the microbiological characterization was 99.0% (P < 0.001). A nested PCR (N-PCR) assay was developed, replacing the PCR-RFLP assay for direct detection of M. tuberculosis and M. bovis in bovine samples. The N-PCR products of M. tuberculosis and M. bovis corresponded to 116 and 89 bp, respectively. The detection limit of mycobacterial DNA by N-PCR was 50 fg, equivalent to five tubercle bacilli. M. tuberculosis and/or M. bovis was detected in 55.5% (105/189) of the samples by N-PCR, compared to 9.4% (18/189) by culture. The sensitivities of N-PCR and culture were 97.3 and 29.7, respectively, and their specificities were 22.2 and 77.7%, respectively. The percentages of animals or samples identified as infected with M. tuberculosis or M. bovis by N-PCR and culture reflected the clinical categorizations of the cattle (P of <0.05 to <0.01). Mixed infection by N-PCR was detected in 22 animals, whereas by culture mixed infection was detected in 1 animal. PMID:16272503

IFN-β: A Contentious Player in Host–Pathogen Interaction in Tuberculosis

PubMed Central

Sabir, Naveed; Hussain, Tariq; Shah, Syed Zahid Ali; Zhao, Deming; Zhou, Xiangmei

2017-01-01

Tuberculosis (TB) is a major health threat to the human population worldwide. The etiology of the disease is Mycobacterium tuberculosis (Mtb), a highly successful intracellular pathogen. It has the ability to manipulate the host immune response and to make the intracellular environment suitable for its survival. Many studies have addressed the interactions between the bacteria and the host immune cells as involving many immune mediators and other cellular players. Interferon-β (IFN-β) signaling is crucial for inducing the host innate immune response and it is an important determinant in the fate of mycobacterial infection. The role of IFN-β in protection against viral infections is well established and has been studied for decades, but its role in mycobacterial infections remains much more complicated and debatable. The involvement of IFN-β in immune evasion mechanisms adopted by Mtb has been an important area of investigation in recent years. These advances have widened our understanding of the pro-bacterial role of IFN-β in host–pathogen interactions. This pro-bacterial activity of IFN-β appears to be correlated with its anti-inflammatory characteristics, primarily by antagonizing the production and function of interleukin 1β (IL-1β) and interleukin 18 (IL-18) through increased interleukin 10 (IL-10) production and by inhibiting the nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome. Furthermore, it also fails to provoke a proper T helper 1 (Th1) response and reduces the expression of major histocompatibility complex II (MHC-II) and interferon-γ receptors (IFNGRs). Here we will review some studies to provide a paradigm for the induction, regulation, and role of IFN-β in mycobacterial infection. Indeed, recent studies suggest that IFN-β plays a role in Mtb survival in host cells and its downregulation may be a useful therapeutic strategy to control Mtb infection. PMID:29258190

IFN-β: A Contentious Player in Host-Pathogen Interaction in Tuberculosis.

PubMed

Sabir, Naveed; Hussain, Tariq; Shah, Syed Zahid Ali; Zhao, Deming; Zhou, Xiangmei

2017-12-16

Tuberculosis (TB) is a major health threat to the human population worldwide. The etiology of the disease is Mycobacterium tuberculosis (Mtb), a highly successful intracellular pathogen. It has the ability to manipulate the host immune response and to make the intracellular environment suitable for its survival. Many studies have addressed the interactions between the bacteria and the host immune cells as involving many immune mediators and other cellular players. Interferon-β (IFN-β) signaling is crucial for inducing the host innate immune response and it is an important determinant in the fate of mycobacterial infection. The role of IFN-β in protection against viral infections is well established and has been studied for decades, but its role in mycobacterial infections remains much more complicated and debatable. The involvement of IFN-β in immune evasion mechanisms adopted by Mtb has been an important area of investigation in recent years. These advances have widened our understanding of the pro-bacterial role of IFN-β in host-pathogen interactions. This pro-bacterial activity of IFN-β appears to be correlated with its anti-inflammatory characteristics, primarily by antagonizing the production and function of interleukin 1β (IL-1β) and interleukin 18 (IL-18) through increased interleukin 10 (IL-10) production and by inhibiting the nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome. Furthermore, it also fails to provoke a proper T helper 1 (Th1) response and reduces the expression of major histocompatibility complex II (MHC-II) and interferon-γ receptors (IFNGRs). Here we will review some studies to provide a paradigm for the induction, regulation, and role of IFN-β in mycobacterial infection. Indeed, recent studies suggest that IFN-β plays a role in Mtb survival in host cells and its downregulation may be a useful therapeutic strategy to control Mtb infection.

Mycothiol acetyltransferase (Rv0819) of Mycobacterium tuberculosis is a potential biomarker for direct diagnosis of tuberculosis using patient serum specimens.

PubMed

Zeitoun, H; Bahey-El-Din, M; Kassem, M A; Aboushleib, H M

2017-12-01

Mycobacterium tuberculosis infection constitutes a global threat that results in significant morbidity and mortality worldwide. Efficient and early diagnosis of tuberculosis (TB) is of paramount importance for successful treatment. The aim of the current study is to investigate the mycobacterial mycothiol acetyltransferase Rv0819 as a potential novel biomarker for the diagnosis of active TB infection. The gene encoding Rv0819 was cloned and successfully expressed in Escherichia coli. The recombinant Rv0819 was purified using metal affinity chromatography and was used to raise murine polyclonal antibodies against Rv0819. The raised antibodies were employed for direct detection of Rv0819 in patient serum samples using dot blot assay and competitive enzyme-linked immunosorbent assay (ELISA). Serum samples were obtained from 68 confirmed new TB patients and 35 healthy volunteers as negative controls. The dot blot assay showed sensitivity of 64·7% and specificity of 100%, whereas the competitive ELISA assay showed lower sensitivity (54·4%) and specificity (88·57%). The overall sensitivity of the combined results of the two tests was found to be 89·7%. Overall, the mycobacterial Rv0819 is a potential TB serum biomarker that can be exploited, in combination with other TB biomarkers, for efficient and reliable diagnosis of active TB infection. The early and accurate diagnosis of tuberculosis infection is of paramount importance for initiating treatment and avoiding clinical complications. Most current diagnostic tests have poor sensitivity and/or specificity and in many cases they are too expensive for routine diagnostic testing in resource-limited settings. In the current study, we examined a novel mycobacterial serum biomarker, namely mycothiol acetyltransferase Rv0819. The antigen was detectable in serum specimens of a significant number of tuberculosis patients. This article proves the importance of Rv0819 and paves the way towards its future use as a useful diagnostic marker for tuberculosis infection. © 2017 The Society for Applied Microbiology.

Mycobacterium smegmatis infection of a prosthetic total knee arthroplasty.

PubMed

Saffo, Zaid; Ognjan, Anthony

2016-01-01

The most common organisms causing prosthetic knee joint infections are staphylococci. However, arthroplasty infections with atypical microbial pathogens, such as Mycobacteria can occur. Due to the rarity of mycobacterial prosthetic joint infections, diagnosis, treatment, and management of these atypical infections represent a clinical challenge. A 71-year old female post-operative day 40 after a left total knee arthroplasty was hospitalized secondary to left knee pain and suspected arthroplasty infection. She had failed outpatient oral antimicrobial treatment for superficial stitch abscess; and outpatient IV/Oral antimicrobials for a clinical postoperative septic bursitis. Ultimately, resection arthroplasty with operative tissue acid fast bacterial cultures demonstrated growth of the Mycobacterium smegmatis group. Post-operatively, she completed a combination course of oral doxycycline and levofloxacin and successfully completed a replacement arthroplasty with clinical and microbial resolution of the infection. To our knowledge, literature review demonstrates three case of knee arthroplasty infection caused by the Mycobacterium smegmatis group. Correspondingly, optimal surgical procedures and antimicrobial management including antimicrobial selection, treatment duration are not well defined. Presently, the best treatment options consists of two step surgical management including prosthesis hardware removal followed by extended antimicrobial therapy, followed by consideration for re-implantation arthroplasty. Our case illustrates importance of considering atypical mycobacterial infections in post-operative arthroplasty infections not responding to traditional surgical manipulations and antimicrobials. For an arthroplasty infection involving the atypical Mycobacterium smegmatis group, two step arthroplasty revision, including arthroplasty resection, with a combination of oral doxycycline and levofloxacin can lead to successful infection resolution, allowing for a successful replacement arthroplasty.

Disseminated Mycobacterium avium--intracellulare complex infection in a miniature schnauzer.

PubMed

Miller, M A; Greene, C E; Brix, A E

1995-01-01

A two-year-old, spayed female, miniature schnauzer was evaluated for respiratory distress associated with a compressive cervical mass. Generalized mycobacterial infection was diagnosed from aspirates of several enlarged lymph nodes. Tissue specimens further identified Mycobacterium avium--intracellulare using polymerase chain reaction followed by nucleic acid hybridization. Treatment with enrofloxacin, clofazamine, rifampin, and interferon did not result in long-term success.

IFNγ-producing CD4+ T lymphocytes: the double-edged swords in tuberculosis.

PubMed

Kumar, Pawan

2017-12-01

IFNγ-producing CD4 + T cells (IFNγ + CD4 + T cells) are the key orchestrators of protective immunity against Mycobacterium tuberculosis (Mtb). Primarily, these cells act by enabling Mtb-infected macrophages to enforce phagosome-lysosome fusion, produce reactive nitrogen intermediates (RNIs), and activate autophagy pathways. However, TB is a heterogeneous disease and a host of clinical and experimental findings has also implicated IFNγ + CD4 + T cells in TB pathogenesis. High frequency of IFNγ + CD4 + T cells is the most invariable feature of the active disease. Active TB patients mount a heightened IFNγ + CD4 + T cell response to mycobacterial antigens and demonstrate an IFNγ-inducible transcriptomic signature. IFNγ + CD4 + T cells have also been shown to mediate TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) observed in a subset of antiretroviral therapy (ART)-treated HIV- and Mtb-coinfected people. The pathological face of IFNγ + CD4 + T cells during mycobacterial infection is further uncovered by studies in the animal model of TB-IRIS and in Mtb-infected PD-1 -/- mice. This manuscript encompasses the evidence supporting the dual role of IFNγ + CD4 + T cells during Mtb infection and sheds light on immune mechanisms involved in protection versus pathogenesis.

Outbreaks of nontuberculous mycobacteria.

PubMed

Sood, Geeta; Parrish, Nikki

2017-08-01

The purpose of this review is to summarize the emerging literature on nontuberculous mycobacteria outbreaks in healthcare settings. As our ability to identify mycobacterial species develops, we are better able to recognize epidemiologic connections and better understand the prevalence and importance of these outbreaks and pseudo-outbreaks in healthcare settings. The number of outbreaks related to nontuberculous outbreaks is increasing because of heightened awareness and better diagnostic tests for species level identification of mycobacteria. Outbreaks in healthcare settings have been related to cardiac surgery, plastic surgery, including medical tourism, colonized humidifiers and heater-cooler devices, imperfect disinfection, and hospital water sources. Mycobacteria have a predilection to form biofilms, are resistant to disinfection and are prevalent in hospital water systems. Patients with structural lung disease like cystic fibrosis patients are at particularly high risk for mycobacterial infection. It has been thought that acquisition in this patient population is from common environmental exposure; however, there is increasing evidence that transmission in this patient population can occur through either direct or indirect patient-to-patient spread. Mycobacteria outbreaks in healthcare settings have been underrecognized. As we identify additional clusters of infection with better diagnostic tools and heightened awareness, we will likely need better infection control practices to prevent infections in healthcare settings.

Mycobacterium kansasii Isolated from Tuberculinpositive Rhesus Macaques (Macaca mulatta) in the Absence of Disease.

PubMed

Shipley, Steven T; Johnson, David K; Roodgar, Morteza; Smith, David Glenn; Montgomery, Charles A; Lloyd, Steven M; Higgins, James A; Kriel, Edwin H; Klein, Hilton J; Porter, William P; Nazareno, Jerome B; Houghton, Paul W; Panda, Aruna; DeTolla, Louis J

2017-08-01

Mycobacterial infections are of primary health concern in NHP colonies in biomedical research. NHP are constantly monitored and screened for Mycobacterium spp. We report 6 Chinese-origin rhesus macaques infected with Mycobacterium kansasii that exhibited positive tuberculin skin tests in the absence of disease. Two of these macaques were being used for research purposes; the remaining 4 macaques were residing at the contract quarantine company. Histopathology and acid-fast staining of fixed tissues from all macaques showed that all were free of disease. Thoracic radiographs were negative for any signs of disease or infection. Samples from bronchial lavage and tissues including lung, spleen, hilar and mesenteric lymph nodes tested negative by PCR assay for Mycobacterium spp. One of the research macaques tested culture-positive for M. kansasii and a poorly characterized M. avium complex organism. One macaque from the contract quarantine facility tested culture positive for M. kansasii. Genomic testing and target gene RNA expression analysis of the 2 M. kansasii isolates were performed to evaluate possible kinship and affected genes that might contribute to susceptibility to mycobacterial infection. Genotyping of the 2 isolates revealed 2 genetically distinct strains (strains 1 and 4). The presence of positive tuberculin skin tests in the absence of disease raises serious concerns regarding diagnostic methods used for infected NHP.

Mycobacterium-Host Cell Relationships in Granulomatous Lesions in a Mouse Model of Latent Tuberculous Infection

PubMed Central

2015-01-01

Tuberculosis (TB) is a dangerous infectious disease characterized by a tight interplay between mycobacteria and host cells in granulomatous lesions (granulomas) during the latent, asymptomatic stage of infection. Mycobacterium-host cell relationships were analyzed in granulomas obtained from various organs of BALB/c mice with chronic TB infection caused by in vivo exposure to the Bacillus Calmette-Guérin (BCG) vaccine. Acid-fast BCG-mycobacteria were found to be morphologically and functionally heterogeneous (in size, shape, and replication rates in colonies) in granuloma macrophages, dendritic cells, and multinucleate Langhans giant cells. Cord formation by BCG-mycobacteria in granuloma cells has been observed. Granuloma macrophages retained their ability to ingest damaged lymphocytes and thrombocytes in the phagosomes; however, their ability to destroy BCG-mycobacteria contained in these cells was compromised. No colocalization of BCG-mycobacteria and the LysoTracker dye was observed in the mouse cells. Various relationships between granuloma cells and BCG-mycobacteria were observed in different mice belonging to the same line. Several mice totally eliminated mycobacterial infection. Granulomas in the other mice had mycobacteria actively replicating in cells of different types and forming cords, which is an indicator of mycobacterial virulence and, probably, a marker of the activation of tuberculous infection in animals. PMID:26064970

Mycobacterium-Host Cell Relationships in Granulomatous Lesions in a Mouse Model of Latent Tuberculous Infection.

PubMed

Ufimtseva, Elena

2015-01-01

Tuberculosis (TB) is a dangerous infectious disease characterized by a tight interplay between mycobacteria and host cells in granulomatous lesions (granulomas) during the latent, asymptomatic stage of infection. Mycobacterium-host cell relationships were analyzed in granulomas obtained from various organs of BALB/c mice with chronic TB infection caused by in vivo exposure to the Bacillus Calmette-Guérin (BCG) vaccine. Acid-fast BCG-mycobacteria were found to be morphologically and functionally heterogeneous (in size, shape, and replication rates in colonies) in granuloma macrophages, dendritic cells, and multinucleate Langhans giant cells. Cord formation by BCG-mycobacteria in granuloma cells has been observed. Granuloma macrophages retained their ability to ingest damaged lymphocytes and thrombocytes in the phagosomes; however, their ability to destroy BCG-mycobacteria contained in these cells was compromised. No colocalization of BCG-mycobacteria and the LysoTracker dye was observed in the mouse cells. Various relationships between granuloma cells and BCG-mycobacteria were observed in different mice belonging to the same line. Several mice totally eliminated mycobacterial infection. Granulomas in the other mice had mycobacteria actively replicating in cells of different types and forming cords, which is an indicator of mycobacterial virulence and, probably, a marker of the activation of tuberculous infection in animals.

Tuberculosis in Auckland autopsies, revisited.

PubMed

Lum, Dennis; Koelmeyer, Timothy

2005-03-11

To review the cases of tuberculosis found at autopsy in the Auckland Coronial Autopsy Service in the previous 10 years, and compare the results with that of a similar study for the period 1975 to 1992. Cases which were not diagnosed prior to autopsy are scrutinised as to why the diagnosis may have been missed. A computerised search of the Forensic Pathology Department database at Auckland Hospital for cases of tuberculosis or atypical mycobacterial infection found at autopsy was done. Basic demographic data, past medical history, and police reports were analysed. The cases were placed into five groups for analysis. A total of 30 cases of tuberculosis (including 3 cases of atypical mycobacterial infection) were found. A large proportion (70%) was undiagnosed before death, and each case was potentially infective. Two cases had respiratory symptoms suggestive of tuberculosis, and a further 5 cases had generalised symptoms which were unexplained yet tuberculosis was not considered. In those cases that were missed, the autopsy played a vital role by identifying the previously undiagnosed cases of tuberculosis and ensuring contact screening. Awareness of tuberculosis and its increasing prevalence in New Zealand is essential for minimising missed diagnoses.

Surgical management of cutaneous infection caused by atypical mycobacteria after penetrating injury: the hidden dangers of horticulture.

PubMed

Holland, J; Smith, C; Childs, P A; Holland, A J

1997-02-01

We identified two patients in a 12-month period who presented with cutaneous infection and secondary lymph node involvement from atypical mycobacterial infection after minor gardening injuries. One patient had a coinfection with Nocardia asteroides. Both patients required multiple surgical interventions, despite appropriate antibiotic therapy, before resolution of the disease. The course of the infection was characterized by chronic relapses with complete healing at 12 to 18 months after the original injury. The identification and management of this clinical problem are reviewed.

The Proprotein Convertase Subtilisin/Kexin FurinA Regulates Zebrafish Host Response against Mycobacterium marinum

PubMed Central

Ojanen, Markus J. T.; Turpeinen, Hannu; Cordova, Zuzet M.; Hammarén, Milka M.; Harjula, Sanna-Kaisa E.; Parikka, Mataleena; Rämet, Mika

2015-01-01

Tuberculosis is a chronic bacterial disease with a complex pathogenesis. An effective immunity against Mycobacterium tuberculosis requires both the innate and adaptive immune responses, including proper T helper (Th) type 1 cell function. FURIN is a proprotein convertase subtilisin/kexin (PCSK) enzyme, which is highly expressed in Th1 type cells. FURIN expression in T cells is essential for maintaining peripheral immune tolerance, but its role in the innate immunity and infections has remained elusive. Here, we utilized Mycobacterium marinum infection models in zebrafish (Danio rerio) to investigate how furin regulates host responses against mycobacteria. In steady-state furinAtd204e/+ fish reduced furinA mRNA levels associated with low granulocyte counts and elevated Th cell transcription factor expressions. Silencing furin genes reduced the survival of M. marinum-infected zebrafish embryos. A mycobacterial infection upregulated furinA in adult zebrafish, and infected furinAtd204e/+ mutants exhibited a proinflammatory phenotype characterized by elevated tumor necrosis factor a (tnfa), lymphotoxin alpha (lta) and interleukin 17a/f3 (il17a/f3) expression levels. The enhanced innate immune response in the furinAtd204e/+ mutants correlated with a significantly decreased bacterial burden in a chronic M. marinum infection model. Our data show that upregulated furinA expression can serve as a marker for mycobacterial disease, since it inhibits early host responses and consequently promotes bacterial growth in a chronic infection. PMID:25624351

Reduced transcript stabilization restricts TNF-alpha expression in RAW264.7 macrophages infected with pathogenic mycobacteria: evidence for an involvement of lipomannan.

PubMed

Basler, Tina; Holtmann, Helmut; Abel, Jens; Eckstein, Torsten; Baumer, Wolfgang; Valentin-Weigand, Peter; Goethe, Ralph

2010-01-01

Despite the critical role that TNF-alpha plays in the containment of mycobacterial infection, the mechanisms involved in regulation of its expression by mycobacteria are poorly defined. We addressed this question by studying MAP, which causes a chronic enteritis in ruminants and is linked to human Crohn's disease. We found that in MAP infected macrophages, TNF-alpha gene expression was substantially lower than in macrophages infected with nonpathogenic MS or stimulated with LPS. TNF-alpha transcriptional one could not fully explain the differential TNF-alpha mRNA expression, suggesting that there must be a substantial contribution by post-transcriptional mechanisms.Accordingly, we found reduced TNF-alpha mRNA stability in MAP-infected macrophages. Further comparison of MAP- and MS-infected macrophages revealed that lower TNF-alpha mRNA stability combined with lower mRNA and protein expression in MAP-infected macrophages correlated with lower p38 MAPK phosphorylation. These findings were independent of viability of MAP and MS. We demonstrate that the major mycobacterial cell-wall lipoglycan LM of MAP and MS induced TNF-alpha mRNA transcription,but only the MS-LM induced p38 MAPK-dependent transcript stabilization. Overall, our data suggest that pathogenic mycobacteria cause weak p38 and TNF-alpha mRNA stabilization as a result of their structural cell-wall components such as LM and thereby, restrict TNF-alpha expression in macrophages.

Histamine plays an essential regulatory role in lung inflammation and protective immunity in the acute phase of Mycobacterium tuberculosis infection.

PubMed

Carlos, D; Fremond, C; Samarina, A; Vasseur, V; Maillet, I; Ramos, S G; Erard, F; Quesniaux, V; Ohtsu, H; Silva, C L; Faccioli, L H; Ryffel, B

2009-12-01

The course and outcome of infection with mycobacteria are determined by a complex interplay between the immune system of the host and the survival mechanisms developed by the bacilli. Recent data suggest a regulatory role of histamine not only in the innate but also in the adaptive immune response. We used a model of pulmonary Mycobacterium tuberculosis infection in histamine-deficient mice lacking histidine decarboxylase (HDC(-/-)), the histamine-synthesizing enzyme. To confirm that mycobacterial infection induced histamine production, we exposed mice to M. tuberculosis and compared responses in C57BL/6 (wild-type) and HDC(-/-) mice. Histamine levels increased around fivefold above baseline in infected C57BL/6 mice at day 28 of infection, whereas only small amounts were detected in the lungs of infected HDC(-/-) mice. Blocking histamine production decreased both neutrophil influx into lung tissue and the release of proinflammatory mediators, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), in the acute phase of infection. However, the accumulation and activation of CD4(+) T cells were augmented in the lungs of infected HDC(-/-) mice and correlated with a distinct granuloma formation that contained abundant lymphocytic infiltration and reduced numbers of mycobacteria 28 days after infection. Furthermore, the production of IL-12, gamma interferon, and nitric oxide, as well as CD11c(+) cell influx into the lungs of infected HDC(-/-) mice, was increased. These findings indicate that histamine produced after M. tuberculosis infection may play a regulatory role not only by enhancing the pulmonary neutrophilia and production of IL-6 and TNF-alpha but also by impairing the protective Th1 response, which ultimately restricts mycobacterial growth.

Aspergillus fumigatus Preexposure Worsens Pathology and Improves Control of Mycobacterium abscessus Pulmonary Infection in Mice.

PubMed

Monin, Leticia; Mehta, Shail; Elsegeiny, Waleed; Gopal, Radha; McAleer, Jeremy P; Oury, Tim D; Kolls, Jay; Khader, Shabaana A

2018-03-01

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Mutations in this chloride channel lead to mucus accumulation, subsequent recurrent pulmonary infections, and inflammation, which, in turn, cause chronic lung disease and respiratory failure. Recently, rates of nontuberculous mycobacterial (NTM) infections in CF patients have been increasing. Of particular relevance is infection with Mycobacterium abscessus , which causes a serious, life-threatening disease and constitutes one of the most antibiotic-resistant NTM species. Interestingly, an increased prevalence of NTM infections is associated with worsening lung function in CF patients who are also coinfected with Aspergillus fumigatus We established a new mouse model to investigate the relationship between A. fumigatus and M. abscessus pulmonary infections. In this model, animals exposed to A. fumigatus and coinfected with M. abscessus exhibited increased lung inflammation and decreased mycobacterial burden compared with those of mice infected with M. abscessus alone. This increased control of M. abscessus infection in coinfected mice was mucus independent but dependent on both transcription factors T-box 21 (Tbx21) and retinoic acid receptor (RAR)-related orphan receptor gamma t (RORγ-t), master regulators of type 1 and type 17 immune responses, respectively. These results implicate a role for both type 1 and type 17 responses in M. abscessus control in A. fumigatus -coinfected lungs. Our results demonstrate that A. fumigatus , an organism found commonly in CF patients with NTM infection, can worsen pulmonary inflammation and impact M. abscessus control in a mouse model. Copyright © 2018 American Society for Microbiology.

Routinely detected indicators in plasma have a predictive effect on the identification of HIV-infected patients with non-tuberculous mycobacterial and tuberculous infections.

PubMed

Cai, Ren-Tian; Yu, Feng-Xue; Tao, Zhen; Qian, Xue-Qin; Chen, Jun; Lu, Hong-Zhou

2017-11-02

It is difficult to quickly distinguish non-tuberculous mycobacterial (NTM) infection from tuberculosis (TB) infection in human immunodeficiency virus (HIV)-infected patients because of many similarities between these diseases. A simple and effective way to determine the differences using routine blood tests is necessary in developing countries. A retrospective cohort study was conducted to recruit HIV-infected patients with either NTM infection or TB infection diagnosed for the first time according to mycobacterial culture and microscopic identification from May 2010 to March 2016. These data included the analysis of blood cells, liver function, renal function, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), and were compared between the HIV/TB and HIV/NTM groups. A total of 240 patients were enrolled. The number of HIV/TB and HIV/NTM patients was 113 and 127, respectively. There were no significant differences in the CD4 T-cell count, age, sex, percentage of patients initiating antiretroviral therapy (ART) before the explicit diagnosis of TB or NTM infection. NTM infection was more likely to be restricted in the pulmonary while TB infection also involves extra-pulmonary sites. Both the leukocyte count(5.60 × 10 9 /L) and the proportion of neutrophils in the leukocyte count (76.70%) in the HIV/TB group were significantly higher than those in the HIV/NTM group (4.40 × 10 9 /L [P = 0.0014] and 69.30% [P < 0.001]. The analysis of liver function markers indicated that the concentration of albumin but not ALT and AST was significantly lower in the HIV/TB group than in the HIV/NTM group (P < 0.001). The creatinine and urea levels were not significantly different between the two groups. The ESR (84.00 mm/h) and the concentration of CRP (59.60 mg/L) were significantly higher in the HIV/TB group than in the HIV/NTM group (52.00 mm/h and 19.60 mg/L, respectively) (P < 0.001). To distinguish TB infection from NTM infection, the best cut-off value was 69.5 mm/h for ESR, with a positive predictive value (PPV) of 0.740 and negative predictive value (NPV) of 0.721, and 48.8 mg/L for CRP, with a PPV of 0.676 and NPV of 0.697. The dissemination character as well as stronger immune response characterized by higher inflammation markers (e.g. WBC, ESR, CRP) can help distinguish TB from NTM infection in HIV-infected patients who need empirical therapy or diagnostic therapy immediately in low-income areas.

Mycobacterium tuberculosis Universal Stress Protein Rv2623 Regulates Bacillary Growth by ATP Binding: Requirement for Establishing Chronic Persistent Infection

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

Drumm, J.; Mi, K; Bilder, P

Tuberculous latency and reactivation play a significant role in the pathogenesis of tuberculosis, yet the mechanisms that regulate these processes remain unclear. The Mycobacterium tuberculosisuniversal stress protein (USP) homolog, rv2623, is among the most highly induced genes when the tubercle bacillus is subjected to hypoxia and nitrosative stress, conditions thought to promote latency. Induction of rv2623 also occurs when M. tuberculosis encounters conditions associated with growth arrest, such as the intracellular milieu of macrophages and in the lungs of mice with chronic tuberculosis. Therefore, we tested the hypothesis that Rv2623 regulates tuberculosis latency. We observed that an Rv2623-deficient mutant failsmore » to establish chronic tuberculous infection in guinea pigs and mice, exhibiting a hypervirulence phenotype associated with increased bacterial burden and mortality. Consistent with this in vivo growth-regulatory role, constitutive overexpression of rv2623 attenuates mycobacterial growth in vitro. Biochemical analysis of purified Rv2623 suggested that this mycobacterial USP binds ATP, and the 2.9-A-resolution crystal structure revealed that Rv2623 engages ATP in a novel nucleotide-binding pocket. Structure-guided mutagenesis yielded Rv2623 mutants with reduced ATP-binding capacity. Analysis of mycobacteria overexpressing these mutants revealed that the in vitro growth-inhibitory property of Rv2623 correlates with its ability to bind ATP. Together, the results indicate that i M. tuberculosis Rv2623 regulates mycobacterial growth in vitro and in vivo, and ii Rv2623 is required for the entry of the tubercle bacillus into the chronic phase of infection in the host; in addition, iii Rv2623 binds ATP; and iv the growth-regulatory attribute of this USP is dependent on its ATP-binding activity. We propose that Rv2623 may function as an ATP-dependent signaling intermediate in a pathway that promotes persistent infection.« less

Immunogenicity and protection conferred by Mycobacterium habana in a murine model of pulmonary tuberculosis.

PubMed

Valdés, Iliana; Montoro, Ernesto; Mata-Espinoza, Dulce; Asín, Odalys; Barrios-Payan, Jorge; Francisco-Cruz, Alejandro; Valdivia, José Antonio; Hernández-Pando, Rogelio

2014-01-01

Mycobacterium habana was isolated in Cuba in 1971. Later, was demonstrated its protection capacity in mycobacterial infection. Here we determined the level of virulence, immunogenicity and the efficacy of three different M. habana strains as attenuated live vaccines. Intratracheal infection of BALB/c mice with high dose M. habana TMC 5135 or IPK-337 strains permitted 100% survival and limited tissue damage. Mice infected with M. habana IPK-220 showed lower attenuation, so it was discarded for the vaccination experiments. Strains IPK-337 and TMC 5135 were used as subcutaneous vaccine and compared with BCG. Nude mice vaccinated with strain 5135 showed longer but non-significant survival than BCG vaccinated animals. Cell suspensions from M. habana vaccinated mice produced higher IFNγ after stimulation with mycobacterial antigens than BCG recipients. After four months of challenge with Mycobacterium tuberculosis strain H37Rv, mice vaccinated with BCG substrain Phipps or strain TMC 5135 showed total survival, while 60% survival was exhibited by animals vaccinated with M. habana IPK-337. Both M. habana strains do not prevent the infection with M. tuberculosis but avoided the progression of the experimental disease; strain TMC 5135 showed similar level of protection than BCG. Copyright © 2013 Elsevier Ltd. All rights reserved.

Granulysin as a Correlate of Immune Response following Mycobacterial Infection

USDA-ARS?s Scientific Manuscript database

Correlates of protection following vaccination against TB are needed in the development of improved vaccines against TB. Evaluation of vaccine efficacy is based on measuring IFN gamma levels and antigen-specific proliferation. Granulysin is an antimicrobial protein expressed by T lymphocytes and NK ...

Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections

PubMed Central

Tobin, David M.; Roca, Francisco J.; Oh, Sungwhan F.; McFarland, Ross; Vickery, Thad W.; Ray, John P.; Ko, Dennis C.; Zou, Yuxia; Bang, Nguyen D.; Chau, Tran T. H.; Vary, Jay C.; Hawn, Thomas R.; Dunstan, Sarah J.; Farrar, Jeremy J.; Thwaites, Guy E.; King, Mary-Claire; Serhan, Charles N.; Ramakrishnan, Lalita

2012-01-01

Summary Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A4 hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B4. We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation. PMID:22304914

Epidemiology of Nontuberculous Mycobacterial Lung Disease and Tuberculosis, Hawaii, USA.

PubMed

Adjemian, Jennifer; Frankland, Timothy B; Daida, Yihe G; Honda, Jennifer R; Olivier, Kenneth N; Zelazny, Adrian; Honda, Stacey; Prevots, D Rebecca

2017-03-01

Previous studies found Hawaiians and Asian-Americans/Pacific Islanders to be independently at increased risk for nontuberculous mycobacterial pulmonary disease (NTMPD) and tuberculosis (TB). To better understand NTM infection and TB risk patterns in Hawaii, USA, we evaluated data on a cohort of patients in Hawaii for 2005-2013. Period prevalence of NTMPD was highest among Japanese, Chinese, and Vietnamese patients (>300/100,000 persons) and lowest among Native Hawaiians and Other Pacific Islanders (50/100,000). Japanese patients were twice as likely as all other racial/ethnic groups to have Mycobacterium abscessus isolated (adjusted odds ratio 2.0, 95% CI 1.2-3.2) but were not at increased risk for infection with other mycobacteria species. In contrast, incidence of TB was stable and was lowest among Japanese patients (no cases) and highest among Filipino, Korean, and Vietnamese patients (>50/100,000). Substantial differences exist in the epidemiology of NTMPD by race/ethnicity, suggesting behavioral and biologic factors that affect disease susceptibility.

Epidemiology of Nontuberculous Mycobacterial Lung Disease and Tuberculosis, Hawaii, USA

PubMed Central

Frankland, Timothy B.; Daida, Yihe G.; Honda, Jennifer R.; Olivier, Kenneth N.; Zelazny, Adrian; Honda, Stacey; Prevots, D. Rebecca

2017-01-01

Previous studies found Hawaiians and Asian-Americans/Pacific Islanders to be independently at increased risk for nontuberculous mycobacterial pulmonary disease (NTMPD) and tuberculosis (TB). To better understand NTM infection and TB risk patterns in Hawaii, USA, we evaluated data on a cohort of patients in Hawaii for 2005–2013. Period prevalence of NTMPD was highest among Japanese, Chinese, and Vietnamese patients (>300/100,000 persons) and lowest among Native Hawaiians and Other Pacific Islanders (50/100,000). Japanese patients were twice as likely as all other racial/ethnic groups to have Mycobacterium abscessus isolated (adjusted odds ratio 2.0, 95% CI 1.2–3.2) but were not at increased risk for infection with other mycobacteria species. In contrast, incidence of TB was stable and was lowest among Japanese patients (no cases) and highest among Filipino, Korean, and Vietnamese patients (>50/100,000). Substantial differences exist in the epidemiology of NTMPD by race/ethnicity, suggesting behavioral and biologic factors that affect disease susceptibility. PMID:28221128

Transmembrane Tumor Necrosis Factor Controls Myeloid-Derived Suppressor Cell Activity via TNF Receptor 2 and Protects from Excessive Inflammation during BCG-Induced Pleurisy

PubMed Central

Chavez-Galan, Leslie; Vesin, Dominique; Uysal, Husnu; Blaser, Guillaume; Benkhoucha, Mahdia; Ryffel, Bernhard; Quesniaux, Valérie F. J.; Garcia, Irene

2017-01-01

Pleural tuberculosis (TB) is a form of extra-pulmonary TB observed in patients infected with Mycobacterium tuberculosis. Accumulation of myeloid-derived suppressor cells (MDSC) has been observed in animal models of TB and in human patients but their role remains to be fully elucidated. In this study, we analyzed the role of transmembrane TNF (tmTNF) in the accumulation and function of MDSC in the pleural cavity during an acute mycobacterial infection. Mycobacterium bovis BCG-induced pleurisy was resolved in mice expressing tmTNF, but lethal in the absence of tumor necrosis factor. Pleural infection induced MDSC accumulation in the pleural cavity and functional MDSC required tmTNF to suppress T cells as did pleural wild-type MDSC. Interaction of MDSC expressing tmTNF with CD4 T cells bearing TNF receptor 2 (TNFR2), but not TNFR1, was required for MDSC suppressive activity on CD4 T cells. Expression of tmTNF attenuated Th1 cell-mediated inflammatory responses generated by the acute pleural mycobacterial infection in association with effective MDSC expressing tmTNF and interacting with CD4 T cells expressing TNFR2. In conclusion, this study provides new insights into the crucial role played by the tmTNF/TNFR2 pathway in MDSC suppressive activity required during acute pleural infection to attenuate excessive inflammation generated by the infection. PMID:28890718

Specificity of the Tuberculin Skin Test Is Modified by Use of a Protein Cocktail Containing ESAT-6 and CFP-10 in Cattle Naturally Infected with Mycobacterium bovis

PubMed Central

Flores-Villalva, S.; Suárez-Güemes, F.; Espitia, C.; Whelan, A. O.; Vordermeier, M.

2012-01-01

The mycobacterial immunodominant ESAT-6 and CFP-10 antigens are strongly recognizable in tuberculosis-infected cattle, and they do not elicit a response in cattle without infection. In addition, they are absent in most environmental mycobacterial species, and therefore, their use can be an alternative to purified protein derivative (PPD) tuberculin in the development of a more specific skin diagnostic test in cattle. The aim of the current study was to assess the potential of an ESAT-6 and CFP-10 (E6-C10) protein cocktail in a skin test format in naturally tuberculosis-infected and paratuberculosis-infected cattle. We also included MPB83 as a third component in one of the protein cocktail preparations. The protein cocktail was tested at different dose concentrations (5, 10, and 15 μg per protein). The best skin response to the E6-C10 protein cocktail was obtained with 10 μg. Subsequently, this concentration was tested in 2 herds with high and low bovine tuberculosis prevalence, the latter with paratuberculosis coinfection. Our data show that the E6-C10 cocktail allows identification of an important proportion of animals that PPDB is not able to recognize, especially in low-prevalence herds. The protein cocktail did not induce reactions in tuberculosis-free cattle or in paratuberculosis-infected cattle. Addition of MPB83 to the protein cocktail did not make any difference in the skin reaction. PMID:22419675

Specificity of the tuberculin skin test is modified by use of a protein cocktail containing ESAT-6 and CFP-10 in cattle naturally infected with Mycobacterium bovis.

PubMed

Flores-Villalva, S; Suárez-Güemes, F; Espitia, C; Whelan, A O; Vordermeier, M; Gutiérrez-Pabello, J A

2012-05-01

The mycobacterial immunodominant ESAT-6 and CFP-10 antigens are strongly recognizable in tuberculosis-infected cattle, and they do not elicit a response in cattle without infection. In addition, they are absent in most environmental mycobacterial species, and therefore, their use can be an alternative to purified protein derivative (PPD) tuberculin in the development of a more specific skin diagnostic test in cattle. The aim of the current study was to assess the potential of an ESAT-6 and CFP-10 (E6-C10) protein cocktail in a skin test format in naturally tuberculosis-infected and paratuberculosis-infected cattle. We also included MPB83 as a third component in one of the protein cocktail preparations. The protein cocktail was tested at different dose concentrations (5, 10, and 15 μg per protein). The best skin response to the E6-C10 protein cocktail was obtained with 10 μg. Subsequently, this concentration was tested in 2 herds with high and low bovine tuberculosis prevalence, the latter with paratuberculosis coinfection. Our data show that the E6-C10 cocktail allows identification of an important proportion of animals that PPDB is not able to recognize, especially in low-prevalence herds. The protein cocktail did not induce reactions in tuberculosis-free cattle or in paratuberculosis-infected cattle. Addition of MPB83 to the protein cocktail did not make any difference in the skin reaction.

Adequate Th2-Type Response Associates with Restricted Bacterial Growth in Latent Mycobacterial Infection of Zebrafish

PubMed Central

Hammarén, Milka Marjut; Luukinen, Bruno Vincent; Pesu, Marko; Rämet, Mika; Parikka, Mataleena

2014-01-01

Tuberculosis is still a major health problem worldwide. Currently it is not known what kind of immune responses lead to successful control and clearance of Mycobacterium tuberculosis. This gap in knowledge is reflected by the inability to develop sufficient diagnostic and therapeutic tools to fight tuberculosis. We have used the Mycobacterium marinum infection model in the adult zebrafish and taken advantage of heterogeneity of zebrafish population to dissect the characteristics of adaptive immune responses, some of which are associated with well-controlled latency or bacterial clearance while others with progressive infection. Differences in T cell responses between subpopulations were measured at the transcriptional level. It was discovered that a high total T cell level was usually associated with lower bacterial loads alongside with a T helper 2 (Th2)-type gene expression signature. At late time points, spontaneous reactivation with apparent symptoms was characterized by a low Th2/Th1 marker ratio and a substantial induction of foxp3 reflecting the level of regulatory T cells. Characteristic gata3/tbx21 has potential as a biomarker for the status of mycobacterial disease. PMID:24968056

The Child with Recurrent Mycobacterial Disease.

PubMed

Reed, Brian; Dolen, William K

2018-06-23

Many genetic conditions predispose affected individuals to opportunistic infections. A number of immunodeficiency diseases, including genetic defects termed Mendelian susceptibility to mycobacterial disease (MSMD), permit infection from many different strains of mycobacteria that would otherwise not cause disease. These include tuberculous and nontuberculous mycobacteria, and bacille Calmette-Guérin vaccine (BCG). Patients may present with infections from other organisms that depend on macrophage function for containment. Defects in multiple genes in the IL-12 and NFKB signaling pathways can cause the MSMD phenotype, some of which include IL12RB1, IL12B, IKBKG, ISG15, IFNGR1, IFNGR2, CYBB, TYK2, IRF8, and STAT1. Multiple autosomal recessive and dominant, and 2 X-linked recessive gene defects resulting in the MSMD phenotype have been reported, and others await discovery. This review presents the known gene defects and describes clinical findings that result from the mutations. If MSMD is suspected, a careful clinical history and examination and basic immunodeficiency screening tests will narrow the differential diagnosis. A specific diagnosis requires more sophisticated laboratory investigation. Genetic testing permits a definitive diagnosis, permitting genetic counseling. Mild cases respond well to appropriate antibiotic therapy, whereas severe disease may require hematopoietic stem cell transplantation.

An unusual pathogen in ambulatory care: two cases of Scedosporium soft tissue infections presenting as "unresponsive cellulitis".

PubMed

Misselbrook, Gary Peter; Lillie, Patrick; Thomas, Claire P

2016-01-01

Soft tissue infections with Scedosporium spp. are an uncommon but serious and emerging cause of infection in immunocompromised patients. Acute Medical Units (AMUs) in the UK are increasingly managing patients with cellulitis in an outpatient setting, therefore acute physicians should be aware of some of the more uncommon causes of soft tissue infection, particularly in patients not responding to initial antibiotic therapy. We present two cases of Scedosporium presenting to the AMU as cellulitis not responding to initial antibiotic therapy and outline the assessment and management of this important condition.

Hepcidin deficiency and iron deficiency do not alter tuberculosis susceptibility in a murine M.tb infection model

PubMed Central

Harrington-Kandt, Rachel; Stylianou, Elena; Eddowes, Lucy A.; Lim, Pei Jin; Stockdale, Lisa; Pinpathomrat, Nawamin; Bull, Naomi; Pasricha, Janet; Ulaszewska, Marta; Beglov, Yulia; Vaulont, Sophie

2018-01-01

Tuberculosis (TB), caused by the macrophage-tropic pathogen Mycobacterium tuberculosis (M.tb) is a highly prevalent infectious disease. Since an immune correlate of protection or effective vaccine have yet to be found, continued research into host-pathogen interactions is important. Previous literature reports links between host iron status and disease outcome for many infections, including TB. For some extracellular bacteria, the iron regulatory hormone hepcidin is essential for protection against infection. Here, we investigated hepcidin (encoded by Hamp1) in the context of murine M.tb infection. Female C57BL/6 mice were infected with M.tb Erdman via aerosol. Hepatic expression of iron-responsive genes was measured by qRT-PCR and bacterial burden determined in organ homogenates. We found that hepatic Hamp1 mRNA levels decreased post-infection, and correlated with a marker of BMP/SMAD signalling pathways. Next, we tested the effect of Hamp1 deletion, and low iron diets, on M.tb infection. Hamp1 knockout mice did not have a significantly altered M.tb mycobacterial load in either the lungs or spleen. Up to 10 weeks of dietary iron restriction did not robustly affect disease outcome despite causing iron deficiency anaemia. Taken together, our data indicate that unlike with many other infections, hepcidin is decreased following M.tb infection, and show that hepcidin ablation does not influence M.tb growth in vivo. Furthermore, because even severe iron deficiency did not affect M.tb mycobacterial load, we suggest that the mechanisms M.tb uses to scavenge iron from the host must be extremely efficient, and may therefore represent potential targets for drugs and vaccines. PMID:29324800

Microarray analysis of Mycobacterium tuberculosis-infected monocytes reveals IL26 as a new candidate gene for tuberculosis susceptibility.

PubMed

Guerra-Laso, José M; Raposo-García, Sara; García-García, Silvia; Diez-Tascón, Cristina; Rivero-Lezcano, Octavio M

2015-02-01

Differences in the activity of monocytes/macrophages, important target cells of Mycobacterium tuberculosis, might influence tuberculosis progression. With the purpose of identifying candidate genes for tuberculosis susceptibility we infected monocytes from both healthy elderly individuals (a tuberculosis susceptibility group) and elderly tuberculosis patients with M. tuberculosis, and performed a microarray experiment. We detected 78 differentially expressed transcripts and confirmed these results by quantitative PCR of selected genes. We found that monocytes from tuberculosis patients showed similar expression patterns for these genes, regardless of whether they were obtained from younger or older patients. Only one of the detected genes corresponded to a cytokine: IL26, a member of the interleukin-10 (IL-10) cytokine family which we found to be down-regulated in infected monocytes from tuberculosis patients. Non-infected monocytes secreted IL-26 constitutively but they reacted strongly to M. tuberculosis infection by decreasing IL-26 production. Furthermore, IL-26 serum concentrations appeared to be lower in the tuberculosis patients. When whole blood was infected, IL-26 inhibited the observed pathogen-killing capability. Although lymphocytes expressed IL26R, the receptor mRNA was not detected in either monocytes or neutrophils, suggesting that the inhibition of anti-mycobacterial activity may be mediated by lymphocytes. Additionally, IL-2 concentrations in infected blood were lower in the presence of IL-26. The negative influence of IL-26 on the anti-mycobacterial activity and its constitutive presence in both serum and monocyte supernatants prompt us to propose IL26 as a candidate gene for tuberculosis susceptibility. © 2014 John Wiley & Sons Ltd.

Host responses to mycobacterial infections: Spotlight on biomarker discovery to predict vaccine

USDA-ARS?s Scientific Manuscript database

The global spread of tuberculosis (TB) in animals and humans result in enormous economic. social and public health burdens. TB vaccine development in both humans and animals has produced a growing portfolio of candidates with potential applicability across species. However, the lack of understandin...

[Riddles in human tuberculous infection].

PubMed

Tsuyuguchi, I

2000-10-01

Tuberculosis is indeed an infectious disease caused by Mycobacterium tuberculosis. However, only a small percentage of individuals infected develops overt disease, tuberculosis whereas the infected bacilli persist alive years long within the vast majority of persons infected but remained healthy. There are several riddles or enigmas in the natural history of M. tuberculosis infection in humans. Some of them are as follows: 1. What is the virulence of M. tuberculosis? 2. How does M. tuberculosis persist dormant within the host? 3. What determines the development of disease from remaining healthy after infection with M. tuberculosis? 4. What is the mechanism of "endogenous reactivation" of dormant M. tuberculosis within the host? 5. Can we expect more potent anti-TB vaccine than BCG in near future? Most of these issues cited above remain unsolved. What is urgently needed today to answer correctly to these questions is the production of appropriate animal model of tuberculosis infection which mimics human tuberculosis. Murine TB does not reflect human TB at all. What characterizes the mycobacterial organism is its armour-plated unique cell wall structure which is rich in lipid and carbohydrate. Cord factor or trehalose dimycolate (TDM), the main component of cell wall, has once been regarded as the virulence factor of mycobacteria. Cord factor is responsible for the pathogenesis of TB and cachexia or even death of the patients infected. However, cord factor in itself is not toxic but exerts its detrimental effect to the host through the excessive stimulation of the host's immune system to produce abundant varied cytokines including TNF-alpha. How to evade this embarrassing effect of mycobacterial cell wall component on the host immune system seems very important for the future development of better TB vaccine than the currently used BCG.

Mycobacterium bovis Bacille Calmette-Guérin Infection in the CNS Suppresses Experimental Autoimmune Encephalomyelitis and Th17 Responses in an IFN-gamma-independent Manner1

PubMed Central

Lee, JangEun; Reinke, Emily K.; Zozulya, Alla L.; Sandor, Matyas; Fabry, Zsuzsanna

2009-01-01

Multiple sclerosis (MS) and an animal model resembling MS, experimental autoimmune encephalomyelitis (EAE), are inflammatory demyelinating diseases of the central nervous system (CNS) that are suppressed by systemic mycobacterial infection in mice and BCG vaccination in humans. Host defense responses against Mycobacterium in mice are influenced by T lymphocytes and their cytokine products, particularly IFN-γ, which plays a protective regulatory role in EAE. To analyze the counter-regulatory role of mycobacterial infection-induced IFN-γ in the CNS on the function of the pathological Th17 cells and the clinical outcome of EAE, we induced EAE in mice that were intracerebrally infected with Mycobacterium bovis bacille Calmette-Guerin (BCG). Here we demonstrate that intracerebral (i.c.) BCG infection prevented inflammatory cell recruitment to the spinal cord and suppressed the development of EAE. Concomitantly, there was a significant decrease in the frequency of MOG-specific IFN-γ-producing CD4+ T cells in the CNS. IL-17+CD4+ T cell responses were significantly suppressed in i.c. BCG-infected mice following EAE induction regardless of T cell specificity. The frequency of Foxp3+CD4+ T cells in these mice was equivalent to that of control mice. The i.c. BCG infection-induced protection of EAE and suppression of MOG-specific IL-17+CD4+ T cell responses were similar in both wild type (WT) and IFN-γ deficient mice. These data show that live BCG infection in the brain suppresses CNS autoimmunity. These findings also reveal that the regulation of Th17-mediated autoimmunity in the CNS can be independent of IFN-γ-mediated mechanisms. PMID:18941210

A spatial epidemiological analysis of nontuberculous mycobacterial infections in Queensland, Australia.

PubMed

Chou, Michael P; Clements, Archie C A; Thomson, Rachel M

2014-05-21

The epidemiology of infections with nontuberculous mycobacteria (NTM) has been changing and the incidence has been increasing in some settings. The main route of transmission to humans is considered to be from the environment. We aimed to describe spatial clusters of cases of NTM infections and to identify associated climatic, environmental and socio-economic variables. NTM data were obtained from the Queensland Mycobacterial Reference Laboratory for the period 2001-2011. A Bayesian spatial conditional autoregressive model was constructed at the postcode level, with covariates including soil variables, maximum, mean and minimum rainfall and temperature, income (proportion of population earning < $32,000 and < $52,000) and land use category. Significant clusters of NTM infection were identified in the central Queensland region overlying the Surat sub-division of the Great Artesian Basin, as well as in the lower North Queensland Local Government Area known as the Whitsunday region. Our models estimated an expected increase of 21% per percentage increase of population earning < $52,000 (95% CI 9-34%) and an expected decrease of 13% for every metre increase of average topsoil depth for risk of Mycobacterium intracellulare infection (95% CI -3 - -22%). There was an estimated increase of 79% per mg/m3 increase of soil bulk density (95% CI 26-156%) and 19% decrease for every percentage increase in population earning < $32,000 for risk of M. kansasii infection (95% CI -3 - -49%). There were distinct spatial clusters of M. kansasii, M. intracellulare and M. abscessus infections in Queensland, and a number of socio-ecological, economic and environmental factors were found to be associated with NTM infection risk.

Healthcare-associated outbreaks due to Mucorales and other uncommon fungi.

PubMed

Davoudi, Setareh; Graviss, Linda S; Kontoyiannis, Dimitrios P

2015-07-01

Healthcare-associated outbreaks of fungal infections, especially with uncommon and emerging fungi, have become more frequent in the past decade. Here, we reviewed the history and definition of healthcare-associated outbreaks of uncommon fungal infections and discussed the principles of investigating, containing and treatment of these outbreaks. In case of these uncommon diseases, occurrence of two or more cases in a short period is considered as an outbreak. Contaminated medical devices and hospital environment are the major sources of these outbreaks. Care must be taken to differentiate a real infection from colonization or contamination. Defining and identifying cases, describing epidemiologic feature of cases, finding and controlling the source of the outbreak, treating patients, and managing asymptomatic exposed patients are main steps for outbreak elimination. These fungal outbreaks are not only difficult to detect but also hard to treat. Early initiation of appropriate antifungal therapy is strongly associated with improved outcomes in infected patients. Choice of antifungal drugs should be made based on spectrum, pharmacodynamic and pharmacokinetic characteristics and adverse effects of available drugs. Combination antifungal therapy and surgical intervention may be also helpful in selected cases. A multidisciplinary approach and close collaboration between all key partners are necessary for successful control of fungal outbreaks. © 2015 Stichting European Society for Clinical Investigation Journal Foundation.

Association of GATA2 Deficiency With Severe Primary Epstein-Barr Virus (EBV) Infection and EBV-associated Cancers

PubMed Central

Cohen, Jeffrey I.; Dropulic, Lesia; Hsu, Amy P.; Zerbe, Christa S.; Krogmann, Tammy; Dowdell, Kennichi; Hornung, Ronald L.; Lovell, Jana; Hardy, Nancy; Hickstein, Dennis; Cowen, Edward W.; Calvo, Katherine R.; Pittaluga, Stefania; Holland, Steven M.

2016-01-01

Background. Most patients infected with Epstein-Barr virus (EBV) are asymptomatic, have nonspecific symptoms, or have self-limiting infectious mononucleosis. EBV, however, may result in severe primary disease or cancer. Methods. We report EBV diseases associated with GATA2 deficiency at one institution and describe the hematology, virology, and cytokine findings. Results. Seven patients with GATA2 deficiency developed severe EBV disease. Three presented with EBV infectious mononucleosis requiring hospitalization, 1 had chronic active EBV disease (B-cell type), 1 had EBV-associated hydroa vacciniforme–like lymphoma with hemophagocytic lymphohistiocytosis, and 2 had EBV-positive smooth muscle tumors. Four of the 7 patients had severe warts and 3 had disseminated nontuberculous mycobacterial infections. All of the patients had low numbers of monocytes, B cells, CD4 T cells, and natural killer cells. All had elevated levels of EBV in the blood; 2 of 3 patients tested had expression of the EBV major immediate-early gene in the blood indicative of active EBV lytic infection. Mean plasma levels of tumor necrosis factor α, interferon γ, and interferon gamma-induced protein 10 were higher in patients with GATA2 deficiency than in controls. Conclusions. GATA2 is the first gene associated with EBV hydroa vacciniforme–like lymphoma. GATA2 deficiency should be considered in patients with severe primary EBV infection or EBV-associated cancer, especially in those with disseminated nontuberculous mycobacterial disease and warts. PMID:27169477

Clinical implications of Mycobacterium chimaera detection in thermoregulatory devices used for extracorporeal membrane oxygenation (ECMO), Germany, 2015 to 2016.

PubMed

Trudzinski, Franziska C; Schlotthauer, Uwe; Kamp, Annegret; Hennemann, Kai; Muellenbach, Ralf M; Reischl, Udo; Gärtner, Barbara; Wilkens, Heinrike; Bals, Robert; Herrmann, Mathias; Lepper, Philipp M; Becker, Sören L

2016-11-17

Mycobacterium chimaera, a non-tuberculous mycobacterium, was recently identified as causative agent of deep-seated infections in patients who had previously undergone open-chest cardiac surgery. Outbreak investigations suggested an aerosol-borne pathogen transmission originating from water contained in heater-cooler units (HCUs) used during cardiac surgery. Similar thermoregulatory devices are used for extracorporeal membrane oxygenation (ECMO) and M. chimaera might also be detectable in ECMO treatment settings. We performed a prospective microbiological study investigating the occurrence of M. chimaera in water from ECMO systems and in environmental samples, and a retrospective clinical review of possible ECMO-related mycobacterial infections among patients in a pneumological intensive care unit. We detected M. chimaera in 9 of 18 water samples from 10 different thermoregulatory ECMO devices; no mycobacteria were found in the nine room air samples and other environmental samples. Among 118 ECMO patients, 76 had bronchial specimens analysed for mycobacteria and M. chimaera was found in three individuals without signs of mycobacterial infection at the time of sampling. We conclude that M. chimaera can be detected in water samples from ECMO-associated thermoregulatory devices and might potentially pose patients at risk of infection. Further research is warranted to elucidate the clinical significance of M. chimaera in ECMO treatment settings. This article is copyright of The Authors, 2016.

Interferon regulatory factor 8-deficiency determines massive neutrophil recruitment but T cell defect in fast growing granulomas during tuberculosis.

PubMed

Rocca, Stefano; Schiavoni, Giovanna; Sali, Michela; Anfossi, Antonio Giovanni; Abalsamo, Laura; Palucci, Ivana; Mattei, Fabrizio; Sanchez, Massimo; Giagu, Anna; Antuofermo, Elisabetta; Fadda, Giovanni; Belardelli, Filippo; Delogu, Giovanni; Gabriele, Lucia

2013-01-01

Following Mycobacterium tuberculosis (Mtb) infection, immune cell recruitment in lungs is pivotal in establishing protective immunity through granuloma formation and neogenesis of lymphoid structures (LS). Interferon regulatory factor-8 (IRF-8) plays an important role in host defense against Mtb, although the mechanisms driving anti-mycobacterial immunity remain unclear. In this study, IRF-8 deficient mice (IRF-8⁻/⁻) were aerogenously infected with a low-dose Mtb Erdman virulent strain and the course of infection was compared with that induced in wild-type (WT-B6) counterparts. Tuberculosis (TB) progression was examined in both groups using pathological, microbiological and immunological parameters. Following Mtb exposure, the bacterial load in lungs and spleens progressed comparably in the two groups for two weeks, after which IRF-8⁻/⁻ mice developed a fatal acute TB whereas in WT-B6 the disease reached a chronic stage. In lungs of IRF-8⁻/⁻, uncontrolled growth of pulmonary granulomas and impaired development of LS were observed, associated with unbalanced homeostatic chemokines, progressive loss of infiltrating T lymphocytes and massive prevalence of neutrophils at late infection stages. Our data define IRF-8 as an essential factor for the maintenance of proper immune cell recruitment in granulomas and LS required to restrain Mtb infection. Moreover, IRF-8⁻/⁻ mice, relying on a common human and mouse genetic mutation linked to susceptibility/severity of mycobacterial diseases, represent a valuable model of acute TB for comparative studies with chronically-infected congenic WT-B6 for dissecting protective and pathological immune reactions.

Interferon Regulatory Factor 8-Deficiency Determines Massive Neutrophil Recruitment but T Cell Defect in Fast Growing Granulomas during Tuberculosis

PubMed Central

Sali, Michela; Anfossi, Antonio Giovanni; Abalsamo, Laura; Palucci, Ivana; Mattei, Fabrizio; Sanchez, Massimo; Giagu, Anna; Antuofermo, Elisabetta; Fadda, Giovanni; Belardelli, Filippo; Delogu, Giovanni; Gabriele, Lucia

2013-01-01

Following Mycobacterium tuberculosis (Mtb) infection, immune cell recruitment in lungs is pivotal in establishing protective immunity through granuloma formation and neogenesis of lymphoid structures (LS). Interferon regulatory factor-8 (IRF-8) plays an important role in host defense against Mtb, although the mechanisms driving anti-mycobacterial immunity remain unclear. In this study, IRF-8 deficient mice (IRF-8−/−) were aerogenously infected with a low-dose Mtb Erdman virulent strain and the course of infection was compared with that induced in wild-type (WT-B6) counterparts. Tuberculosis (TB) progression was examined in both groups using pathological, microbiological and immunological parameters. Following Mtb exposure, the bacterial load in lungs and spleens progressed comparably in the two groups for two weeks, after which IRF-8−/− mice developed a fatal acute TB whereas in WT-B6 the disease reached a chronic stage. In lungs of IRF-8−/−, uncontrolled growth of pulmonary granulomas and impaired development of LS were observed, associated with unbalanced homeostatic chemokines, progressive loss of infiltrating T lymphocytes and massive prevalence of neutrophils at late infection stages. Our data define IRF-8 as an essential factor for the maintenance of proper immune cell recruitment in granulomas and LS required to restrain Mtb infection. Moreover, IRF-8−/− mice, relying on a common human and mouse genetic mutation linked to susceptibility/severity of mycobacterial diseases, represent a valuable model of acute TB for comparative studies with chronically-infected congenic WT-B6 for dissecting protective and pathological immune reactions. PMID:23717393

Identification of the Infection Source of an Outbreak of Mycobacterium Chelonae Keratitis After Laser in Situ Keratomileusis.

PubMed

Nascimento, Heloisa; Viana-Niero, Cristina; Nogueira, Christiane Lourenço; Martins Bispo, Paulo José; Pinto, Fernando; de Paula Pereira Uzam, Camila; Matsumoto, Cristianne Kayoko; Oliveira Machado, Antônia Maria; Leão, Sylvia Cardoso; Höfling-Lima, Ana Luisa; de Freitas, Denise

2018-01-01

Nontuberculous mycobacteria keratitis is a rare but challenging complication of laser in situ keratomileusis (LASIK). This study was conducted to determine the source(s) of infection in a cluster of cases of keratitis after LASIK and to describe this outbreak and patients' outcomes. In this retrospective, case series, single-center study, 86 patients were included who underwent LASIK or photorefractive keratectomy between December 2011 and February 2012. Corneal scrapes from the affected eyes, samples of tap and distilled water, water from the reservoir of the distilling equipment, steamer, and autoclave cassette; antiseptic and anesthetic solutions and surgical instrument imprints were cultivated in liquid and on solid media. Gram-negative bacteria and yeasts were identified using automated systems and mycobacteria by polymerase chain reaction-restriction enzyme analysis of the hsp65 gene (PRA-hsp65) and DNA sequencing. Mycobacterial isolates were typed by pulsed-field gel electrophoresis. The cases and outcomes are described. The main outcome measure was identification of the source(s) of the mycobacterial infections. Eight (15 eyes) of 86 patients (172 eyes) who underwent LASIK developed infections postoperatively; no patients who underwent photorefractive keratectomy developed infections. Mycobacterium chelonae was isolated from 4 eyes. The distilled water collected in the surgical facility contained the same M. chelonae strain isolated from the patients' eyes. Different gram-negative bacteria and yeasts were isolated from samples collected at the clinic but not from the patients' eyes. Tap water distilled locally in surgical facilities may be a source of infection after ocular surgery and its use should be avoided.

Inhaled Antibiotics for Lower Airway Infections

PubMed Central

Quon, Bradley S.; Goss, Christopher H.

2014-01-01

Inhaled antibiotics have been used to treat chronic airway infections since the 1940s. The earliest experience with inhaled antibiotics involved aerosolizing antibiotics designed for parenteral administration. These formulations caused significant bronchial irritation due to added preservatives and nonphysiologic chemical composition. A major therapeutic advance took place in 1997, when tobramycin designed for inhalation was approved by the U.S. Food and Drug Administration (FDA) for use in patients with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa infection. Attracted by the clinical benefits observed in CF and the availability of dry powder antibiotic formulations, there has been a growing interest in the use of inhaled antibiotics in other lower respiratory tract infections, such as non-CF bronchiectasis, ventilator-associated pneumonia, chronic obstructive pulmonary disease, mycobacterial disease, and in the post–lung transplant setting over the past decade. Antibiotics currently marketed for inhalation include nebulized and dry powder forms of tobramycin and colistin and nebulized aztreonam. Although both the U.S. Food and Drug Administration and European Medicines Agency have approved their use in CF, they have not been approved in other disease areas due to lack of supportive clinical trial evidence. Injectable formulations of gentamicin, tobramycin, amikacin, ceftazidime, and amphotericin are currently nebulized “off-label” to manage non-CF bronchiectasis, drug-resistant nontuberculous mycobacterial infections, ventilator-associated pneumonia, and post-transplant airway infections. Future inhaled antibiotic trials must focus on disease areas outside of CF with sample sizes large enough to evaluate clinically important endpoints such as exacerbations. Extrapolating from CF, the impact of eradicating organisms such as P. aeruginosa in non-CF bronchiectasis should also be evaluated. PMID:24673698

Inhaled antibiotics for lower airway infections.

PubMed

Quon, Bradley S; Goss, Christopher H; Ramsey, Bonnie W

2014-03-01

Inhaled antibiotics have been used to treat chronic airway infections since the 1940s. The earliest experience with inhaled antibiotics involved aerosolizing antibiotics designed for parenteral administration. These formulations caused significant bronchial irritation due to added preservatives and nonphysiologic chemical composition. A major therapeutic advance took place in 1997, when tobramycin designed for inhalation was approved by the U.S. Food and Drug Administration (FDA) for use in patients with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa infection. Attracted by the clinical benefits observed in CF and the availability of dry powder antibiotic formulations, there has been a growing interest in the use of inhaled antibiotics in other lower respiratory tract infections, such as non-CF bronchiectasis, ventilator-associated pneumonia, chronic obstructive pulmonary disease, mycobacterial disease, and in the post-lung transplant setting over the past decade. Antibiotics currently marketed for inhalation include nebulized and dry powder forms of tobramycin and colistin and nebulized aztreonam. Although both the U.S. Food and Drug Administration and European Medicines Agency have approved their use in CF, they have not been approved in other disease areas due to lack of supportive clinical trial evidence. Injectable formulations of gentamicin, tobramycin, amikacin, ceftazidime, and amphotericin are currently nebulized "off-label" to manage non-CF bronchiectasis, drug-resistant nontuberculous mycobacterial infections, ventilator-associated pneumonia, and post-transplant airway infections. Future inhaled antibiotic trials must focus on disease areas outside of CF with sample sizes large enough to evaluate clinically important endpoints such as exacerbations. Extrapolating from CF, the impact of eradicating organisms such as P. aeruginosa in non-CF bronchiectasis should also be evaluated.

Percutaneous Management of Systemic Fungal Infection Presenting As Bilateral Renal Fungal Ball

PubMed Central

Shukla, Abhishek; Shrivastava, Nitin; Singh, Chirom Amit

2016-01-01

Abstract Background: Zygomycoses are uncommon, frequently fatal diseases caused by fungi of the class Zygomycetes. The majority of human cases are caused by Mucorales (genus—rhizopus, mucor, and absidia) fungi. Renal involvement is uncommon and urine microscopy, pottasium hydroxide mount, and fungal cultures are frequently negative. Case Presentation: A twenty-one-year-old young unmarried lady presented to our emergency department with bilateral flank pain, fever, nausea, and decreased urine output of one-month duration. She was found to have azotemia with sepsis with bilateral hydronephrosis with a left renal pelvic obstructing stone. Even after nephrostomy drainage and broad spectrum antibiotics, her condition worsened. She developed disseminated fungal infection, and timely systemic antifungal followed by bilateral nephroscopic clearance saved the patient. Conclusion: Although renal fungal infections are uncommon, a high index of suspicion and early antifungal and surgical intervention can give favorable outcomes. PMID:27704055

Percutaneous Management of Systemic Fungal Infection Presenting As Bilateral Renal Fungal Ball.

PubMed

Shukla, Abhishek; Shrivastava, Nitin; Singh, Chirom Amit; Nayak, Brusabhanu

2016-01-01

Background: Zygomycoses are uncommon, frequently fatal diseases caused by fungi of the class Zygomycetes. The majority of human cases are caused by Mucorales (genus-rhizopus, mucor, and absidia) fungi. Renal involvement is uncommon and urine microscopy, pottasium hydroxide mount, and fungal cultures are frequently negative. Case Presentation: A twenty-one-year-old young unmarried lady presented to our emergency department with bilateral flank pain, fever, nausea, and decreased urine output of one-month duration. She was found to have azotemia with sepsis with bilateral hydronephrosis with a left renal pelvic obstructing stone. Even after nephrostomy drainage and broad spectrum antibiotics, her condition worsened. She developed disseminated fungal infection, and timely systemic antifungal followed by bilateral nephroscopic clearance saved the patient. Conclusion: Although renal fungal infections are uncommon, a high index of suspicion and early antifungal and surgical intervention can give favorable outcomes.

Humoral Immune Responses of White-tailed Deer (Odocoileus virginianus) to Mycobacterium bovis BCG Vaccination and Experimental Challenge with M. bovis

USDA-ARS?s Scientific Manuscript database

Monitoring serum antibody production kinetics to multiple mycobacterial antigens can be useful as a diagnostic tool for the detection of Mycobacterium bovis infection as well as for the characterization of disease progression and efficacy of intervention strategies in several species. Humoral immun...

ESRRA (estrogen-related receptor α) is a key coordinator of transcriptional and post-translational activation of autophagy to promote innate host defense.

PubMed

Kim, Soo Yeon; Yang, Chul-Su; Lee, Hye-Mi; Kim, Jin Kyung; Kim, Yi-Sak; Kim, Ye-Ram; Kim, Jae-Sung; Kim, Tae Sung; Yuk, Jae-Min; Dufour, Catherine Rosa; Lee, Sang-Hee; Kim, Jin-Man; Choi, Hueng-Sik; Giguère, Vincent; Jo, Eun-Kyeong

2018-01-01

The orphan nuclear receptor ESRRA (estrogen-related receptor α) is a key regulator of energy homeostasis and mitochondrial function. Macroautophagy/autophagy, an intracellular degradation process, is a critical innate effector against intracellular microbes. Here, we demonstrate that ESRRA is required for the activation of autophagy to promote innate antimicrobial defense against mycobacterial infection. AMP-activated protein kinase pathway and SIRT1 (sirtuin 1) activation led to induction of ESRRA, which is essential for autophagosome formation, in bone marrow-derived macrophages. ESRRA enhanced the transcriptional activation of numerous autophagy-related (Atg) genes containing ERR response elements in their promoter regions. Furthermore, ESRRA, operating in a feed-forward loop with SIRT1, was required for autophagy activation through deacetylation of ATG5, BECN1, and ATG7. Importantly, ESRRA deficiency resulted in a decrease of phagosomal maturation and antimicrobial responses against mycobacterial infection. Thus, we identify ESRRA as a critical activator of autophagy via both transcriptional and post-translational control to promote antimicrobial host responses.

Genotyping and drug susceptibility testing of mycobacterial isolates from population-based tuberculosis prevalence survey in Ghana.

PubMed

Addo, Kennedy Kwasi; Addo, Samuel Ofori; Mensah, Gloria Ivy; Mosi, Lydia; Bonsu, Frank Adae

2017-12-02

Mycobacterium tuberculosis complex (MTBC) and Non-tuberculosis Mycobacterium (NTM) infections differ clinically, making rapid identification and drug susceptibility testing (DST) very critical for infection control and drug therapy. This study aims to use World Health Organization (WHO) approved line probe assay (LPA) to differentiate mycobacterial isolates obtained from tuberculosis (TB) prevalence survey in Ghana and to determine their drug resistance patterns. A retrospective study was conducted whereby a total of 361 mycobacterial isolates were differentiated and their drug resistance patterns determined using GenoType Mycobacterium Assays: MTBC and CM/AS for differentiating MTBC and NTM as well MTBDRplus and NTM-DR for DST of MTBC and NTM respectively. Out of 361 isolates, 165 (45.7%) MTBC and 120 (33.2%) NTM (made up of 14 different species) were identified to the species levels whiles 76 (21.1%) could not be completely identified. The MTBC comprised 161 (97.6%) Mycobacterium tuberculosis and 4 (2.4%) Mycobacterium africanum. Isoniazid and rifampicin monoresistant MTBC isolates were 18/165 (10.9%) and 2/165(1.2%) respectively whiles 11/165 (6.7%) were resistant to both drugs. Majority 42/120 (35%) of NTM were M. fortuitum. DST of 28 M. avium complex and 8 M. abscessus complex species revealed that all were susceptible to macrolides (clarithromycin, azithromycin) and aminoglycosides (kanamycin, amikacin, and gentamicin). Our research signifies an important contribution to TB control in terms of knowledge of the types of mycobacterium species circulating and their drug resistance patterns in Ghana.

Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection

PubMed Central

Kalia, Nitin P.; Hasenoehrl, Erik J.; Ab Rahman, Nurlilah B.; Koh, Vanessa H.; Ang, Michelle L. T.; Sajorda, Dannah R.; Hards, Kiel; Grüber, Gerhard; Alonso, Sylvie; Cook, Gregory M.; Berney, Michael; Pethe, Kevin

2017-01-01

The recent discovery of small molecules targeting the cytochrome bc1:aa3 in Mycobacterium tuberculosis triggered interest in the terminal respiratory oxidases for antituberculosis drug development. The mycobacterial cytochrome bc1:aa3 consists of a menaquinone:cytochrome c reductase (bc1) and a cytochrome aa3-type oxidase. The clinical-stage drug candidate Q203 interferes with the function of the subunit b of the menaquinone:cytochrome c reductase. Despite the affinity of Q203 for the bc1:aa3 complex, the drug is only bacteriostatic and does not kill drug-tolerant persisters. This raises the possibility that the alternate terminal bd-type oxidase (cytochrome bd oxidase) is capable of maintaining a membrane potential and menaquinol oxidation in the presence of Q203. Here, we show that the electron flow through the cytochrome bd oxidase is sufficient to maintain respiration and ATP synthesis at a level high enough to protect M. tuberculosis from Q203-induced bacterial death. Upon genetic deletion of the cytochrome bd oxidase-encoding genes cydAB, Q203 inhibited mycobacterial respiration completely, became bactericidal, killed drug-tolerant mycobacterial persisters, and rapidly cleared M. tuberculosis infection in vivo. These results indicate a synthetic lethal interaction between the two terminal respiratory oxidases that can be exploited for anti-TB drug development. Our findings should be considered in the clinical development of drugs targeting the cytochrome bc1:aa3, as well as for the development of a drug combination targeting oxidative phosphorylation in M. tuberculosis. PMID:28652330

New Targets and Inhibitors of Mycobacterial Sulfur Metabolism§

PubMed Central

Paritala, Hanumantharao; Carroll, Kate S.

2015-01-01

The identification of new antibacterial targets is urgently needed to address multidrug resistant and latent tuberculosis infection. Sulfur metabolic pathways are essential for survival and the expression of virulence in many pathogenic bacteria, including Mycobacterium tuberculosis. In addition, microbial sulfur metabolic pathways are largely absent in humans and therefore, represent unique targets for therapeutic intervention. In this review, we summarize our current understanding of the enzymes associated with the production of sulfated and reduced sulfur-containing metabolites in Mycobacteria. Small molecule inhibitors of these catalysts represent valuable chemical tools that can be used to investigate the role of sulfur metabolism throughout the Mycobacterial lifecycle and may also represent new leads for drug development. In this light, we also summarize recent progress made in the development of inhibitors of sulfur metabolism enzymes. PMID:23808874

Pulmonary immune responses to Mycobacterium tuberculosis in exposed individuals

PubMed Central

Ernst, Martin; Lange, Christoph; Stenger, Steffen; Kaufmann, Stefan H. E.; Reiling, Norbert; Schaberg, Tom; van der Merwe, Lize; Maertzdorf, Jeroen

2017-01-01

Background Blood based Interferon-(IFN)-γ release assays (IGRAs) have a poor predictive value for the development of tuberculosis. This study aimed to investigate the correlation between IGRAs and pulmonary immune responses in tuberculosis contacts in Germany. Methods IGRAs were performed on bronchoalveolar lavage (BAL) cells and peripheral blood from close healthy contacts of patients with culturally confirmed tuberculosis. Cellular BAL composition was determined by flow cytometry. BAL cells were co-cultured with three strains of Mycobacterium tuberculosis (Mtb) and Mtb derived antigens including Purified Protein Derivative (PPD), 6 kD Early Secretory Antigenic Target (ESAT-6) and 10 kD Culture Filtrate Protein (CFP-10). Levels of 29 cytokines and chemokines were analyzed in the supernatants by multiplex assay. Associations and effects were examined using linear mixed-effects models. Results There were wide variations of inter-individual cytokine levels in BAL cell culture supernatants. Mycobacterial infection and stimulation with PPD showed a clear induction of several macrophage and lymphocyte associated cytokines, reflecting activation of these cell types. No robust correlation between cytokine patterns and blood IGRA status of the donor was observed, except for slightly higher Interleukin-2 (IL-2) responses in BAL cells from IGRA-positive donors upon mycobacterial infection compared to cells from IGRA-negative donors. Stronger correlations were observed when cytokine patterns were stratified according to BAL IGRA status. BAL cells from donors with BAL IGRA-positive responses produced significantly more IFN-γ and IL-2 upon PPD stimulation and mycobacterial infection than cells from BAL IGRA-negative individuals. Correlations between BAL composition and basal cytokine release from unstimulated cells were suggestive of pre-activated lymphocytes but impaired macrophage activity in BAL IGRA-positive donors, in contrast to BAL IGRA-negative donors. Conclusions In vitro BAL cell cytokine responses to M. tuberculosis antigens or infection do not reflect blood IGRA status but do correlate with stronger cellular responses in BAL IGRA-positive donors. The cytokine patterns observed suggest a pre-activated state of lymphocytes and suppressed macrophage responsiveness in BAL cells from BAL IGRA-positive individuals. PMID:29125874

Identification of uncommon oral yeasts from cancer patients by MALDI-TOF mass spectrometry.

PubMed

Aslani, Narges; Janbabaei, Ghasem; Abastabar, Mahdi; Meis, Jacques F; Babaeian, Mahasti; Khodavaisy, Sadegh; Boekhout, Teun; Badali, Hamid

2018-01-08

Opportunistic infections due to Candida species occur frequently in cancer patients because of their inherent immunosuppression. The aim of the present study was to investigate the epidemiology of yeast species from the oral cavity of patients during treatment for oncological and haematological malignancies. MALDI-TOF was performed to identify yeasts isolated from the oral cavity of 350 cancer patients. Moreover, antifungal susceptibility testing was performed in according to CLSI guidelines (M27-A3). Among 162 yeasts and yeast-like fungi isolated from the oral cavity of cancer patients, Candida albicans was the most common species (50.6%), followed by Candida glabrata (24.7%), Pichia kudriavzevii (Candida krusei (9.9%)), Candida tropicalis (4.3%), Candida dubliniensis (3.7%), Kluyveromyces marxianus (Candida kefyr (3.7%)) and Candida parapsilosis (1%). In addition, uncommon yeast species i.e., Saprochaete capitata, Saccharomyces cerevisiae, Clavispora lusitaniae (C. lusitaniae) and Pichia kluyveri (C. eremophila) were recovered from oral lesions. Oral colonization by C. albicans, non-albicans Candida species and uncommon yeasts were as follow; 55%, 44% and 1%, whereas oral infection due to C. albicans was 33.3%, non-albicans Candida species 60.6%, and uncommon yeasts 6.1%. Poor oral hygiene and xerostomia were identified as independent risk factors associated with oral yeast colonization. The overall resistance to fluconazole was 11.7% (19/162). Low MIC values were observed for anidulafungin for all Candida and uncommon yeast species. This current study provides insight into the prevalence and susceptibility profiles of Candida species, including emerging Candida species and uncommon yeasts, isolated from the oral cavity of Iranian cancer patients. The incidence of oral candidiasis was higher amongst patients with hematological malignancies. The majority of oral infections were caused by non-albicans Candida species which were often more resistant to anti-fungal agents. Our findings suggest that anidulafungin should be used as antifungal of choice for prophylaxis in clinically high-risk patients with documented oral colonization or infection.

Pseudoepidemic of Nocardia asteroides associated with a mycobacterial culture system.

PubMed Central

Patterson, J E; Chapin-Robertson, K; Waycott, S; Farrel, P; McGeer, A; McNeil, M M; Edberg, S C

1992-01-01

Nocardia isolations increased from 0.7 to 11.7/1,000 acid-fast bacillus and mycological cultures (P less than 0.000001). Only three isolations from one patient represented infection. Pseudoepidemic strain identity was confirmed by DNA fingerprinting; the isolate causing infection was distinct. The end of the pseudoepidemic was associated with changing the needle sterilizer and prolonging needle sterilization time on the BACTEC 460 machine. To our knowledge, this is the first reported Nocardia asteroides pseudoepidemic. Images PMID:1583150

Neutrophils Promote Mycobacterial Trehalose Dimycolate-Induced Lung Inflammation via the Mincle Pathway

PubMed Central

Lee, Wook-Bin; Kang, Ji-Seon; Yan, Ji-Jing; Lee, Myeong Sup; Jeon, Bo-Young; Cho, Sang-Nae; Kim, Young-Joon

2012-01-01

Trehalose 6,6′-dimycolate (TDM), a cord factor of Mycobacterium tuberculosis (Mtb), is an important regulator of immune responses during Mtb infections. Macrophages recognize TDM through the Mincle receptor and initiate TDM-induced inflammatory responses, leading to lung granuloma formation. Although various immune cells are recruited to lung granulomas, the roles of other immune cells, especially during the initial process of TDM-induced inflammation, are not clear. In this study, Mincle signaling on neutrophils played an important role in TDM-induced lung inflammation by promoting adhesion and innate immune responses. Neutrophils were recruited during the early stage of lung inflammation following TDM-induced granuloma formation. Mincle expression on neutrophils was required for infiltration of TDM-challenged sites in a granuloma model induced by TDM-coated-beads. TDM-induced Mincle signaling on neutrophils increased cell adherence by enhancing F-actin polymerization and CD11b/CD18 surface expression. The TDM-induced effects were dependent on Src, Syk, and MAPK/ERK kinases (MEK). Moreover, coactivation of the Mincle and TLR2 pathways by TDM and Pam3CSK4 treatment synergistically induced CD11b/CD18 surface expression, reactive oxygen species, and TNFα production by neutrophils. These synergistically-enhanced immune responses correlated with the degree of Mincle expression on neutrophil surfaces. The physiological relevance of the Mincle-mediated anti-TDM immune response was confirmed by defective immune responses in Mincle−/− mice upon aerosol infections with Mtb. Mincle-mutant mice had higher inflammation levels and mycobacterial loads than WT mice. Neutrophil depletion with anti-Ly6G antibody caused a reduction in IL-6 and monocyte chemotactic protein-1 expression upon TDM treatment, and reduced levels of immune cell recruitment during the initial stage of infection. These findings suggest a new role of Mincle signaling on neutrophils during anti-mycobacterial responses. PMID:22496642

Enlarged Dural Sac in Idiopathic Bronchiectasis Implicates Heritable Connective Tissue Gene Variants

PubMed Central

Birchard, Katherine R.; Lowe, Jared R.; Patrone, Michael V.

2016-01-01

Rationale: Patients with idiopathic bronchiectasis are predominantly female and have an asthenic body morphotype and frequent nontuberculous mycobacterial respiratory infections. They also demonstrate phenotypic features (scoliosis, pectus deformity, mitral valve prolapse) that are commonly seen in individuals with heritable connective tissue disorders. Objectives: To determine whether lumbar dural sac size is increased in patients with idiopathic bronchiectasis as compared with control subjects, and to assess whether dural sac size is correlated with phenotypic characteristics seen in individuals with heritable connective tissue disorders. Methods: Two readers blinded to diagnosis measured anterior–posterior and transverse dural sac diameter using L1–L5 magnetic resonance images of 71 patients with idiopathic bronchiectasis, 72 control subjects without lung disease, 29 patients with cystic fibrosis, and 24 patients with Marfan syndrome. We compared groups by pairwise analysis of means, using Tukey’s method to adjust for multiple comparisons. Dural sac diameter association with phenotypic and clinical features was also tested. Measurements and Main Results: The L1–L5 (average) anterior–posterior dural sac diameter of the idiopathic bronchiectasis group was larger than those of the control group (P < 0.001) and the cystic fibrosis group (P = 0.002). There was a strong correlation between increased dural sac size and the presence of pulmonary nontuberculous mycobacterial infection (P = 0.007) and long fingers (P = 0.003). A trend toward larger dural sac diameter was seen in those with scoliosis (P = 0.130) and those with a family history of idiopathic bronchiectasis (P = 0.149). Conclusions: Individuals with idiopathic bronchiectasis have an enlarged dural sac diameter, which is associated with pulmonary nontuberculous mycobacterial infection, long fingers, and family history of idiopathic bronchiectasis. These findings support our hypothesis that “idiopathic” bronchiectasis development reflects complex genetic variation in heritable connective tissue and associated transforming growth factor-β–related pathway genes. PMID:27409985

Unusual Methylobacterium fujisawaense Infection in a Patient with Acute Leukaemia Undergoing Hematopoietic Stem Cell Transplantation: First Case Report

PubMed Central

Fanci, Rosa; Corti, Giampaolo; Bartoloni, Alessandro; Tortoli, Enrico; Mariottini, Alessandro; Pecile, Patrizia

2010-01-01

Microorganisms of the genus Methylobacterium are facultative methylotrophic, gram-negative rods that are ubiquitous in nature and rarely cause human disease, mostly in subjects with preexisting causes of immune depression. Methylobacterium fujisawaense, first proposed as a new species in 1988, has never been reported as a bacterial agent of human infections so far. Here we describe a case of M. fujisawaense infection in a relapsed acute leukaemia undergoing unrelated allogeneic hematopoietic stem cell transplantation. Molecular identification of an M. fujisawaense strain was obtained from multiple mycobacterial blood cultures. PMID:20396386

The P-type ATPase CtpG preferentially transports Cd2+ across the Mycobacterium tuberculosis plasma membrane.

PubMed

López, Marcela; Quitian, Laudy-Viviana; Calderón, Martha-Nancy; Soto, Carlos-Y

2018-04-01

P 1B -type ATPases are involved in heavy metal transport across the plasma membrane. Some Mycobacterium tuberculosis P-type ATPases are induced during infection, suggesting that this type of transporter could play a critical role in mycobacterial survival. To date, the ion specificity of M. tuberculosis heavy metal-transporting P 1B -ATPases is not well understood. In this work, we observed that, although divalent heavy metal cations such as Cu 2+ , Co 2+ , Ni 2+ , Zn 2+ Cd 2+ and Pb 2+ stimulate the ATPase activity of the putative P 1B -type ATPase CtpG in the plasma membrane, whole cells of M. smegmatis expressing CtpG only tolerate high levels of Cd 2+ and Cu 2+ . As indicator of the catalytic constant, Michaelis-Menten kinetics showed that CtpG embedded in the mycobacterial cell membrane has a V max /K m ratio 7.4-fold higher for Cd 2+ than for Cu 2+ ions. Thus, although CtpG can accept different substrates in vitro, this P-type ATPase transports Cd 2+ more efficiently than other heavy metal cations across the mycobacterial plasma membrane.

Naive helper T cells from BCG-vaccinated volunteers produce IFN-gamma and IL-5 to mycobacterial antigen-pulsed dendritic cells.

PubMed

Kowalewicz-Kulbat, Magdalena; Kaźmierczak, Dominik; Donevski, Stefan; Biet, Franck; Pestel, Joël; Rudnicka, Wiesława

2008-01-01

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is a live vaccine that has been used in routine vaccination against tuberculosis for nearly 80 years. However, its efficacy is controversial. The failure of BCG vaccination may be at least partially explained by the induction of poor or inappropriate host responses. Dendritic cells (DCs) are likely to play a key role in the induction of immune response to mycobacteria by polarizing the reactivity of T lymphocytes toward a Th1 profile, contributing to the generation of protective cellular immunity against mycobacteria. In this study we aimed to investigate the production of Th1 and Th2 cytokines by naive CD4+ T cells to mycobacterial antigen-pulsed DCs in the group of young, healthy BCG vaccinated volunteers. The response of naive helper T cells was compared with the response of total blood lymphocytes. Our present results clearly showed that circulating naive CD45RA+CD4+ lymphocytes from BCG-vaccinated subjects can become effector helper cells producing IFN-gamma and IL-5 under the stimulation by autologous dendritic cells presenting mycobacterial protein antigen-PPD or infected with live M. bovis BCG bacilli.

Mycobacterium tuberculosis surface protein Rv0227c contains high activity binding peptides which inhibit cell invasion.

PubMed

Rodríguez, Diana Marcela; Ocampo, Marisol; Curtidor, Hernando; Vanegas, Magnolia; Patarroyo, Manuel Elkin; Patarroyo, Manuel Alfonso

2012-12-01

Mycobacterium tuberculosis surface proteins involved in target cell invasion may be identified as a strategy for developing subunit-based, chemically-synthesized vaccines. The Rv0227c protein was thus selected to assess its role in the invasion and infection of Mycobacterium tuberculosis target cells. Results revealed Rv0227c localization on mycobacterial surface by immunoelectron microscopy and Western blot. Receptor-ligand assays using 20-mer, non-overlapping peptides covering the complete Rv0227c protein sequence revealed three high activity binding peptides for U937 phagocytic cells and seven for A549 cells. Peptide 16944 significantly inhibited mycobacterial entry to both cell lines while 16943 and 16949 only managed to inhibit entrance to U937 cells and 16951 to A549 cells. The Jnet bioinformatics tool predicted secondary structure elements for the complete protein, agreeing with elements determined for such chemically-synthesized peptides. It was thus concluded that high activity binding peptides which were able to inhibit mycobacterial entry to target cells are of great importance when selecting peptide candidates for inclusion in an anti-tuberculosis vaccine. Copyright © 2012 Elsevier Inc. All rights reserved.

Nitric Oxide Production Inhibition and Anti-Mycobacterial Activity of Extracts and Halogenated Sesquiterpenes from the Brazilian Red Alga Laurencia Dendroidea J. Agardh

PubMed Central

Biá Ventura, Thatiana Lopes; da Silva Machado, Fernanda Lacerda; de Araujo, Marlon Heggdorne; de Souza Gestinari, Lísia Mônica; Kaiser, Carlos Roland; de Assis Esteves, Francisco; Lasunskaia, Elena B.; Soares, Angélica Ribeiro; Muzitano, Michelle Frazão

2015-01-01

Background: Red algae of the genus Laurencia J. V. Lamouroux are a rich source of secondary metabolites with important pharmacological activities such as anti-tumoral, anti-inflammatory, anti-fungal, anti-viral, anti-leishmanial, anti-helminthic, anti-malarial, anti-trypanosomal, anti-microbial as well as anti-bacterial against Mycobacterium tuberculosis. Objective: In the present study, we evaluated the inhibition of nitric oxide (NO) and tumor necrosis factor-α production and the anti-mycobacterial activity of crude extracts from the red Alga Laurencia dendroidea (from the South-Eastern coast of Brazil). Halogenated sesquiterpenes elatol (1), obtusol (2) and cartilagineol (3), previously isolated from this Alga by our group, were also studied. Materials and Methods: The lipopolysaccharide-activated macrophage cells (RAW 264.7) were used as inflammation model. Cytotoxic effect was determined using a commercial lactate dehydrogenase (LDH) kit and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The growing Mycobacterium inhibition was verified against Mycobacterium bovis Bacillus Calmette–Guérin and M. tuberculosis H37 Rv strains. Results: The crude extract from Alga collected at Angra dos Reis, RJ, Brazil, was the most active inhibitor of both mycobacterial growth (half maximal inhibitory concentration [IC50] 8.7 ± 1.4 μg/mL) and NO production by activated macrophages (IC50 5.3 ± 1.3 μg/mL). The assays with isolated compounds revealed the anti-mycobacterial activity of obtusol (2), whereas (-)-elatol (1) inhibited the release of inflammatory mediators, especially NO. To our knowledge, this is the first report describing an anti-mycobacterial effect of L. dendroidea extract and demonstrating the association of this activity with obtusol (2). Conclusion: The described effects of active compounds from L. dendroidea are promising for the control of inflammation in infectious diseases and specifically, against mycobacterial infections associated with exacerbated inflammation. SUMMARY Inflammation is strongly involved in the pathogenesis of most infectious diseases, including TB. The treatment of TB is based on the use of anti mycobacterial drugs, however the most severe forms of TB, require additional anti inflammatory therapy to prevent excessive inflammation. A combination of these properties in one compound could provide additional therapeutic benefits. In this work, we studied L. dendroidea extracts and purified compounds and demonstrated that the LDA extract and (-)-elatol (1) were potent in inhibiting NO production by macrophages through the specific inhibition of iNOS expression. The LDA and LDM extracts and obtusol (2) were active against virulent strain of M. tuberculosis. This is the first report demonstrating that the anti-inflammatory activities of L. dendroidea were associated with the presence of (-)-elatol (1), whereas anti-mycobacterial activities of L. dendroidea extracts were associated with obtusol (2). PMID:27013803

Association of GATA2 Deficiency With Severe Primary Epstein-Barr Virus (EBV) Infection and EBV-associated Cancers.

PubMed

Cohen, Jeffrey I; Dropulic, Lesia; Hsu, Amy P; Zerbe, Christa S; Krogmann, Tammy; Dowdell, Kennichi; Hornung, Ronald L; Lovell, Jana; Hardy, Nancy; Hickstein, Dennis; Cowen, Edward W; Calvo, Katherine R; Pittaluga, Stefania; Holland, Steven M

2016-07-01

Most patients infected with Epstein-Barr virus (EBV) are asymptomatic, have nonspecific symptoms, or have self-limiting infectious mononucleosis. EBV, however, may result in severe primary disease or cancer. We report EBV diseases associated with GATA2 deficiency at one institution and describe the hematology, virology, and cytokine findings. Seven patients with GATA2 deficiency developed severe EBV disease. Three presented with EBV infectious mononucleosis requiring hospitalization, 1 had chronic active EBV disease (B-cell type), 1 had EBV-associated hydroa vacciniforme-like lymphoma with hemophagocytic lymphohistiocytosis, and 2 had EBV-positive smooth muscle tumors. Four of the 7 patients had severe warts and 3 had disseminated nontuberculous mycobacterial infections. All of the patients had low numbers of monocytes, B cells, CD4 T cells, and natural killer cells. All had elevated levels of EBV in the blood; 2 of 3 patients tested had expression of the EBV major immediate-early gene in the blood indicative of active EBV lytic infection. Mean plasma levels of tumor necrosis factor α, interferon γ, and interferon gamma-induced protein 10 were higher in patients with GATA2 deficiency than in controls. GATA2 is the first gene associated with EBV hydroa vacciniforme-like lymphoma. GATA2 deficiency should be considered in patients with severe primary EBV infection or EBV-associated cancer, especially in those with disseminated nontuberculous mycobacterial disease and warts. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Characterization of mycobacteria in HIV/AIDS patients of Nepal.

PubMed

Dhungana, G P; Ghimire, P; Sharma, S; Rijal, B P

2008-01-01

Besides Mycobacterium tuberculosis, a number of other Mycobacterium species are also occasional human pathogens. Tuberculosis due to Mycobacterium avium complex (MAC) and Mycobacterium kansasii is particularly prevalent in AIDS patients as compared to the normal population. A cross-sectional study was carried out during January 2004 to August 2005 in 100 HIV-infected persons visiting Tribhuvan University, Teaching Hospital, and about a dozen of HIV/AIDS care centers of Kathmandu with the objectives to characterize the different mycobacterial species in HIV/AIDS patients. Three sputum specimens from each person were used to investigate tuberculosis by Ziehl-Neelsen staining, culture and identification tests. Among the 100 HIV-infected cases, 66 (66%) were males and 34 (34%) were females. Sixty percent of the cases were in the age group of 21-30 years. Mycobacteria were detected in 23 (23%) HIV cases of which 15 (65.2%) were in the age group of 21-30 years ; 17(74%) were males and 6 (26 %) were females. Among 23 co-infected cases, 22 were culture positive for mycobacteria. Among these, the predominant one was Mycobacterium avium complex (MAC), 9 (41%), followed by M. tuberculosis, 6 (27%), M .kansasii, 4 (18%), M. fortuitum, 2 (10%) and M. chelonae 1 (4%). Significant relationship was established between smoking/alcoholism and the subsequent development of tuberculosis (chi(2)=7.24, p<0.05 for smoking habit and chi(2)=4.39, p<0.05 for alcoholism). Fourteen (61%) co-infected cases presented with weight loss and cough whereas diarrhea was presented only by those patients with atypical mycobacterial co-infection, which was as high as 5 (56%) in patients with MAC co-infection. This study demonstrated the predominance of atypical mycobacteria, mainly MAC, in HIV/AIDS cases and most of them were from sputum smear-negative cases.

IL17A augments autophagy in Mycobacterium tuberculosis-infected monocytes from patients with active tuberculosis in association with the severity of the disease.

PubMed

Tateosian, Nancy Liliana; Pellegrini, Joaquín Miguel; Amiano, Nicolás Oscar; Rolandelli, Agustín; Casco, Nicolás; Palmero, Domingo Juan; Colombo, María Isabel; García, Verónica Edith

2017-07-03

During mycobacterial infection, macroautophagy/autophagy, a process modulated by cytokines, is essential for mounting successful host responses. Autophagy collaborates with human immune responses against Mycobacterium tuberculosis (Mt) in association with specific IFNG secreted against the pathogen. However, IFNG alone is not sufficient to the complete bacterial eradication, and other cytokines might be required. Actually, induction of Th1 and Th17 immune responses are required for protection against Mt. Accordingly, we showed that IL17A and IFNG expression in lymphocytes from tuberculosis patients correlates with disease severity. Here we investigate the role of IFNG and IL17A during autophagy in monocytes infected with Mt H37Rv or the mutant MtΔRD1. Patients with active disease were classified as high responder (HR) or low responder (LR) according to their T cell responses against Mt. IL17A augmented autophagy in infected monocytes from HR patients through a mechanism that activated MAPK1/ERK2-MAPK3/ERK1 but, during infection of monocytes from LR patients, IL17A had no effect on the autophagic response. In contrast, addition of IFNG to infected monocytes, increased autophagy by activating MAPK14/p38 α both in HR and LR patients. Interestingly, proteins codified in the RD1 region did not interfere with IFNG and IL17A autophagy induction. Therefore, in severe tuberculosis patients' monocytes, IL17A was unable to augment autophagy because of a defect in the MAPK1/3 signaling pathway. In contrast, both IFNG and IL17A increased autophagy levels in patients with strong immunity to Mt, promoting mycobacterial killing. Our findings might contribute to recognize new targets for the development of novel therapeutic tools to fight the pathogen.

Non-tuberculous mycobacterial infection of the musculoskeletal system: pattern of infection and efficacy of combined surgical/antimicrobial treatment.

PubMed

Park, J W; Kim, Y S; Yoon, J O; Kim, J S; Chang, J S; Kim, J M; Chun, J M; Jeon, I H

2014-11-01

Non-tuberculous mycobacterial (NTM) infection of the musculoskeletal tissue is a rare disease. An early and accurate diagnosis is often difficult because of the indolent clinical course and difficulty of isolating pathogens. Our goal was to determine the clinical features of musculoskeletal NTM infection and to present the treatment outcomes. A total of 29 patients (nine females, 20 males between 34 and 85 years old, mean age 61.7 years; 34 to 85) with NTM infection of the musculoskeletal system between 1998 to 2011 were identified and their treatment retrospectively analysed. Microbiological studies demonstrated NTM in 29 patients: the isolates were Mycobacterium intracellulare in six patients, M. fortuitum in three, M. abscessus in two and M. marinum in one. In the remaining patients we failed to identify the species. The involved sites were the hand/wrist in nine patients the knee in five patients, spine in four patients, foot in two patients, elbow in two patients, shoulder in one, ankle in two patients, leg in three patients and multiple in one patient. The mean interval between the appearance of symptoms and diagnosis was 20.8 months (1.5 to 180). All patients underwent surgical treatment and antimicrobial medication according to our protocol for chronic musculoskeletal infection: 20 patients had NTM-specific medication and nine had conventional antimicrobial therapy. At the final follow-up 22 patients were cured, three failed to respond to treatment and four were lost to follow-up. Identifying these diseases due the initial non-specific presentation can be difficult. Treatment consists of surgical intervention and adequate antimicrobial therapy, which can result in satisfactory outcomes. ©2014 The British Editorial Society of Bone & Joint Surgery.

In Vivo Assessment of Drug Efficacy against Mycobacterium abscessus Using the Embryonic Zebrafish Test System

PubMed Central

Bernut, Audrey; Le Moigne, Vincent; Lesne, Tiffany; Lutfalla, Georges; Herrmann, Jean-Louis

2014-01-01

Mycobacterium abscessus is responsible for a wide spectrum of clinical syndromes and is one of the most intrinsically drug-resistant mycobacterial species. Recent evaluation of the in vivo therapeutic efficacy of the few potentially active antibiotics against M. abscessus was essentially performed using immunocompromised mice. Herein, we assessed the feasibility and sensitivity of fluorescence imaging for monitoring the in vivo activity of drugs against acute M. abscessus infection using zebrafish embryos. A protocol was developed where clarithromycin and imipenem were directly added to water containing fluorescent M. abscessus-infected embryos in a 96-well plate format. The status of the infection with increasing drug concentrations was visualized on a spatiotemporal level. Drug efficacy was assessed quantitatively by measuring the index of protection, the bacterial burden (CFU), and the number of abscesses through fluorescence measurements. Both drugs were active in infected embryos and were capable of significantly increasing embryo survival in a dose-dependent manner. Protection from bacterial killing correlated with restricted mycobacterial growth in the drug-treated larvae and with reduced pathophysiological symptoms, such as the number of abscesses within the brain. In conclusion, we present here a new and efficient method for testing and compare the in vivo activity of two clinically relevant drugs based on a fluorescent reporter strain in zebrafish embryos. This approach could be used for rapid determination of the in vivo drug susceptibility profile of clinical isolates and to assess the preclinical efficacy of new compounds against M. abscessus. PMID:24798271

Round pneumonia in an adult.

PubMed

Zhang, Yi; Yu, Yong-Sheng; Tang, Zheng-Hao; Chen, Xiao-Hua; Zang, Guo-Qing

2014-01-01

Round pneumonia is an uncommon form of pulmonary infection usually found in children. It may resemble pulmonary neoplasm on radiographs. We present a case of round pneumonia in a 43-year-old male with a history of smoking and a family history of lung cancer. The patient was treated with antibiotics for more than two weeks, after which the infection resolved completely both clinically and radiologically. Clinicians should consider this uncommon type of pneumonia in the differential diagnosis of spherical pulmonary masses to avoid unnecessary diagnostic tests.

Epidemiology of salivary gland infections.

PubMed

Cascarini, Luke; McGurk, Mark

2009-08-01

This article approaches sialadenitis from a personal perspective based on 15 years of clinical practice limited mainly to salivary gland diseases. Disorders of the salivary glands are uncommon. When they occur, experience in managing the process is diluted over a range of disciplines. The result is that traditional views go unchallenged and are recast unchanged from one textbook to another. Sialadenitis of bacterial origin is a relatively uncommon occurrence today and is normally associated with sialoliths. The most common viral infection of the salivary glands is mumps.

Mycobacterial peritonitis: difference between non-tuberculous mycobacteria and Mycobacterium tuberculosis.

PubMed

Shu, C-C; Wang, J-T; Wang, J-Y; Yu, C-J; Lee, L-N

2012-03-01

Unlike tuberculous peritonitis, peritonitis due to non-tuberculous mycobacteria (NTM) has unclear clinical manifestations. This study aimed to clarify the clinical manifestations and laboratory results of NTM peritonitis and compare it to tuberculous peritonitis. This retrospective study was conducted from 2000 to 2008 in a medical centre in Taiwan. Patients with mycobacteria isolated from ascites were identified and compared according to causative pathogens (Mycobacterium tuberculosis or NTM). Those with NTM peritonitis were further classified into the 'probable' and 'possible' groups based on diagnostic evidence. Twenty-five patients with NTM peritonitis and 65 with tuberculous peritonitis were reviewed. Mycobacterium avium complex was the most common NTM pathogen (52%). There was no obvious difference between the 'probable' and 'possible' NTM peritonitis groups regarding age and laboratory data. Patients with NTM peritonitis and those with tuberculous peritonitis had no differences in age or gender but varied in symptoms and serum laboratory data. NTM peritonitis was 100% associated with underlying co-morbidities and had lower proportions of lymphocytes and albumin level in ascites. Twelve (48%) NTM peritonitis and 21 (32%) tuberculous peritonitis patients died during the 6-month follow-up. Anti-mycobacterial treatment, but not mycobacterial species, was correlated with better 6-month survival. In Taiwan, NTM is responsible for 28% of mycobacterial peritonitis cases, which have a poor prognosis if untreated. There are some differences in clinical manifestations between NTM and tuberculous peritonitis. NTM peritonitis should be considered in patients with peritonitis but without causative microorganisms identified other than NTM. © 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.

Pulmonary Non-tuberculous Mycobacterial Infections in Category II Failures from National Tuberculosis Programme.

PubMed

Dholakia, Y N; Shah, D P

2015-01-01

Pulmonary infections due to non-tuberculous mycobacteria (NTM) are increasingly being reported. These can mimic drug-resitant tubercuolosis. A diagnosis of NTM infections needs a high degree of clinical suspicion and repeated isolation of the organism on culture. NTM infections occur commonly in immunocompromised individuals and in people with lung abnormalities. Currently there are no guidelines on drug combinations and the duration of treatment is not adequately defined. Two cases of pulmonary infection with NTM in immune-competent individuals are described in the present report. Although the bacteriological, radiological and clinical response to treatment was good; early discontinuation of treatment resulted in recurrence and change in drug susceptibility pattern, suggesting the need for prolonged treatment for achieving cure.

Protective activity of Lentinan in experimental tuberculosis.

PubMed

Markova, Nadya; Kussovski, Vesselin; Drandarska, Ivanka; Nikolaeva, Sascha; Georgieva, Neli; Radoucheva, Tatyana

2003-10-01

Protective effects of Lentinan (Ajinomoto, Japan) against Mycobacterium tuberculosis infection were studied by in vitro and in vivo mouse models. The effectiveness of Lentinan administrated intraperitoneally (i.p.) before infection at a dose of 1 mg/kg three times at 2-day intervals was monitored in vivo by several parameters (body temperature; spleen weight; CFU counts of M. tuberculosis in spleen, liver and lung; and histomorphological observations). Peritoneal macrophages obtained from animals treated with Lentinan were greatly stimulated, as assayed by establishing their number, acid phosphatase activity, H2O2 production and killing ability against M. tuberculosis in vitro. The in vivo model demonstrated that administration of Lentinan before infection can mobilize host defense potential and reduce mycobacterial infection.

[Development of antituberculous drugs: current status and future prospects].

PubMed

Tomioka, Haruaki; Namba, Kenji

2006-12-01

Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (MTB), the etiologic agent of TB. The World Health Organization estimates that about eight to ten million new TB cases occur annually worldwide and the incidence of TB is currently increasing. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and approximately two million deaths are attributable to TB annually. In particular, pulmonary TB, the most common form of TB, is a highly contagious and life-threatening infection. Moreover, enhanced susceptibility to TB in HIV-infected populations is another serious health problem throughout the world. In addition, multidrug-resistant TB (MDR-TB) has been increasing in incidence in many areas, not only in developing countries but industrialized countries as well, during the past decade. These situations, particularly the global resurgence of TB and the rapid emergence of MDR-TB, underscore the importance of the development of new antituberculous drugs and new protocols for efficacious clinical control of TB patients using ordinary antimycobacterial drugs. Concerning the development of new antituberculous drugs, the following points are of particular importance. (1) Development of drugs which display lasting antimycobacterial activity in vivo is desirable, since they can be administered with long intervals and consequently facilitate directly observed therapy and enhance patient compliance. (2) Development of novel antituberculosis compounds to combat MDR-TB is urgently needed. (3) The eradication of slowly metabolizing and, if possible, dormant populations of MTB organisms that cause relapse, using new classes of anti-TB drugs is very promising for prevention of TB incidence, because it will markedly reduce the incidence of active TB from persons who are latently infected with MTB. Unfortunately, no new drugs except rifabutin and rifapentine has been marketed for TB in the US and other countries during the 40 years after release of rifampicin. There are a number of constraints that have deterred companies from investing in new anti-TB drugs. The research is expensive, slow and difficult, and requires specialized facilities for handling MTB. There are few animal models that closely mimic the human TB disease. Development time of any anti-TB drug will be long. In fact, clinical trials will require the minimum six-month therapy, with a follow-up period of one year or more. In addition, it is hard to demonstrate obvious benefit of a new anti-TB agents over pre-existing drugs, since clinical trials involve multidrug combination therapy using highly effective ordinary anti-TB drugs. Finaly, there is the perceived lack of commercial return to companies engaged in the development of new anti-TB drugs, because over 95% of TB cases worldwide are in developing countries. In this symposium, we reviewed the following areas. 1. Critical new information on the entire genome of MTB recently obtained and increasing knowledge of various mycobacterial virulence genes are greatly promoting the identification of genes that code for new drug targets. In this context, Dr. Namba reviewed the status of new types of compounds which are being developed as anti-TB drug. He also discussed the development of new antimycobacterial drugs according to new and potential pharmacological targets and the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Using such findings for mycobacterial genomes, bioinformatics/genomics/proteomics-based drug design and drug development using quantitative structure-activity relationships may be possible in the near future. In this context, Dr. Suwa and Dr. Suzuki reviewed the usefulness of chemical genomics in searching novel drug targets for development of new antituberculous drugs. The authors reviewed (1) the history and present status of chemical genomics that is defined as the systemic search for a selective small molecular modulator for each function of all gene products, (2) recent studies of the authors on profiles of the interactions between various kinds of human proteins and small molecule modulators using the new technology devised by Reverse Proteomics Research Institute, and (3) future prospects of the development of new antituberculous drugs based on chemical genomics. 3. It appears also promising to develop new types of drug administration systems using drug vehicles, which enable efficacious drug delivery to their target in vivo. Dr. Izumikawa, Dr. Ohno and Dr. Kohno reviewed the usefulness of liposome- and polymer-based technologies, which enable efficacious delivery of encapsulated drugs at required doses for prolonged periods of time with only a single shot without toxicity, and also enable highly targeted delivery of drugs to their target in vivo. They indicated that the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better clinical outcome. 4. Immunoadjunctive therapy appears to be promising in improving outcome of clinical control of refractory mycobacterial infections, including MDR-TB and M. avium complex infection. Dr. Shimizu, Dr. Sato and Dr. Tomioka reviewed the present status of immunotherapy of mycobacterial infections in combination with antimycobacterial drugs. They indicated that the development of new classes of immunomodulators other than cytokines (IL-2, IFN-gamma, GM-CSF, IL-12, etc.) particularly those with no severe side-effects, are urgently needed. Their review dealed with some promising immunoadjunctive agents, especially ATP and its analogues, which potentiate macrophage antimycobacterial activity via purinergic P2 receptors. The aim of this symposium is to address the future prospects of the development of new drugs and drug regimens for anti-TB chemotherapy. There are a number of difficulties in drug-design for the development of new drug formulations with increased potential for antimycobacterial effects, excellent pharmacokinetics, and tolerability. It should be emphasized that the most urgent goal of chemotherapy of TB and MAC infections, especially that associated with HIV infection, is to develop highly active, low-cost drugs which can be used not only in industrialized countries but also in developing countries, since the incidences of AIDS-associated intractable TB and MAC infections are rapidly increasing in the latter. We strongly wish a great advance of fundametal and practical studies in developing such kinds of new anti-TB drugs in the near future. 1. Prospects for non-clinical or clinical development of new antituberculous drugs in relation to corporate strategy: Kenji NAMBA (New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd.) Tuberculosis (TB) remains one of the deadliest threats to public health. No new anti-TB drugs have been brought into the clinic in the past 40 years. Current non-clinical works with progressed technology and Global Alliance for TB Drug Development, a non-profit organization established in 2000, accelerate research and development of faster-acting anti-TB compounds. We reviewed the status of new types of compounds which are being developed as anti-TB drug, such as diarylquinoline (TMC 207), nitroimidazole (PA-824 and OPC-67683), and moxifloxacin (MFLX). We also discussed the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Exploring novel drug targets through the chemical genomics approach and its possible application to the development of anti-tuberculosis drugs: Yorimasa SUWA (Reverse Proteomics Research Institute Co., Ltd.), Yohji SUZUKI (Teijin Ltd.) Recently, chemical genomics approach has been focused as an emerging technology for the drug discovery. In advance to a very large scale national project in US started last year, Reverse Proteomics Research Institute Co., Ltd. (REPRORI) has developed the core technologies for chemical genomics. Here we describe the outline of chemical genomics study, especially that of REPRORI, and discuss about its possible application to the development of anti-tuberculosis drugs. 3. Anti-mycobacterial agents and drug delivery: Koichi IZUMIKAWA, Hideaki OHNO, Shigeru KOHNO (Second Department of Internal Medicine, Nagasaki University School of Medicine) Mycobacterium infection is a major clinical concern in whole world. Since the newly developed anti-mycobacterial agents are few and still unavailable in clinical settings, the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better efficacy. The efficacy of anti-mycobacterial agents modified by liposome or polymer based technology have been investigated and reported using various animal models. Drug delivery system increased and prolonged the drug concentrations at the blood and targeted organs and the duration of sustained drug release, respectively. These effects lead to decrease in the frequency of drug administrations dramatically and better efficacy rates. The studies, however, were performed only in animal models, the further investigations and evaluations in human are required for practical use. 4. Adjunctive immunotherapy of mycobacterial infections: Toshiaki SHIMIZU, Katsumasa SATO, Haruaki TOMIOKA (Department of Microbiology and Immunology, Shimane University School of Medicine) There is an urgent need to develop new antimicrobials and protocols for the administration of drugs that are potently efficacious against intractable mycobacterial infections. Unfortunately, development of the new drugs for solving this problem is not progressing. (ABSTRACT TRUNCATED)

Nonclassical T Cells and Their Antigens in Tuberculosis

PubMed Central

De Libero, Gennaro; Singhal, Amit; Lepore, Marco; Mori, Lucia

2014-01-01

T cells that recognize nonpeptidic antigens, and thereby are identified as nonclassical, represent important yet poorly characterized effectors of the immune response. They are present in large numbers in circulating blood and tissues and are as abundant as T cells recognizing peptide antigens. Nonclassical T cells exert multiple functions including immunoregulation, tumor control, and protection against infections. They recognize complexes of nonpeptidic antigens such as lipid and glycolipid molecules, vitamin B2 precursors, and phosphorylated metabolites of the mevalonate pathway. Each of these antigens is presented by antigen-presenting molecules other than major histocompatibility complex (MHC), including CD1, MHC class I–related molecule 1 (MR1), and butyrophilin 3A1 (BTN3A1) molecules. Here, we discuss how nonclassical T cells participate in the recognition of mycobacterial antigens and in the mycobacterial-specific immune response. PMID:25059739

Immunotherapy of tuberculosis with Mycobacterium leprae Hsp65 as a DNA vaccine triggers cross-reactive antibodies against mammalian Hsp60 but not pathological autoimmunity.

PubMed

Doimo, Nayara T S; Zárate-Bladés, Carlos R; Rodrigues, Rodrigo F; Tefé-Silva, Cristiane; Trotte, Marcele N S; Souza, Patrícia R M; Soares, Luana S; Rios, Wendy M; Floriano, Elaine M; Brandão, Izaira T; Masson, Ana P; Coelho, Verônica; Ramos, Simone G; Silva, Celio L

2014-01-01

Despite substantial efforts in recent years toward the development of new vaccines and drugs against tuberculosis (TB), success has remained elusive. Immunotherapy of TB with mycobacterial Hsp65 as a DNA vaccine (DNA-hsp65) results in a reduction of systemic bacterial loads and lung tissue damage, but the high homology of Hsp65 with the mammalian protein raises concern that pathological autoimmune responses may also be triggered. We searched for autoimmune responses elicited by DNA-hsp65 immunotherapy in mice chronically infected with TB by evaluating the humoral immune response and comprehensive histopathology using stereology. Cross-reactive antibodies between mycobacterial and mammalian Hsp60/65 were detected; however, no signs of pathological autoimmunity were found up to 60 days after the end of the therapy.

Paradigm for diagnosing mycobacterial disease: direct detection and differentiation of Mycobacterium tuberculosis complex and non-tuberculous mycobacteria in clinical specimens using multiplex real-time PCR.

PubMed

Kim, Jeong-Uk; Ryu, Dae-Shick; Cha, Choong-Hwan; Park, Seon-Hee

2018-03-20

Mycobacterium tuberculosis and non-tuberculous mycobacteria (NTM) are clinically different, and the rapid detection and differentiation of M. tuberculosis complex (MTBC) and NTM is crucial for patient management and infection control. Given the slow growth of most pathogenic mycobacteria, nucleic acid amplification assays are excellent tools for direct identification of mycobacteria in clinical specimens. Recently, a multiplex real-time PCR assay was developed that can directly detect 20 mycobacterial species in clinical specimens. Here, we evaluated the diagnostic performance of the assay for diagnosing mycobacterial disease under routine laboratory conditions. A total of 3334 specimens collected from 1437 patients suspected of tuberculosis infection were subjected to acid-fast bacilli staining, conventional culture and the multiplex real-time PCR assay. To evaluate the sensitivity and specificity of the assay, the overall diagnosis of tuberculosis was defined by positive culture plus medical history, and the 2007 American Thoracic Society and Infectious Disease Society of America diagnostic criteria for NTM disease were applied. The sensitivity, specificity, positive predictive value and negative predictive value were 87.5%, 99.6%, 96.1% and 98.5%, respectively, for the detection of MTBC isolates and 53.3%, 99.9%, 95.2%, and 98.9%, respectively, for detecting NTM isolates. Thus, the assay can correctly differentiate between MTBC and NTM isolates in clinical specimens and would be a useful tool for the rapid differentiation of tuberculosis and NTM disease, despite its limited sensitivity for the diagnosis of NTM disease. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Pseudomonas aeruginosa infections of intact skin.

PubMed

Agger, W A; Mardan, A

1995-02-01

Pseudomonas aeruginosa infections of healthy skin are uncommon. We report four cases of P. aeruginosa infections of intact skin. These cases illustrate the clinical spectrum of these cutaneous infections: localized, mild epidermal infections (the green nail syndrome and webbed space infections), moderately serious infections (cutaneous folliculitis and otitis externa), and, in immunocompromised patients, extremely serious infections (malignant otitis externa, perirectal infection, and ecthyma gangrenosum).

Assessment of vaccine testing at three laboratories using the guinea pig model of tuberculosis.

PubMed

Grover, Ajay; Troudt, Jolynn; Arnett, Kimberly; Izzo, Linda; Lucas, Megan; Strain, Katie; McFarland, Christine; Hall, Yper; McMurray, David; Williams, Ann; Dobos, Karen; Izzo, Angelo

2012-01-01

The guinea pig model of tuberculosis is used extensively in different locations to assess the efficacy of novel tuberculosis vaccines during pre-clinical development. Two key assays are used to measure protection against virulent challenge: a 30 day post-infection assessment of mycobacterial burden and long-term post-infection survival and pathology analysis. To determine the consistency and robustness of the guinea pig model for testing vaccines, a comparative assessment between three sites that are currently involved in testing tuberculosis vaccines from external providers was performed. Each site was asked to test two "subunit" type vaccines in their routine animal model as if testing vaccines from a provider. All sites performed a 30 day study, and one site also performed a long-term survival/pathology study. Despite some differences in experimental approach between the sites, such as the origin of the Mycobacterium tuberculosis strain and the type of aerosol exposure device used to infect the animals and the source of the guinea pigs, the data obtained between sites were consistent in regard to the ability of each "vaccine" tested to reduce the mycobacterial burden. The observations also showed that there was good concurrence between the results of short-term and long-term studies. This validation exercise means that efficacy data can be compared between sites. Copyright © 2011 Elsevier Ltd. All rights reserved.

Anthelmintic Therapy Modifies the Systemic and Mycobacterial Antigen-Stimulated Cytokine Profile in Helminth-Latent Mycobacterium tuberculosis Coinfection.

PubMed

Anuradha, Rajamanickam; Munisankar, Saravanan; Bhootra, Yukthi; Dolla, Chandrakumar; Kumaran, Paul; Nutman, Thomas B; Babu, Subash

2017-04-01

Helminth infections are known to modulate cytokine responses in latent tuberculosis (LTB). However, very few studies have examined whether this modulation is reversible upon anthelmintic therapy. We measured the systemic and mycobacterial (TB) antigen-stimulated levels of type 1, type 2, type 17, and regulatory cytokines in individuals with LTB and with or without coexistent Strongyloides stercoralis infection before and after anthelmintic therapy. Our data reveal that individuals with LTB and coexistent S. stercoralis infection have significantly lower levels of systemic and TB antigen-stimulated type 1 (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-2 [IL-2]) and type 17 (IL-17A and/or IL-17F) cytokines and significantly higher levels of systemic but not TB antigen-stimulated type 2 (IL-4 and IL-5) and regulatory (transforming growth factor beta [TGF-β]) cytokines. Anthelmintic therapy resulted in significantly increased systemic levels of type 1 and/or type 17 cytokines and in significantly decreased systemic levels of type 2 and regulatory (IL-10 and TGF-β) cytokines. In addition, anthelmintic therapy resulted in significantly increased TB antigen-stimulated levels of type 1 cytokines only. Our data therefore confirm that the modulation of systemic and TB antigen-stimulated cytokine responses in S. stercoralis -LTB coinfection is reversible (for the most part) by anthelmintic treatment. Copyright © 2017 American Society for Microbiology.

Qualitative Immune Modulation by Interleukin-2 (IL-2) Adjuvant Therapy in Immunological Non Responder HIV-Infected Patients

PubMed Central

Sabbatini, Francesca; Bandera, Alessandra; Ferrario, Giulio; Trabattoni, Daria; Marchetti, Giulia; Franzetti, Fabio; Clerici, Mario; Gori, Andrea

2010-01-01

Background Treatment of HIV-infected patients with interleukin-2 (IL-2) produces significant increases in CD4 T cell counts; however an associated qualitative improvement in cells function has yet to be conclusively demonstrated. By measuring mycobacterial killing activity, we evaluated IL-2-mediated functional immune enhancement ex vivo in immunological non-responders (INRs). Methods and Findings PBMC from 12 immunological non-responders (INRs) (CD4+<200/µl, HIV-RNA<50 cp/ml) on combination antiretroviral treatment (cART) were collected at baseline, and after 3 IL-2 cycles. Eight INRs receiving only cART were studied as controls. After 21 days of PBMC incubation with a virulent M. avium suspension, counts of residual colony forming units (CFUs) and concentrations of TNF-α, IL-10 and IFN-γ were determined. In IL-2 treated patients, a significant reduction in mean residual CFUs of PBMC cultures was observed (p<0.01). Moreover, following IL-2 treatment, significant increases in PBMC's IFNγ production (p = 0.02) and substantial reductions in IL-10 levels were observed. Conclusions IL-2 therapy restores the ability of the lympho-monocyte system in eliciting an effective response against mycobacterial infections. Our data indicate the possibility of a clinical role held by IL-2 in enhancing the immune function of subjects unable to achieve immune competence through cART alone. PMID:21124762

Novel high throughput pooled shRNA screening identifies NQO1 as a potential drug target for host directed therapy for tuberculosis

PubMed Central

Li, Qing; Karim, Ahmad F.; Ding, Xuedong; Das, Biswajit; Dobrowolski, Curtis; Gibson, Richard M.; Quiñones-Mateu, Miguel E.; Karn, Jonathan; Rojas, Roxana E.

2016-01-01

Chemical regulation of macrophage function is one key strategy for developing host-directed adjuvant therapies for tuberculosis (TB). A critical step to develop these therapies is the identification and characterization of specific macrophage molecules and pathways with a high potential to serve as drug targets. Using a barcoded lentivirus-based pooled short-hairpin RNA (shRNA) library combined with next generation sequencing, we identified 205 silenced host genes highly enriched in mycobacteria-resistant macrophages. Twenty-one of these “hits” belonged to the oxidoreductase functional category. NAD(P)H:quinone oxidoreductase 1 (NQO1) was the top oxidoreductase “hit”. NQO1 expression was increased after mycobacterial infection, and NQO1 knockdown increased macrophage differentiation, NF-κB activation, and the secretion of pro-inflammatory cytokines TNF-α and IL-1β in response to infection. This suggests that mycobacteria hijacks NQO1 to down-regulate pro-inflammatory and anti-bacterial functions. The competitive inhibitor of NQO1 dicoumarol synergized with rifampin to promote intracellular killing of mycobacteria. Thus, NQO1 is a new host target in mycobacterial infection that could potentially be exploited to increase antibiotic efficacy in vivo. Our findings also suggest that pooled shRNA libraries could be valuable tools for genome-wide screening in the search for novel druggable host targets for adjunctive TB therapies. PMID:27297123

Mucosal-associated invariant T cells are numerically and functionally deficient in patients with mycobacterial infection and reflect disease activity.

PubMed

Kwon, Yong-Soo; Cho, Young-Nan; Kim, Moon-Ju; Jin, Hye-Mi; Jung, Hyun-Ju; Kang, Jeong-Hwa; Park, Ki-Jeong; Kim, Tae-Jong; Kee, Hae Jin; Kim, Nacksung; Kee, Seung-Jung; Park, Yong-Wook

2015-05-01

Mucosal-associated invariant T (MAIT) cells contribute to protection against certain microorganism infections. The aims of this study were to examine the levels of MAIT cells in pulmonary tuberculosis (TB) and nontuberculous mycobacteria (NTM) lung disease patients, to evaluate the clinical relevance of MAIT cell levels, and to investigate the functions of MAIT cells. Patients with pulmonary TB (n = 35), NTM (n = 29), and healthy controls (n = 75) were enrolled in the study. MAIT cell levels and functions were measured by flow cytometry. Circluating MAIT cell levels were found to be reduced in TB and NTM patients. MAIT cell deficiency reflects a variety of clinical conditions. In particular, MAIT cell numbers were significantly correlated with sputum AFB positivity, extent of disease, hemoglobin levels, lymphocyte counts, CRP and ESR levels. MAIT cells in TB patients failed to produce interferon-γ irrespective of the mode of stimulation, whereas NTM patients displayed a defect in MR1-dependent signaling pathway. Notably, an elevated expression of programmed death-1 was also associated with MAIT cell deficiency in TB. This study shows that MAIT cells are numerically and functionally deficient in TB and NTM patients and these deficiencies could contribute to immune system dysreguation in mycobacterial infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

Subcutaneous aspergillosis with coexisting atypical mycobacterial infection.

PubMed

Duraipandian, Jeyakumari; Rengasamy, Gopal; Madasamy, Balamurugan; Kulanthaivelu, Ambedkarraj; Subramanian, Girija

2010-01-01

A 60-year-old woman, a known diabetic and asthmatic, was admitted for acute exacerbation of chronic obstructive pulmonary disease. Physical examination revealed two soft nodules in the left infra axillary region. Fine needle aspiration cytology (FNAC) showed fungal granulomatous reaction suggestive of fungal infection. Periodic acid Schiff stain (PAS stain) revealed PAS positive, acutely branching, septate fungal hyphae. Wet mount of the aspirate revealed plenty of pus cells and branching septate hyphae. Ziehl-Neelsen (ZN) stain showed moderate numbers of acid fast bacilli. Culture yielded Aspergillus flavus and Mycobacterium fortuitum.

Mycobacteriosis in two captive Florida manatees (Trichechus manatus latirostris).

PubMed

Sato, Tsuneo; Shibuya, Hisashi; Ohba, Shigeo; Nojiri, Toshio; Shirai, Wataru

2003-06-01

Two male Florida manatees (Trichechus manatus latirostris) died at the marine aquarium in Inagi City, Tokyo, Japan. Acid-fast bacteria were demonstrated in tuberculoid nodules in the lungs from both manatees. Mycobacterium marinum and M. fortuitum were isolated from one manatee; M. marinum and M. kansasii were cultured from the second animal. This report confirms the pathogenicity and potentially fatal outcome of mycobacterial infection in manatees. In addition, the pathologic response to infection with these mycobacteria in manatees is similar to that associated with Mycobacterium spp. in other animals.

Severe Paradoxical Reaction During Treatment of Disseminated Tuberculosis in a Patient With Neutralizing Anti-IFNγ Autoantibodies

PubMed Central

Xie, Yingda L.; Rosen, Lindsey B.; Sereti, Irini; Barber, Daniel L.; Chen, Ray Y.; Hsu, Denise C.; Qasba, S. Sonia; Zerbe, Christa S.; Holland, Steven M.; Browne, Sarah K.

2016-01-01

Interferon-gamma (IFNγ) neutralizing autoantibodies are associated with disseminated nontuberculous mycobacterial infections. We report a previously healthy Thai woman with disseminated tuberculosis and high-titer IFNγ-neutralizing autoantibodies, who developed a severe inflammatory reaction during anti-tuberculosis treatment. IFNγ contributes to host control of tuberculosis but appears inessential for tuberculosis paradoxical reactions. PMID:26646678

Inhibitors Selective for Mycobacterial Versus Human Proteasomes

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

Lin, G.; Li, D; Sorio de Carvalho, L

Many anti-infectives inhibit the synthesis of bacterial proteins, but none selectively inhibits their degradation. Most anti-infectives kill replicating pathogens, but few preferentially kill pathogens that have been forced into a non-replicating state by conditions in the host. To explore these alternative approaches we sought selective inhibitors of the proteasome of Mycobacterium tuberculosis. Given that the proteasome structure is extensively conserved, it is not surprising that inhibitors of all chemical classes tested have blocked both eukaryotic and prokaryotic proteasomes, and no inhibitor has proved substantially more potent on proteasomes of pathogens than of their hosts. Here we show that certain oxathiazol-2-onemore » compounds kill non-replicating M.?tuberculosis and act as selective suicide-substrate inhibitors of the M.?tuberculosis proteasome by cyclocarbonylating its active site threonine. Major conformational changes protect the inhibitor-enzyme intermediate from hydrolysis, allowing formation of an oxazolidin-2-one and preventing regeneration of active protease. Residues outside the active site whose hydrogen bonds stabilize the critical loop before and after it moves are extensively non-conserved. This may account for the ability of oxathiazol-2-one compounds to inhibit the mycobacterial proteasome potently and irreversibly while largely sparing the human homologue.« less

Post-translational Acetylation of MbtA Modulates Mycobacterial Siderophore Biosynthesis*

PubMed Central

Vergnolle, Olivia; Xu, Hua; Tufariello, JoAnn M.; Favrot, Lorenza; Malek, Adel A.; Jacobs, William R.; Blanchard, John S.

2016-01-01

Iron is an essential element for life, but its soluble form is scarce in the environment and is rarer in the human body. Mtb (Mycobacterium tuberculosis) produces two aryl-capped siderophores, mycobactin (MBT) and carboxymycobactin (cMBT), to chelate intracellular iron. The adenylating enzyme MbtA catalyzes the first step of mycobactin biosynthesis in two half-reactions: activation of the salicylic acid as an acyl-adenylate and ligation onto the acyl carrier protein (ACP) domain of MbtB to form covalently salicylated MbtB-ACP. We report the first apo-MbtA structure from Mycobacterium smegmatis at 2.3 Å. We demonstrate here that MbtA activity can be reversibly, post-translationally regulated by acetylation. Indeed the mycobacterial Pat (protein lysine acetyltransferase), Rv0998, specifically acetylates MbtA on lysine 546, in a cAMP-dependent manner, leading to enzyme inhibition. MbtA acetylation can be reversed by the NAD+-dependent DAc (deacetyltransferase), Rv1151c. Deletion of Pat and DAc genes in Mtb revealed distinct phenotypes for strains lacking one or the other gene at low pH and limiting iron conditions. This study establishes a direct connection between the reversible acetylation system Pat/DAc and the ability of Mtb to adapt in limited iron conditions, which is critical for mycobacterial infection. PMID:27566542

[Uncommon non-fermenting Gram-negative rods as pathogens of lower respiratory tract infection].

PubMed

Juhász, Emese; Iván, Miklós; Pongrácz, Júlia; Kristóf, Katalin

2018-01-01

Glucose non-fermenting Gram-negative bacteria are ubiquitous environmental organisms. Most of them are identified as opportunistic, nosocomial pathogens in patients. Uncommon species are identified accurately, mainly due to the introduction of matrix-assisted laser desorption-ionization time of flight mass spectrometry (MALDI-TOF MS) in clinical microbiology practice. Most of these uncommon non-fermenting rods are isolated from lower respiratory tract samples. Their significance in lower respiratory tract infections, such as rules of their testing are not clarified yet. The aim of this study was to review the clinical microbiological features of these bacteria, especially their roles in lower respiratory tract infections and antibiotic treatment options. Lower respiratory tract samples of 3589 patients collected in a four-year period (2013-2016) were analyzed retrospectively at Semmelweis University (Budapest, Hungary). Identification of bacteria was performed by MALDI-TOF MS, the antibiotic susceptibility was tested by disk diffusion method. Stenotrophomonas maltophilia was revealed to be the second, whereas Acinetobacter baumannii the third most common non-fermenting rod in lower respiratory tract samples, behind the most common Pseudomonas aeruginosa. The total number of uncommon non-fermenting Gram-negative isolates was 742. Twenty-three percent of isolates were Achromobacter xylosoxidans. Beside Chryseobacterium, Rhizobium, Delftia, Elizabethkingia, Ralstonia and Ochrobactrum species, and few other uncommon species were identified among our isolates. The accurate identification of this species is obligatory, while most of them show intrinsic resistance to aminoglycosides. Resistance to ceftazidime, cefepime, piperacillin-tazobactam and carbapenems was frequently observed also. Ciprofloxacin, levofloxacin and trimethoprim-sulfamethoxazole were found to be the most effective antibiotic agents. Orv Hetil. 2018; 159(1): 23-30.

Moyamoya Syndrome in a Child With HIV-1 Infection.

PubMed

Jindal, Ankur Kumar; Bhattad, Sagar; Suri, Deepti; Singhal, Manphool; Gupta, Aman; Singh, Paramjeet

2018-06-01

Neurologic manifestations of HIV infection are not uncommon. However, stroke secondary to Moyamoya syndrome has rarely been described in children with HIV infection. We report a 10-year-old boy with perinatally acquired HIV-1 infection, who presented with recurrent strokes while on antiretroviral therapy.

Mycobacterial Hsp65 potentially cross-reacts with autoantibodies of diabetes sera and also induces (in vitro) cytokine responses relevant to diabetes mellitus.

PubMed

Rani, Pittu Sandhya; Babajan, Banaganapalli; Tulsian, Nikhil K; Begum, Mahabubunnisa; Kumar, Ashutosh; Ahmed, Niyaz

2013-11-01

Diabetes mellitus is a multifactorial disease and its incidence is increasing worldwide. Among the two types of diabetes, type-2 accounts for about 90% of all diabetic cases, whereas type-1 or juvenile diabetes is less prevalent and presents with humoral immune responses against some of the autoantigens. We attempted to test whether the sera of type-1 diabetes patients cross-react with mycobacterial heat shock protein 65 (Hsp65) due to postulated epitope homologies between mycobacterial Hsp65 and an important autoantigen of type-1 diabetes, glutamic acid decarboxylase-65 (GAD65). In our study, we used either recombinant mycobacterial Hsp65 protein or synthetic peptides corresponding to some of the potential epitopes of mycobacterial Hsp65 that are shared with GAD65 or human Hsp60, and a control peptide sourced from mycobacterial Hsp65 which is not shared with GAD65, Hsp60 and other autoantigens of type-1 diabetes. The indirect ELISA results indicated that both type-1 diabetes and type-2 diabetes sera cross-react with conserved mycobacterial Hsp65 peptides and recombinant mycobacterial Hsp65 protein but do not do so with the control peptide. Our results suggest that cross-reactivity of mycobacterial Hsp65 with autoantibodies of diabetes sera could be due to the presence of significantly conserved peptides between mycobacterial Hsp65 and human Hsp60 rather than between mycobacterial Hsp65 and GAD65. The treatment of human peripheral blood mononuclear cells (PBMCs) with recombinant mycobacterial Hsp65 protein or the synthetic peptides resulted in a significant increase in the secretion of cytokines such as IL-1β, IL-8, IL-6, TNF-α and IL-10. Taken together, these findings point towards a dual role for mycobacterial Hsp65: in inducing autoimmunity and in inflammation, the two cardinal features of diabetes mellitus.

Evolution of granulomas in lungs of mice infected aerogenically with Mycobacterium tuberculosis.

PubMed

Cardona, P J; Llatjós, R; Gordillo, S; Díaz, J; Ojanguren, I; Ariza, A; Ausina, V

2000-08-01

Aerogenous infection of C57Bl/6 mice with a virulent strain of Mycobacterium tuberculosis (CL 511) leads to the formation of primary granulomas in the lung where neutrophils, macrophages and subsequently, lymphocytes accumulate progressively around an initial cluster of infected macrophages. The spread of infection through the lung parenchyma gives rise to secondary granulomas featuring numerous lymphocytes that surround a small number of infected macrophages. Afterwards, foamy macrophages add an outer layer to the granulomas, which characteristically respect the pulmonary interstitium and remain confined within the alveolar spaces. This feature, in conjunction with the constant presence of M. tuberculosis in the products of broncho-alveolar lavage, suggests that the upward bronchial migration of infected macrophages may contribute significantly to pulmonary dissemination of mycobacterial infection. The latter would be in agreement with the persistence of chronic pulmonary infection in spite of a concomitant strong T helper 1 cell response.

Neutralization or Absence of the Interleukin-23 Pathway Does Not Compromise Immunity to Mycobacterial Infection▿

PubMed Central

Chackerian, Alissa A.; Chen, Shi-Juan; Brodie, Scott J.; Mattson, Jeanine D.; McClanahan, Terrill K.; Kastelein, Robert A.; Bowman, Edward P.

2006-01-01

Interleukin-23 (IL-23), a member of the IL-12 family, is a heterodimeric cytokine that is composed of the p40 subunit of IL-12 plus a unique p19 subunit. IL-23 is critical for autoimmune inflammation, in part due to its stimulation of the proinflammatory cytokine IL-17A. It is less clear, however, if IL-23 is required during the immune response to pathogens. We examined the role of IL-23 during Mycobacterium bovis BCG infection. We found that IL-23 reduces the bacterial burden and promotes granuloma formation when IL-12 is absent. However, IL-23 does not contribute substantially to host resistance when IL-12 is present, as the ability to control bacterial growth and form granulomata is not affected in IL-23p19-deficient mice and mice treated with a specific anti-IL-23p19 antibody. IL-23p19-deficient mice are also able to mount an effective memory response to secondary infection with BCG. While IL-23p19-deficient mice do not produce IL-17A, this cytokine is not necessary for effective control of infection, and antibody blocking of IL-17A in both wild-type and IL-12-deficient mice also has little effect on the bacterial burden. These data suggest that IL-23 by itself does not play an essential role in the protective immune response to BCG infection; however, the presence of IL-23 can partially compensate for the absence of IL-12. Furthermore, neutralization of IL-23 or IL-17A does not increase susceptibility to mycobacterial BCG infection. PMID:16923792

Mycobacterium avium Complex Empyema in a Patient with Interferon Gamma Autoantibodies

PubMed Central

Chung, Heath H; Opal, Steven M; Dworkin, Jonathan D

2014-01-01

Interferon gamma (IFN-γ) autoantibodies are a relatively recently discovered clinical entity, which have been shown to be associated with disseminated non-tuberculous mycobacterial (NTM) infections and other opportunistic infections. Interestingly, isolated NTM infections (without disseminated NTM infection) have not been shown to be a good predictor of the presence of IFN-γ autoantibodies. This case describes an isolated NTM empyema in a patient with IFN-γ autoantibodies and makes the argument that the development of an NTM empyema in a patient with no known immunodeficiency should prompt consideration for IFN-γ testing. Additionally, this case underscores the importance for clinicians to recognize that an unusual infection without the typical cause of impairment in immunity should prompt a more thorough investigation of the patient's immune system. PMID:25285250

Benefits of breastfeeding

MedlinePlus

... Breast cancer or other cancer Breast infection or breast abscess Poor milk supply (uncommon) Previous surgery or radiation treatment Breastfeeding is not recommended for mothers who have: Active ... tuberculosis Human immunodeficiency virus (HIV) infection ...

The acylation state of mycobacterial lipomannans modulates innate immunity response through toll-like receptor 2.

PubMed

Gilleron, Martine; Nigou, Jérôme; Nicolle, Delphine; Quesniaux, Valérie; Puzo, Germain

2006-01-01

Detection of Mycobacterium tuberculosis antigens by professional phagocytes via toll-like receptors (TLR) contributes to controlling chronic M. tuberculosis infection. Lipomannans (LM), which are major lipoglycans of the mycobacterial envelope, were recently described as agonists of TLR2 with potent activity on proinflammatory cytokine regulation. LM correspond to a heterogeneous population of acyl- and glyco-forms. We report here the purification and the complete structural characterization of four LM acyl-forms from Mycobacterium bovis BCG using MALDI MS and 2D (1)H-(31)P NMR analyses. All this biochemical work provided the tools to investigate the implication of LM acylation degree on its proinflammatory activity. The latter was ascribed to the triacylated LM form, essentially an agonist of TLR2, using TLR2/TLR1 heterodimers for signaling. Altogether, these findings shed more light on the molecular basis of LM recognition by TLR.

Novel semisynthetic antibiotics from caprazamycins A-G: caprazene derivatives and their antibacterial activity.

PubMed

Takahashi, Yoshiaki; Igarashi, Masayuki; Miyake, Toshiaki; Soutome, Hiromi; Ishikawa, Kanae; Komatsuki, Yasuhiro; Koyama, Yoshiko; Nakagawa, Naoko; Hattori, Seiko; Inoue, Kunio; Doi, Norio; Akamatsu, Yuzuru

2013-03-01

Acidic treatment of a mixture of caprazamycins (CPZs) A-G isolated from a screen of novel antimycobacterial agents gave caprazene, a core structure of CPZs, in high yield. Chemical modification of the resulting caprazene was performed to give its various derivatives. The structure-activity relationships of the caprazene derivatives against several mycobacterial species and pathogenic Gram-positive and Gram-negative bacteria were studied. Although caprazene showed no antibacterial activity, the antibacterial activity was restored for its 1'''-alkylamide, 1'''-anilide and 1'''-ester derivatives. Compounds 4b (CPZEN-45), 4d (CPZEN-48), 4f and 4g (CPZEN-51) exhibited more potent activities against Mycobacterium tuberculosis and M. avium complex strains than CPZ-B. These results suggest that caprazene would be a good precursor from which novel semisynthetic antibacterial antibiotics can be designed for the treatment of mycobacterial diseases such as tuberculosis and M. avium complex infection.

Discovery of Imidazo[1,2-a]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis.

PubMed

Tantry, Subramanyam J; Markad, Shankar D; Shinde, Vikas; Bhat, Jyothi; Balakrishnan, Gayathri; Gupta, Amit K; Ambady, Anisha; Raichurkar, Anandkumar; Kedari, Chaitanyakumar; Sharma, Sreevalli; Mudugal, Naina V; Narayan, Ashwini; Naveen Kumar, C N; Nanduri, Robert; Bharath, Sowmya; Reddy, Jitendar; Panduga, Vijender; Prabhakar, K R; Kandaswamy, Karthikeyan; Saralaya, Ramanatha; Kaur, Parvinder; Dinesh, Neela; Guptha, Supreeth; Rich, Kirsty; Murray, David; Plant, Helen; Preston, Marian; Ashton, Helen; Plant, Darren; Walsh, Jarrod; Alcock, Peter; Naylor, Kathryn; Collier, Matthew; Whiteaker, James; McLaughlin, Robert E; Mallya, Meenakshi; Panda, Manoranjan; Rudrapatna, Suresh; Ramachandran, Vasanthi; Shandil, Radha; Sambandamurthy, Vasan K; Mdluli, Khisi; Cooper, Christopher B; Rubin, Harvey; Yano, Takahiro; Iyer, Pravin; Narayanan, Shridhar; Kavanagh, Stefan; Mukherjee, Kakoli; Balasubramanian, V; Hosagrahara, Vinayak P; Solapure, Suresh; Ravishankar, Sudha; Hameed P, Shahul

2017-02-23

The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report the discovery of two diverse lead series imidazo[1,2-a]pyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial ATP synthesis. Through medicinal chemistry exploration, we established a robust structure-activity relationship of these two scaffolds, resulting in nanomolar potencies in an ATP synthesis inhibition assay. A biochemical deconvolution cascade suggested cytochrome c oxidase as the potential target of IPE class of molecules, whereas characterization of spontaneous resistant mutants of SQAs unambiguously identified ATP synthase as its molecular target. Absence of cross resistance against bedaquiline resistant mutants suggested a different binding site for SQAs on ATP synthase. Furthermore, SQAs were found to be noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis infection.

Mycobacteria exploit nitric oxide-induced transformation of macrophages into permissive giant cells.

PubMed

Gharun, Kourosh; Senges, Julia; Seidl, Maximilian; Lösslein, Anne; Kolter, Julia; Lohrmann, Florens; Fliegauf, Manfred; Elgizouli, Magdeldin; Vavra, Martina; Schachtrup, Kristina; Illert, Anna L; Gilleron, Martine; Kirschning, Carsten J; Triantafyllopoulou, Antigoni; Henneke, Philipp

2017-12-01

Immunity to mycobacteria involves the formation of granulomas, characterized by a unique macrophage (MΦ) species, so-called multinucleated giant cells (MGC). It remains unresolved whether MGC are beneficial to the host, that is, by prevention of bacterial spread, or whether they promote mycobacterial persistence. Here, we show that the prototypical antimycobacterial molecule nitric oxide (NO), which is produced by MGC in excessive amounts, is a double-edged sword. Next to its antibacterial capacity, NO propagates the transformation of MΦ into MGC, which are relatively permissive for mycobacterial persistence. The mechanism underlying MGC formation involves NO-induced DNA damage and impairment of p53 function. Moreover, MGC have an unsurpassed potential to engulf mycobacteria-infected apoptotic cells, which adds a further burden to their antimycobacterial capacity. Accordingly, mycobacteria take paradoxical advantage of antimicrobial cellular efforts by driving effector MΦ into a permissive MGC state. © 2017 The Authors.

Oleoyl Coenzyme A Regulates Interaction of Transcriptional Regulator RaaS (Rv1219c) with DNA in Mycobacteria*

PubMed Central

Turapov, Obolbek; Waddell, Simon J.; Burke, Bernard; Glenn, Sarah; Sarybaeva, Asel A.; Tudo, Griselda; Labesse, Gilles; Young, Danielle I.; Young, Michael; Andrew, Peter W.; Butcher, Philip D.; Cohen-Gonsaud, Martin; Mukamolova, Galina V.

2014-01-01

We have recently shown that RaaS (regulator of antimicrobial-assisted survival), encoded by Rv1219c in Mycobacterium tuberculosis and by bcg_1279c in Mycobacterium bovis bacillus Calmette-Guérin, plays an important role in mycobacterial survival in prolonged stationary phase and during murine infection. Here, we demonstrate that long chain acyl-CoA derivatives (oleoyl-CoA and, to lesser extent, palmitoyl-CoA) modulate RaaS binding to DNA and expression of the downstream genes that encode ATP-dependent efflux pumps. Moreover, exogenously added oleic acid influences RaaS-mediated mycobacterial improvement of survival and expression of the RaaS regulon. Our data suggest that long chain acyl-CoA derivatives serve as biological indicators of the bacterial metabolic state. Dysregulation of efflux pumps can be used to eliminate non-growing mycobacteria. PMID:25012658

Oleoyl coenzyme A regulates interaction of transcriptional regulator RaaS (Rv1219c) with DNA in mycobacteria.

PubMed

Turapov, Obolbek; Waddell, Simon J; Burke, Bernard; Glenn, Sarah; Sarybaeva, Asel A; Tudo, Griselda; Labesse, Gilles; Young, Danielle I; Young, Michael; Andrew, Peter W; Butcher, Philip D; Cohen-Gonsaud, Martin; Mukamolova, Galina V

2014-09-05

We have recently shown that RaaS (regulator of antimicrobial-assisted survival), encoded by Rv1219c in Mycobacterium tuberculosis and by bcg_1279c in Mycobacterium bovis bacillus Calmette-Guérin, plays an important role in mycobacterial survival in prolonged stationary phase and during murine infection. Here, we demonstrate that long chain acyl-CoA derivatives (oleoyl-CoA and, to lesser extent, palmitoyl-CoA) modulate RaaS binding to DNA and expression of the downstream genes that encode ATP-dependent efflux pumps. Moreover, exogenously added oleic acid influences RaaS-mediated mycobacterial improvement of survival and expression of the RaaS regulon. Our data suggest that long chain acyl-CoA derivatives serve as biological indicators of the bacterial metabolic state. Dysregulation of efflux pumps can be used to eliminate non-growing mycobacteria. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Evidence for Mycobacteria in Sarcoidosis

PubMed Central

Brownell, Isaac; Ramírez-Valle, Francisco; Sanchez, Miguel

2011-01-01

Despite its recognition as a distinct granulomatous disease for over a century, the etiology of sarcoidosis remains to be defined. Since the early 1900s, infectious agents have been suspected in causing sarcoidosis. For much of this time, mycobacteria were considered a likely culprit, yet until recently, the supporting evidence has been tenuous at best. In this review, we evaluate the reported association between mycobacteria and sarcoidosis. Historically, mycobacterial infection has been investigated using histologic stains, cultures of lesional tissue or blood, and identification of bacterial nucleic acids or bacterial antigens. More recently, advances in biochemical, molecular, and immunological methods have produced a more rigorous analysis of the antigenic drivers of sarcoidosis. The result of these efforts indicates that mycobacterial products likely play a role in at least a subset of sarcoidosis cases. This information, coupled with a better understanding of genetic susceptibility to this complex disease, has therapeutic implications. PMID:21659662

Immunotherapy of tuberculosis with Mycobacterium leprae Hsp65 as a DNA vaccine triggers cross-reactive antibodies against mammalian Hsp60 but not pathological autoimmunity

PubMed Central

Doimo, Nayara TS; Zárate-Bladés, Carlos R; Rodrigues, Rodrigo F; Tefé-Silva, Cristiane; Trotte, Marcele NS; Souza, Patrícia RM; Soares, Luana S; Rios, Wendy M; Floriano, Elaine M; Brandão, Izaira T; Masson, Ana P; Coelho, Verônica; Ramos, Simone G; Silva, Celio L

2014-01-01

Despite substantial efforts in recent years toward the development of new vaccines and drugs against tuberculosis (TB), success has remained elusive. Immunotherapy of TB with mycobacterial Hsp65 as a DNA vaccine (DNA-hsp65) results in a reduction of systemic bacterial loads and lung tissue damage, but the high homology of Hsp65 with the mammalian protein raises concern that pathological autoimmune responses may also be triggered. We searched for autoimmune responses elicited by DNA-hsp65 immunotherapy in mice chronically infected with TB by evaluating the humoral immune response and comprehensive histopathology using stereology. Cross-reactive antibodies between mycobacterial and mammalian Hsp60/65 were detected; however, no signs of pathological autoimmunity were found up to 60 days after the end of the therapy. PMID:24607935

Evaluation of the results of Mycobacterium tuberculosis direct test (MTD) and Mycobacterial culture in urine samples

PubMed Central

Sener, Asli Gamze; Kurultay, Nukhet; Afsar, Ilhan

2008-01-01

Tuberculosis remains a public health problem in Turkey. Rapid detection of Mycobacterium tuberculosis plays a key role in control of infection. In this article, the Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test (MTD) was evaluated for detection of M. tuberculosis in urine samples. The performance of the MTD was very good and appropriate for routine laboratory diagnosis. PMID:24031287

Effects of recombinant granulocyte-colony stimulating factor administration during Mycobacterium avium infection in mice

PubMed Central

Gonçalves, A S; Appelberg, R

2001-01-01

Granulocyte colony-stimulating factor (G-CSF) administration in vivo has been shown to improve the defence mechanisms against infection by different microbes. Here we evaluated a possible protective role of this molecule in a mouse model of mycobacterial infection. The administration of recombinant G-CSF promoted an extensive blood neutrophilia but failed to improve the course of Mycobacterium avium infection in C57Bl/6 or beige mice. G-CSF administration also failed to improve the efficacy of a triple chemotherapeutic regimen (clarithromycin + ethambutol + rifabutin). G-CSF treatment did not protect interleukin-10 gene disrupted mice infected with M. avium. Spleen cells from infected mice treated with G-CSF had a decreased priming for antigen-specific production of interferon gamma compared to control infected mice. Our data do not substantiate previous reports on the protective activity of G-CSF in antimycobacterial immunity using mouse models. PMID:11422200

Pseudomonal breast infection

PubMed Central

Rastall, S; Catchpole, C; Bright-Thomas, R; Thrush, S

2010-01-01

Breast infection and breast sepsis secondary to Pseudomonas aeruginosa is uncommon. We report two cases of pseudomonal breast infection leading to septic shock and abscess formation in women with non-responding breast infection. The management of breast infection is broad-spectrum antibiotics and ultrasound with aspiration of any collection. To treat breast infection effectively, the causative organism must be isolated to enable appropriate antibiotic therapy. PMID:20412664

Second generation multiple reaction monitoring assays for enhanced detection of ultra-low abundance Mycobacterium tuberculosis peptides in human serum.

PubMed

Mehaffy, Carolina; Dobos, Karen M; Nahid, Payam; Kruh-Garcia, Nicole A

2017-01-01

Mycobacterium tuberculosis (Mtb) is the causative agent of Tuberculosis (TB), the number one cause of death due to an infectious disease. TB diagnosis is performed by microscopy, culture or PCR amplification of bacterial DNA, all of which require patient sputum or the biopsy of infected tissue. Detection of mycobacterial products in serum, as biomarkers of diagnosis or disease status would provide an improvement over current methods. Due to the low-abundance of mycobacterial products in serum, we have explored exosome enrichment to improve sensitivity. Mtb resides intracellularly where its secreted proteins have been shown to be packaged into host exosomes and released into the bloodstream. Exosomes can be readily purified assuring an enrichment of mycobacterial analytes from the complex mix of host serum proteins. Multiple reaction monitoring assays were optimized for the enhanced detection of 41 Mtb peptides in exosomes purified from the serum of individuals with TB. Exosomes isolated from the serum of healthy individuals was used to create and validate a unique data analysis algorithm and identify filters to reduce the rate of false positives, attributed to host m / z interference. The final optimized method was tested in 40 exosome samples from TB positive patients. Our enhanced methods provide limit of detection and quantification averaging in the low femtomolar range for detection of mycobacterial products in serum. At least one mycobacterial peptide was identified in 92.5% of the TB positive patients. Four peptides from the Mtb proteins, Cfp2, Mpt32, Mpt64 and BfrB, show normalized total peak areas significantly higher in individuals with active TB as compared to healthy controls; three of the peptides from these proteins have not previously been associated with serum exosomes from individuals with active TB disease. Some of the detected peptides were significantly associated with specific geographical locations, highlighting potential markers that can be linked to the Mtb strains circulating within each given region. An enhanced MRM method to detect ultra-low abundance Mtb peptides in human serum exosomes is demonstrated, highlighting the potential of this methodology for TB diagnostic biomarker development.

Human Infection with Burkholderia thailandensis, China, 2013.

PubMed

Chang, Kai; Luo, Jie; Xu, Huan; Li, Min; Zhang, Fengling; Li, Jin; Gu, Dayong; Deng, Shaoli; Chen, Ming; Lu, Weiping

2017-08-01

Burkholderia thailandensis infection in humans is uncommon. We describe a case of B. thailandensis infection in a person in China, a location heretofore unknown for B. thailandensis. We identified the specific virulence factors of B. thailandensis, which may indicate a transition to a new virulent form.

Listeria monocytogenes empyema in an HIV infected patient

PubMed Central

Marron, A.; Roson, B.; Mascaro, J.; Carratala, J.

1997-01-01

Listeriosis in HIV infected patients is uncommon and usually presents as meningitis or bacteraemia. Pleural fluid infections caused by this organism are extremely rare. A case is described of empyema caused by Listeria monocytogenes in an HIV infected patient that was successfully treated with medical treatment only. 




 PMID:9337838

Challenges encountered in the diagnosis of tuberculous otitis media: case report and literature review.

PubMed

Dale, O T; Clarke, A R; Drysdale, A J

2011-07-01

To report a rare case of tuberculous otitis media, and to highlight barriers to clinical and microbiological diagnosis. Case report and literature review. Tuberculous otitis media is a rare cause of chronic ear infection in the UK. Its symptoms may mimic a range of other otological conditions, including otitis media, chronic suppurative otitis media, cholesteatoma and necrotising otitis media. This case report highlights the challenges of obtaining a clinical diagnosis of tuberculous otitis media, and emphasises the fact that screening for acid-fast bacilli is not sufficient, in isolation, to rule out mycobacterial infection.

From the mouths of monkeys: Detection of Mycobacterium tuberculosis complex DNA from buccal swabs of synanthropic macaques

PubMed Central

Wilbur, AK; Engel, G; Rompis, A; Putra, IGA A; Lee, BP Y-H; Aggimarangsee, N; Chalise, M; Shaw, E; Oh, G; Schillaci, MA; Jones-Engel, L

2012-01-01

Although the Mycobacterium tuberculosis complex (MTBC) infects a third of all humans, little is known regarding the prevalence of mycobacterial infection in nonhuman primates (NHP). For more than a century, tuberculosis has been regarded as a serious infectious threat to NHP species. Advances in the detection of MTBC open new possibilities for investigating the effects of this poorly understood pathogen in diverse populations of NHP. Here we report results of a cross-sectional study using well-described molecular methods to detect a nucleic acid sequence (IS6110) unique to the MTBC. Sample collection was focused on the oral cavity, the presumed route of transmission of MTBC. Buccal swabs were collected from 263 macaques representing 11 species in four Asian countries and Gibraltar. Contexts of contact with humans included free ranging, pets, performing monkeys, zoos, and monkey temples. Following DNA isolation from buccal swabs, the PCR amplified IS6110 from 84 (31.9%) of the macaques. In general, prevalence of MTBC DNA was higher among NHP in countries where the World Health Organization reports higher prevalence of humans infected with MTBC. This is the first demonstration of MTBC DNA in the mouths of macaques. Further research is needed to establish the significance of this finding at both the individual and population levels. PCR of buccal samples holds promise as a method to elucidate the mycobacterial landscape among NHP, particularly macaques that thrive in areas of high human MTBC prevalence. PMID:22644580

Acid-fast Smear and Histopathology Results Provide Guidance for the Appropriate Use of Broad-Range Polymerase Chain Reaction and Sequencing for Mycobacteria.

PubMed

Miller, Kennon; Harrington, Susan M; Procop, Gary W

2015-08-01

New molecular diagnostic tests are attractive because of the potential they hold for improving diagnostics in microbiology. The value of these tests, which is often assumed, should be investigated to determine the best use of these potentially powerful tools. To investigate the usefulness of broad-range polymerase chain reaction (PCR), followed by sequencing, in mycobacterial infections. We reviewed the test performance of acid-fast bacilli (AFB) PCR and traditional diagnostic methods (histopathology, AFB smear, and culture). We assessed the diagnostic effect and cost of the unrestricted ordering of broad-range PCR for the detection and identification of mycobacteria in clinical specimens. The AFB PCR was less sensitive than culture and histopathology and was less specific than culture, AFB smear, and histopathology. During 18 months, $93 063 was spent on 183 patient specimens for broad-range PCR and DNA sequencing for mycobacteria to confirm one culture-proven Mycobacterium tuberculosis infection that was also known to be positive by AFB smear and histopathology. In this cohort, there was a false-negative AFB PCR for M tuberculosis and a false-positive AFB PCR for Mycobacterium lentiflavum . Testing of AFB smear-negative specimens from patients without an inflammatory response supportive of a mycobacterial infection is costly and has not been proven to improve patient care. Traditional diagnostics (histopathology, AFB smear, and culture) should remain the primary methods for the detection of mycobacteria in clinical specimens.

Catheter-associated bacteremia by Mycobacterium senegalense in Korea

PubMed Central

Oh, Won Sup; Ko, Kwan Soo; Song, Jae-Hoon; Lee, Mi Young; Ryu, Seong Yeol; Heo, Sangtaek; Kwon, Ki Tae; Lee, Jang-Ho; Peck, Kyong Ran; Lee, Nam Yong

2005-01-01

Background Rapidly growing mycobacteria is recognized as one of the causative agents of catheter-related infections, especially in immunocompromised hosts. To date, however, Mycobacterium senegalense, which was known as the principal pathogen of bovine farcy, has not been reported in human infection. Case presentation We describe the first case of human infection by M. senegalense, which has caused catheter-related bloodstream infection in a cancer patient in Korea. The microorganism was identified by the 16S rRNA gene, rpoB, and 16S-23S rRNA gene internal transcribed spacer (ITS) sequence analyses. Conclusion Our first report of catheter-associated bacteremia caused by M. senegalense suggests the zoonotic nature of this species and indicates the expansion of mycobacterial species relating to human infection. M. senegalense should be considered as one of the causes of human infections in the clinical practice. PMID:16307688

Mycobacterium tuberculosis promotes genomic instability in macrophages.

PubMed

Castro-Garza, Jorge; Luévano-Martínez, Miriam Lorena; Villarreal-Treviño, Licet; Gosálvez, Jaime; Fernández, José Luis; Dávila-Rodríguez, Martha Imelda; García-Vielma, Catalina; González-Hernández, Silvia; Cortés-Gutiérrez, Elva Irene

2018-03-01

Mycobacterium tuberculosis is an intracellular pathogen, which may either block cellular defensive mechanisms and survive inside the host cell or induce cell death. Several studies are still exploring the mechanisms involved in these processes. To evaluate the genomic instability of M. tuberculosis-infected macrophages and compare it with that of uninfected macrophages. We analysed the possible variations in the genomic instability of Mycobacterium-infected macrophages using the DNA breakage detection fluorescence in situ hybridisation (DBD-FISH) technique with a whole human genome DNA probe. Quantitative image analyses showed a significant increase in DNA damage in infected macrophages as compared with uninfected cells. DNA breaks were localised in nuclear membrane blebs, as confirmed with DNA fragmentation assay. Furthermore, a significant increase in micronuclei and nuclear abnormalities were observed in infected macrophages versus uninfected cells. Genomic instability occurs during mycobacterial infection and these data may be seminal for future research on host cell DNA damage in M. tuberculosis infection.

Comparison of clinical and laboratory findings between those with pulmonary tuberculosis and those with nontuberculous mycobacterial lung disease.

PubMed

Thanachartwet, Vipa; Desakorn, Varunee; Duangrithi, Duangjai; Chunpongthong, Pongsak; Phojanamongkolkij, Kamol; Jitruckthai, Pasakorn; Kasetjaroen, Yuttichai; Pitisuttithum, Punnee

2014-01-01

In tuberculosis endemic areas, patients with sputum positive for acid-fast bacilli (AFB) are usually diagnosed and treated for pulmonary tuberculosis. The diagnosis of nontuberculous mycobacteria (NTM) lung disease is often ascertained only after lung disease progression occurs, increasing the risk of severe morbidity and mortality. We conducted a matched case-control study among a prospective cohort of 300 patients with newly diagnosed AFB-positive sputum in Thailand during 2010-2012. We compared clinical and laboratory parameters and outcomes among patients with pulmonary tuberculosis, NTM lung disease and NTM colonization. A mycobacterial culture was performed in all patients. Ten patients with NTM lung disease were compared to 50 patients with pulmonary tuberculosis and 10 patients with NTM colonization. The presence of diabetes mellitus or human immunodeficiency virus infection, were associated with NTM lung disease (p = 0.030). Patients with NTM lung disease had a significantly lower body weight prior to treatment (p = 0.021), a higher body weight change from baseline (p = 0.038), and were more likely to have cavitations on chest radiograph (p = 0.033) than those with NTM colonization. In tuberculosis endemic areas, mycobacterial identification should be performed among patients with impaired immune function. NTM lung disease treatment should be considered in patients with NTM sputum isolates who have a history of significant weight loss or cavitations on chest radiography.

Ag85A-specific CD4+ T cell lines derived after boosting BCG-vaccinated cattle with Ad5-85A possess both mycobacterial growth inhibition and anti-inflammatory properties.

PubMed

Metcalfe, Hannah J; Biffar, Lucia; Steinbach, Sabine; Guzman, Efrain; Connelley, Tim; Morrison, Ivan; Vordermeier, H Martin; Villarreal-Ramos, Bernardo

2018-05-11

There is a need to improve the efficacy of the BCG vaccine against human and bovine tuberculosis. Previous data showed that boosting bacilli Calmette-Guerin (BCG)-vaccinated cattle with a recombinant attenuated human type 5 adenovirally vectored subunit vaccine (Ad5-85A) increased BCG protection and was associated with increased frequency of Ag85A-specific CD4 + T cells post-boosting. Here, the capacity of Ag85A-specific CD4 + T cell lines - derived before and after viral boosting - to interact with BCG-infected macrophages was evaluated. No difference before and after boosting was found in the capacity of these Ag85A-specific CD4 + T cell lines to restrict mycobacterial growth, but the secretion of IL-10 in vitro post-boost increased significantly. Furthermore, cell lines derived post-boost had no statistically significant difference in the secretion of pro-inflammatory cytokines (IL-1β, IL-12, IFNγ or TNFα) compared to pre-boost lines. In conclusion, the protection associated with the increased number of Ag85A-specific CD4 + T cells restricting mycobacterial growth may be associated with anti-inflammatory properties to limit immune-pathology. Copyright © 2018 Department for Environment Food and Rural Affairs. Published by Elsevier Ltd.. All rights reserved.

Immune Responses to Bacillus Calmette–Guérin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?

PubMed Central

Moliva, Juan I.; Turner, Joanne; Torrelles, Jordi B.

2017-01-01

Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), is the current leading cause of death due to a single infectious organism. Although curable, the broad emergence of multi-, extensive-, extreme-, and total-drug resistant strains of M.tb has hindered eradication efforts of this pathogen. Furthermore, computational models predict a quarter of the world’s population is infected with M.tb in a latent state, effectively serving as the largest reservoir for any human pathogen with the ability to cause significant morbidity and mortality. The World Health Organization has prioritized new strategies for improved vaccination programs; however, the lack of understanding of mycobacterial immunity has made it difficult to develop new successful vaccines. Currently, Mycobacterium bovis bacillus Calmette–Guérin (BCG) is the only vaccine approved for use to prevent TB. BCG is highly efficacious at preventing meningeal and miliary TB, but is at best 60% effective against the development of pulmonary TB in adults and wanes as we age. In this review, we provide a detailed summary on the innate immune response of macrophages, dendritic cells, and neutrophils in response to BCG vaccination. Additionally, we discuss adaptive immune responses generated by BCG vaccination, emphasizing their specific contributions to mycobacterial immunity. The success of future vaccines against TB will directly depend on our understanding of mycobacterial immunity. PMID:28424703

Post-translational Acetylation of MbtA Modulates Mycobacterial Siderophore Biosynthesis.

PubMed

Vergnolle, Olivia; Xu, Hua; Tufariello, JoAnn M; Favrot, Lorenza; Malek, Adel A; Jacobs, William R; Blanchard, John S

2016-10-14

Iron is an essential element for life, but its soluble form is scarce in the environment and is rarer in the human body. Mtb (Mycobacterium tuberculosis) produces two aryl-capped siderophores, mycobactin (MBT) and carboxymycobactin (cMBT), to chelate intracellular iron. The adenylating enzyme MbtA catalyzes the first step of mycobactin biosynthesis in two half-reactions: activation of the salicylic acid as an acyl-adenylate and ligation onto the acyl carrier protein (ACP) domain of MbtB to form covalently salicylated MbtB-ACP. We report the first apo-MbtA structure from Mycobacterium smegmatis at 2.3 Å. We demonstrate here that MbtA activity can be reversibly, post-translationally regulated by acetylation. Indeed the mycobacterial Pat (protein lysine acetyltransferase), Rv0998, specifically acetylates MbtA on lysine 546, in a cAMP-dependent manner, leading to enzyme inhibition. MbtA acetylation can be reversed by the NAD + -dependent DAc (deacetyltransferase), Rv1151c. Deletion of Pat and DAc genes in Mtb revealed distinct phenotypes for strains lacking one or the other gene at low pH and limiting iron conditions. This study establishes a direct connection between the reversible acetylation system Pat/DAc and the ability of Mtb to adapt in limited iron conditions, which is critical for mycobacterial infection. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Nitazoxanide is active against Mycobacterium leprae

PubMed Central

Bailey, Mai Ann; Na, Hana; Duthie, Malcolm S.; Gillis, Thomas P.; Lahiri, Ramanuj

2017-01-01

Nitazoxanide (NTZ) is an anti-parasitic drug that also has activity against bacteria, including Mycobacterium tuberculosis. Our data using both radiorespirometry and live-dead staining in vitro demonstrate that NTZ similarly has bactericidal against M. leprae. Further, gavage of M. leprae-infected mice with NTZ at 25mg/kg provided anti-mycobacterial activity equivalent to rifampicin (RIF) at 10 mg/kg. This suggests that NTZ could be considered for leprosy treatment. PMID:28850614

First report of a mycolactone-producing Mycobacterium infection in fish agriculture in Belgium.

PubMed

Stragier, Pieter; Hermans, Katleen; Stinear, Tim; Portaels, Françoise

2008-09-01

In the past few years, a mycolactone-producing subgroup of the Mycobacterium marinum complex has been identified and analyzed. These IS2404-positive species cause pathology in frogs and fish. A recently isolated mycobacterial strain from a fish in Belgium was analyzed using a variety of molecular methods and the results were identical to those obtained from a mycolactone-producing M. marinum from Israel.

Complete Genome Sequence of Mycobacterium chimaera Strain AH16.

PubMed

Hasan, Nabeeh A; Honda, Jennifer R; Davidson, Rebecca M; Epperson, L Elaine; Bankowski, Matthew J; Chan, Edward D; Strong, Michael

2016-11-23

Mycobacterium chimaera is a nontuberculous mycobacterial species that causes cardiovascular, pulmonary, and postsurgical infections. Here, we report the first complete genome sequence of M. chimaera This genome is 6.33 Mbp, with a G+C content of 67.56%, and encodes 4,926 protein-coding genes, as well as 74 tRNAs, one ncRNA, and three rRNA genes. Copyright © 2016 Hasan et al.

A novel vaccine p846 encoding Rv3615c, Mtb10.4, and Rv2660c elicits robust immune response and alleviates lung injury induced by Mycobacterium infection.

PubMed

Kong, Hongmei; Dong, Chunsheng; Xiong, Sidong

2014-01-01

Development of effective anti-tuberculosis (TB) vaccines is one of the important steps to improve control of TB. Cell-mediated immune response significantly affects the control of M. tuberculosis infection. Thus, vaccines able to elicit strong cellular immune response hold special advantages against TB. In this study, three well-defined mycobacterial antigens (Rv3615c, Mtb10.4 [Rv0228], and Rv2660c) were engineered as a novel triple-antigen fusion DNA vaccine p846. The p846 vaccine consists of a high density of CD4(+) and CD8(+) T-cell epitopes. Intramuscular immunization of p846 induced robust T cells mediated immune response comparable to that of bacillus Calmette-Guérin (BCG) vaccination but more effective than that of individual antigen vaccination. After mycobacterial challenge, p846 immunization decreased bacterial burden at least 15-fold compared with individual antigen-based vaccination. Notably, the lungs of mice immunized with p846 exhibited fewer inflammatory cell infiltrates and less damage than those of control group mice. Our data demonstrate that the potential of p846 vaccine to protect against TB and the feasibility of this design strategy for further TB vaccine development.

Absence of Mycobacterium bovis infection in dogs and cats residing on infected cattle farms: Michigan, 2002

PubMed Central

WILKINS, M. J.; BARTLETT, P. C.; BERRY, D. E.; PERRY, R. L.; FITZGERALD, S. D.; BERNARDO, T. M.; THOEN, C. O.; KANEENE, J. B.

2008-01-01

SUMMARY A cross-sectional field study was performed to evaluate infection in dogs and cats living on farms with Mycobacterium bovis-infected cattle. The purpose was to determine pet infection status and assess their risk to farm families and/or tuberculosis-free livestock. Data and specimens were collected from 18 cats and five dogs from nine participating farms. ELISA testing for M. bovis and M. avium was conducted. Fifty-one biological samples were cultured; all were negative for M. bovis, although other Mycobacterium species were recovered. No radiographic, serological or skin test evidence of mycobacterial infection was found. These negative results may be due to the low level of M. bovis infection in the cattle and the limited duration of exposure of pets to infected cattle residing on the same farm. No evidence was found to indicate that pets residing on M. bovis-infected Michigan cattle farms pose a risk to humans or M. bovis-free livestock; however, precautionary advice for farm owners was provided. PMID:18325127

Infections in solid-organ transplant recipients.

PubMed Central

Patel, R; Paya, C V

1997-01-01

Solid-organ transplantation is a therapeutic option for many human diseases. Infections are a major complication of solid-organ transplantation. All candidates should undergo a thorough infectious-disease screening prior to transplantation. There are three time frames, influenced by surgical factors, the level of immunosuppression, and environmental exposures, during which infections of specific types most frequently occur posttransplantation. Most infections during the first month are related to surgical complications. Opportunistic infections typically occur from the second to the sixth month. During the late posttransplant period (beyond 6 months), transplantation recipients suffer from the same infections seen in the general community. Opportunistic bacterial infections seen in transplant recipients include those caused by Legionella spp., Nocardia spp., Salmonella spp., and Listeria monocytogenes. Cytomegalovirus is the most common cause of viral infections. Herpes simplex virus, varicella-zoster virus, Epstein-Barr virus and others are also significant pathogens. Fungal infections, caused by both yeasts and mycelial fungi, are associated with the highest mortality rates. Mycobacterial, pneumocystis, and parasitic diseases may also occur. PMID:8993860

High prevalence of Mycobacterium tuberculosis mixed infection in the capital of moderate tuberculosis incidence country.

PubMed

Hajimiri, Elahe Sadat; Masoomi, Morteza; Ebrahimzadeh, Nayereh; Fateh, Abolfazl; Hadizadeh Tasbiti, Alireza; Rahimi Jamnani, Fatemeh; Bahrmand, Ahmad Reza; Mirsaeidi, Mehdi; Vaziri, Farzam; Siadat, Seyed Davar

2016-04-01

Recent studies using molecular epidemiological techniques have demonstrated mixed infection with multiple strains of Mycobacterium tuberculosis especially in countries with high tuberculosis (TB) burden. We aimed to determine the prevalence of mixed infection among patients with TB in the capital of Iran as a country with moderate incidence rate. Samples were collected randomly from January 2011 to December 2013 in Tehran, capital of Iran. A total of 75 M. tuberculosis isolates were genotyped by 24 loci mycobacterial interspersed repetitive unit-variable number tandem repeat typing (MIRU-VNTR) for screening the mixed infection. Twenty patients (20/75) were identified with mixed infection, and the estimated rate of mixed infection was 26.6%. Thirteen out of the 24 loci were able to detect the mixed infection in our study. Mixed infections occur at high prevalence among studied Iranian TB patients. Further research is inevitable to evaluate the association of mixed infection and disease progression and treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Catheter-Salvage in Home Infusion Patients with Central Line-Associated Bloodstream Infection

PubMed Central

Caroff, Daniel A.; Norris, Anne H.; Keller, Sara; Vinnard, Christopher; Zeitler, Kristen E.; Lukaszewicz, Jennifer; Zborowski, Kristine A.; Linkin, Darren R.

2014-01-01

In a retrospective study of home infusion patients with central line-associated bloodstream infection, use of a central venous port, cancer diagnosis, and the absence of systemic inflammatory response syndrome were associated with use of catheter-salvage. Relapse of infection was uncommon. PMID:25465266

Report of two paediatric cases of central line infections caused by species of the genus Kocuria

PubMed Central

Hamula, Camille L.; Dingle, Tanis C.

2016-01-01

Introduction: Species of the genus Kocuria are Gram-positive cocci of the family Micrococcacceae that are ubiquitous in the environment and part of the normal skin and oral flora in humans. A paucity of cases have been reported of Kocuria as human pathogens and there are currently no evidence-based guidelines for managing these uncommon infections. Case presentation: We present two paediatric cases of central line infections with species of the genus Kocuria that required line removal despite antimicrobial therapy. Conclusion: Species of the genus Kocuria are uncommon human pathogens that have rarely been reported to cause opportunistic infections in both adult and paediatric populations. The cases presented here add to the growing body of literature documenting the pathogenicity of these organisms and the possible need for line removal to achieve clinical cure in central line-associated bacteraemia caused by species of the genus Kocuria. PMID:28348760

The Host Response to a Clinical MDR Mycobacterial Strain Cultured in a Detergent-Free Environment: A Global Transcriptomics Approach.

PubMed

Leisching, Gina; Pietersen, Ray-Dean; Mpongoshe, Vuyiseka; van Heerden, Carel; van Helden, Paul; Wiid, Ian; Baker, Bienyameen

2016-01-01

During Mycobacterium tuberculosis (M.tb) infection, the initial interactions between the pathogen and the host cell determines internalization and innate immune response events. It is established that detergents such as Tween alter the mycobacterial cell wall and solubilize various lipids and proteins. The implication of this is significant since induced changes on the cell wall affect macrophage uptake and the immune response to M.tb. Importantly, during transmission between hosts, aerosolized M.tb enters the host in its native form, i.e. in a detergent-free environment, thus in vitro and in vivo studies should mimic this as closely as possible. To this end, we have optimized a procedure for growing and processing detergent-free M.tb and assessed the response of murine macrophages (BMDM) infected with multi drug-resistant M.tb (R179 Beijing 220 clinical isolate) using RNAseq. We compared the effects of the host response to M.tb cultured under standard laboratory conditions (Tween 80 containing medium -R179T), or in detergent-free medium (R179NT). RNAseq comparisons reveal 2651 differentially expressed genes in BMDMs infected with R179T M.tb vs. BMDMs infected with R179NT M.tb. A range of differentially expressed genes involved in BMDM receptor interaction with M.tb (Mrc1, Ifngr1, Tlr9, Fpr1 and Itgax) and pro-inflammatory cytokines/chemokines (Il6, Il1b, Tnf, Ccl5 and Cxcl14) were selected for analysis through qPCR. BMDMs infected with R179NT stimulate a robust inflammatory response. Interestingly, R179NT M.tb induce transcription of Fpr1, a receptor which detects bacterial formyl peptides and initiates a myriad of immune responses. Additionally we show that the host components Cxcl14, with an unknown role in M.tb infection, and Tlr9, an emerging role player, are only stimulated by infection with R179NT M.tb. Taken together, our results suggest that the host response differs significantly in response to Tween 80 cultured M.tb and should therefore not be used in infection experiments.

Imaging the NADH:NAD+ Homeostasis for Understanding the Metabolic Response of Mycobacterium to Physiologically Relevant Stresses

PubMed Central

Bhat, Shabir A.; Iqbal, Iram K.; Kumar, Ashwani

2016-01-01

The NADH:NAD+ ratio is the primary indicator of the metabolic state of bacteria. NAD(H) homeostasis is critical for Mycobacterium tuberculosis (Mtb) survival and is thus considered an important drug target, but the spatio-temporal measurements of NAD(H) remain a challenge. Genetically encoded fluorescent biosensors of the NADH:NAD+ ratios were recently described, paving the way for investigations of the metabolic state of pathogens during infection. Here we have adapted the genetically encoded biosensor Peredox for measurement of the metabolic state of Mtb in vitro and during infection of macrophage cells. Using Peredox, here we show that inhibition of the electron transport chain, disruption of the membrane potential and proton gradient, exposure to reactive oxygen species and treatment with antimycobacterial drugs led to the accumulation of NADH in mycobacterial cells. We have further demonstrated that Mtb residing in macrophages displays higher NADH:NAD+ ratios, that may indicate a metabolic stress faced by the intracellular Mtb. We also demonstrate that the Mtb residing in macrophages display a metabolic heterogeneity, which may perhaps explain the tolerance displayed by intracellular Mtb. Next we studied the effect of immunological modulation by interferon gamma on metabolism of intracellular Mtb, since macrophage activation is known to restrict mycobacterial growth. We observed that activation of resting macrophages with interferon-gamma results in higher NADH:NAD+ levels in resident Mtb cells. We have further demonstrated that exposure of Isoniazid, Bedaquiline, Rifampicin, and O-floxacin results in higher NADH:NAD+ ratios in the Mtb residing in macrophages. However, intracellular Mtb displays lower NADH:NAD+ ratio upon exposure to clofazimine. In summary, we have generated reporter strains capable of measuring the metabolic state of Mtb cells in vitro and in vivo with spatio-temporal resolution. We believe that this tool will facilitate further studies on mycobacterial physiology and will create new avenues of research for anti-tuberculosis drug discovery. PMID:27878107

Imaging the NADH:NAD+ Homeostasis for Understanding the Metabolic Response of Mycobacterium to Physiologically Relevant Stresses.

PubMed

Bhat, Shabir A; Iqbal, Iram K; Kumar, Ashwani

2016-01-01

The NADH:NAD + ratio is the primary indicator of the metabolic state of bacteria. NAD(H) homeostasis is critical for Mycobacterium tuberculosis (Mtb) survival and is thus considered an important drug target, but the spatio-temporal measurements of NAD(H) remain a challenge. Genetically encoded fluorescent biosensors of the NADH:NAD + ratios were recently described, paving the way for investigations of the metabolic state of pathogens during infection. Here we have adapted the genetically encoded biosensor Peredox for measurement of the metabolic state of Mtb in vitro and during infection of macrophage cells. Using Peredox, here we show that inhibition of the electron transport chain, disruption of the membrane potential and proton gradient, exposure to reactive oxygen species and treatment with antimycobacterial drugs led to the accumulation of NADH in mycobacterial cells. We have further demonstrated that Mtb residing in macrophages displays higher NADH:NAD + ratios, that may indicate a metabolic stress faced by the intracellular Mtb. We also demonstrate that the Mtb residing in macrophages display a metabolic heterogeneity, which may perhaps explain the tolerance displayed by intracellular Mtb. Next we studied the effect of immunological modulation by interferon gamma on metabolism of intracellular Mtb, since macrophage activation is known to restrict mycobacterial growth. We observed that activation of resting macrophages with interferon-gamma results in higher NADH:NAD + levels in resident Mtb cells. We have further demonstrated that exposure of Isoniazid, Bedaquiline, Rifampicin, and O-floxacin results in higher NADH:NAD + ratios in the Mtb residing in macrophages. However, intracellular Mtb displays lower NADH:NAD + ratio upon exposure to clofazimine. In summary, we have generated reporter strains capable of measuring the metabolic state of Mtb cells in vitro and in vivo with spatio-temporal resolution. We believe that this tool will facilitate further studies on mycobacterial physiology and will create new avenues of research for anti-tuberculosis drug discovery.

Detection and differentiation of Mycobacterium tuberculosis and nontuberculous mycobacterial isolates by real-time PCR.

PubMed

Shrestha, Nabin K; Tuohy, Marion J; Hall, Gerri S; Reischl, Udo; Gordon, Steven M; Procop, Gary W

2003-11-01

Mycobacteria cause a variety of illnesses that differ in severity and public health implications. The differentiation of Mycobacterium tuberculosis from nontuberculous mycobacteria (NTM) is of primary importance for infection control and choice of antimicrobial therapy. Despite advances in molecular diagnostics, the ability to rapidly diagnose M. tuberculosis infections by PCR is still inadequate, largely because of the possibility of false-negative reactions. We designed and validated a real-time PCR for mycobacteria by using the LightCycler system with 18 reference strains and 168 clinical mycobacterial isolates. All clinically significant mycobacteria were detected; the mean melting temperatures (with 99.9% confidence intervals [99.9% CI] in parentheses) for the different mycobacteria were as follows: M. tuberculosis, 64.35 degrees C (63.27 to 65.42 degrees C); M. kansasii, 59.20 degrees C (58.07 to 60.33 degrees C); M. avium, 57.82 degrees C (57.05 to 58.60 degrees C); M. intracellulare, 54.46 degrees C (53.69 to 55.23 degrees C); M. marinum, 58.91 degrees C (58.28 to 59.55 degrees C); rapidly growing mycobacteria, 53.09 degrees C (50.97 to 55.20 degrees C) or 43.19 degrees C (42.19 to 44.49 degrees C). This real-time PCR assay with melting curve analysis consistently accurately detected and differentiated M. tuberculosis from NTM. Detection of an NTM helps ensure that the negative result for M. tuberculosis is a true negative. The specific melting temperature also provides a suggestion of the identity of the NTM present, when the most commonly encountered mycobacterial species are considered. In a parallel comparison, both the LightCycler assay and the COBAS Amplicor M. tuberculosis assay correctly categorized 48 of 50 specimens that were proven by culture to contain M. tuberculosis, and the LightCycler assay correctly characterized 3 of 3 specimens that contained NTM.

Detection and Differentiation of Mycobacterium tuberculosis and Nontuberculous Mycobacterial Isolates by Real-Time PCR

PubMed Central

Shrestha, Nabin K.; Tuohy, Marion J.; Hall, Gerri S.; Reischl, Udo; Gordon, Steven M.; Procop, Gary W.

2003-01-01

Mycobacteria cause a variety of illnesses that differ in severity and public health implications. The differentiation of Mycobacterium tuberculosis from nontuberculous mycobacteria (NTM) is of primary importance for infection control and choice of antimicrobial therapy. Despite advances in molecular diagnostics, the ability to rapidly diagnose M. tuberculosis infections by PCR is still inadequate, largely because of the possibility of false-negative reactions. We designed and validated a real-time PCR for mycobacteria by using the LightCycler system with 18 reference strains and 168 clinical mycobacterial isolates. All clinically significant mycobacteria were detected; the mean melting temperatures (with 99.9% confidence intervals [99.9% CI] in parentheses) for the different mycobacteria were as follows: M. tuberculosis, 64.35°C (63.27 to 65.42°C); M. kansasii, 59.20°C (58.07 to 60.33°C); M. avium, 57.82°C (57.05 to 58.60°C); M. intracellulare, 54.46°C (53.69 to 55.23°C); M. marinum, 58.91°C (58.28 to 59.55°C); rapidly growing mycobacteria, 53.09°C (50.97 to 55.20°C) or 43.19°C (42.19 to 44.49°C). This real-time PCR assay with melting curve analysis consistently accurately detected and differentiated M. tuberculosis from NTM. Detection of an NTM helps ensure that the negative result for M. tuberculosis is a true negative. The specific melting temperature also provides a suggestion of the identity of the NTM present, when the most commonly encountered mycobacterial species are considered. In a parallel comparison, both the LightCycler assay and the COBAS Amplicor M. tuberculosis assay correctly categorized 48 of 50 specimens that were proven by culture to contain M. tuberculosis, and the LightCycler assay correctly characterized 3 of 3 specimens that contained NTM. PMID:14605148

Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders.

PubMed

Park, Sanghui; Ko, Young H

2014-01-01

Primary infection with Epstein-Barr virus (EBV) is usually asymptomatic and, in a normal host, EBV remains latent in B cells after primary infection for the remainder of life. Uncommonly, EBV can infect T or natural killer (NK) cells in a person with a defect in innate immunity, and EBV infection can cause unique systemic lymphoproliferative diseases (LPD) of childhood. Primary infection in young children can be complicated by hemophagocytic lymphohistiocytosis or fulminant systemic T-cell LPD of childhood. Uncommonly, patients can develop chronic active EBV (CAEBV) disease-type T/NK LPD, which includes CAEBV infection of the systemic form, hydroa vacciniforme-like T-cell LPD, and mosquito-bite hypersensitivity. The clinical course of CAEBV disease-type T/NK LPD can be smoldering, persistent or progressive, depending on the balance between viral factors and host immunity. Aggressive NK-cell leukemia, hydroa vacciniforme-like T-cell lymphoma, or uncommonly extranodal NK/T-cell lymphoma can develop in children and young adults with CAEBV disease-type T/NK-cell LPD. Extranodal T/NK-cell lymphoma is a disease of adults, and its incidence begins to increase in the third decade and comprises the major subtype of T/NK LPD throughout life. Aggressive NK-cell leukemia and nodal T/NK-cell lymphoma of the elderly are fulminant diseases, and immune senescence may be an important pathogenetic factor. This review describes the current progress in identifying different types of EBV-associated T/NK-cell LPD and includes a brief presentation of data from Korea. © 2014 Japanese Dermatological Association.

Coincident filarial, intestinal helminth, and mycobacterial infection: helminths fail to influence tuberculin reactivity, but BCG influences hookworm prevalence.

PubMed

Lipner, Ettie M; Gopi, P G; Subramani, R; Kolappan, C; Sadacharam, K; Kumaran, Paul; Prevots, D Rebecca; Narayanan, P R; Nutman, Thomas B; Kumaraswami, V

2006-05-01

The prevalence of helminth and tuberculosis infections is high in South India, whereas Bacille-Calmette-Guerin (BCG) vaccine efficacy is low. Our aim was to determine whether concurrent helminth infection alters the ability to mount a delayed-type hypersensitivity response to tuberculin. In a cross-sectional study in southern India, individuals 6-65 years of age were screened for intestinal helminths, circulating filarial antigenemia, tuberculin reactivity, active tuberculosis, and history of BCG vaccination; 54% were purified protein derivative (PPD) positive, 32% had intestinal helminth infection, 9% were circulating filarial antigen positive, and 0.5% had culture-confirmed active tuberculosis. Only age and BCG vaccination were significantly associated with PPD reactivity; however, BCG vaccination was associated with a lower prevalence of hookworm infection relative to those without prior BCG vaccination. Neither intestinal helminth infection nor filarial infection was associated with diminished frequencies of PPD positivity. Our findings suggest that preceding helminth infection does not influence significantly the delayed-type hypersensitivity response to tuberculin.

Mycobacterium fortuitum Infection at Umbilical Hernioplasty Site

PubMed Central

Chogtu, Bharti; Malik, Daliparty Vasudev; Shenoy, Vishnu Prasad

2017-01-01

Non Tuberculous Mycobacteria (NTM) are a group of rapidly growing mycobacteria and are generally considered to be of low virulence. Of late, there has been an increase in incidence of infections due to these organisms. Among them, Mycobacterium fortuitum, M. chelonae and M. abscessus are the common species which have been identified. Though they are occasionally implicated in pulmonary infections, NTM are very commonly associated with cutaneous infections, especially surgical site infections. Identification of NTM infection at such sites should be suspected when there is delayed healing of the wound. Histopathological Examination (HPE) of the wound site may reveal a classical picture of granulomas, epithelioid cells and giant cells which may lead to a suspicion of tuberculosis. It is important to perform mycobacterial culture and sensitivity testing of the wound tissue as this helps to differentiate tuberculous and non tuberculous infections. Here, we present a case of a patient who underwent mesh hernioplasty for umbilical hernia and was diagnosed with M. fortuitum infection at the site of umbilical hernioplasty. PMID:29207758

Obstructive sleep apnea (OSA): a complication of acute infectious mononucleosis infection in a child.

PubMed

Cheng, Jeffrey

2014-03-01

Independently, obstructive sleep apnea (OSA) and infectious mononucleosis are not uncommon in the pediatric population, but acute onset of OSA, as a respiratory complication in the setting of acute EBV infection is extremely uncommon. Previous reports of this clinical entity are sparse and from nearly two decades ago. Urgent adenotonsillectomy was commonly advocated. This complication may be managed medically with systemic corticosteroids and non-invasive continuous positive airway pressure (CPAP), and a case is presented to highlight an updated management approach to this rarely encountered clinical problem in children. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Co-occurrence of chancroid and gonorrhea.

PubMed

Nawaf, Al-Mutairi; Joshi, Arun; Tayeh, Mohammad

2006-01-01

Gonorrhea and chancroid are common sexually transmitted infections in many parts of the world. Still, co-occurrence of these two conditions is uncommonly reported. We present here a patient who presented with painful genital ulcers and urethral discharge simultaneously acquired from a single exposure, which turned out to be chancroid and gonorrhea, respectively. Both conditions responded well to a single intramuscular dose of ceftriaxone 250 mg. This report describes the uncommon occurrence of gonorrhea and chancroid in a patient. Clinical features, relevant investigations, treatment options of these two sexually transmitted infections, and possible implications in view of the human immunodeficiency virus (HIV) pandemic are briefly discussed.

Seroepidemiological Study of Toxoplasmosis in Intellectual Disability Children in Rehabilitation Centers of Northern Iran

ERIC Educational Resources Information Center

Sharif, M.; Ziaei, H.; Daryani, A.; Ajami, A.

2007-01-01

Serological studies revealed that toxoplasmosis has world wide distribution. Although the infection by "Toxoplasma gondii" is widely prevalent in humans and animals, the disease is uncommon and most of the acquired infections are asymptomatic. The important aspect of this parasitic infection is the probable danger of congenital…

Impact of polymicrobial biofilms in catheter-associated urinary tract infections.

PubMed

Azevedo, Andreia S; Almeida, Carina; Melo, Luís F; Azevedo, Nuno F

2017-08-01

Recent reports have demonstrated that most biofilms involved in catheter-associated urinary tract infections are polymicrobial communities, with pathogenic microorganisms (e.g. Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and uncommon microorganisms (e.g. Delftia tsuruhatensis, Achromobacter xylosoxidans) frequently co-inhabiting the same urinary catheter. However, little is known about the interactions that occur between different microorganisms and how they impact biofilm formation and infection outcome. This lack of knowledge affects CAUTIs management as uncommon bacteria action can, for instance, influence the rate at which pathogens adhere and grow, as well as affect the overall biofilm resistance to antibiotics. Another relevant aspect is the understanding of factors that drive a single pathogenic bacterium to become prevalent in a polymicrobial community and subsequently cause infection. In this review, a general overview about the IMDs-associated biofilm infections is provided, with an emphasis on the pathophysiology and the microbiome composition of CAUTIs. Based on the available literature, it is clear that more research about the microbiome interaction, mechanisms of biofilm formation and of antimicrobial tolerance of the polymicrobial consortium are required to better understand and treat these infections.

HLA-B*35-Restricted CD8+-T-Cell Epitope in Mycobacterium tuberculosis Rv2903c

PubMed Central

Klein, Michèl R.; Hammond, Abdulrahman S.; Smith, Steve M.; Jaye, Assan; Lukey, Pauline T.; McAdam, Keith P. W. J.

2002-01-01

Few human CD8+ T-cell epitopes in mycobacterial antigens have been described to date. Here we have identified a novel HLA-B*35-restricted CD8+ T-cell epitope in Mycobacterium tuberculosis Rv2903c based on a reverse immunogenetics approach. Peptide-specific CD8 T cells were able to kill M. tuberculosis-infected macrophages and produce gamma interferon and tumor necrosis factor alpha. PMID:11796635

Conflicting Role of Mycobacterium Species in Multiple Sclerosis

PubMed Central

Cossu, Davide; Yokoyama, Kazumasa; Hattori, Nobutaka

2017-01-01

Mycobacterium is a genus of aerobic and acid-fast bacteria, which include several pathogenic organisms that cause serious diseases in mammals. Previous studies have associated the immune response against mycobacteria with multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system with unknown etiology. The role of mycobacteria in the pathological process has been controversial and often conflicting. We provide a detailed review of the mycobacteria that have been linked to MS over the last three decades, with a focus on Mycobacterium bovis bacille Calmette–Guérin vaccine for human and oral exposure to Mycobacterium avium subsp. paratuberculosis. We will also discuss the exposure and genetic susceptibility to mycobacterial infection, the protective role of vaccination, as well as the possible mechanisms involved in initiating or worsening MS symptoms, with particular emphasis on the molecular mimicry between mycobacterial and human proteins. Finally, we will introduce topics such as heat shock proteins and recognition by innate immunity, and toll-like receptor signaling-mediated responses to Mycobacterium exposure. PMID:28579973

Origin, Spread and Demography of the Mycobacterium tuberculosis Complex

PubMed Central

Wirth, Thierry; Hildebrand, Falk; Allix-Béguec, Caroline; Wölbeling, Florian; Kubica, Tanja; Kremer, Kristin; van Soolingen, Dick; Rüsch-Gerdes, Sabine; Locht, Camille; Brisse, Sylvain; Meyer, Axel

2008-01-01

The evolutionary timing and spread of the Mycobacterium tuberculosis complex (MTBC), one of the most successful groups of bacterial pathogens, remains largely unknown. Here, using mycobacterial tandem repeat sequences as genetic markers, we show that the MTBC consists of two independent clades, one composed exclusively of M. tuberculosis lineages from humans and the other composed of both animal and human isolates. The latter also likely derived from a human pathogenic lineage, supporting the hypothesis of an original human host. Using Bayesian statistics and experimental data on the variability of the mycobacterial markers in infected patients, we estimated the age of the MTBC at 40,000 years, coinciding with the expansion of “modern” human populations out of Africa. Furthermore, coalescence analysis revealed a strong and recent demographic expansion in almost all M. tuberculosis lineages, which coincides with the human population explosion over the last two centuries. These findings thus unveil the dynamic dimension of the association between human host and pathogen populations. PMID:18802459

Infectious complications of the primary immunodeficiencies.

PubMed

Stiehm, E R; Chin, T W; Haas, A; Peerless, A G

1986-07-01

The primary manifestation of the immunodeficiencies is undue susceptibility to infection. This means too many, too severe, too prolonged, too complicated and too unusual infections. Infections in immunodeficiency have a characteristic cause depending on the nature of the immune deficiency. Antibody deficiencies are associated with infections with gram-positive infections. Cellular immune deficiencies are associated with mycobacterial, protozoan, fungus, virus, and opportunistic bacterial infection. Phagocytic disorders are associated with staphylococcal, fungal, and gram-negative organisms. Complement disorders are associated by neisserial infections. Infections have also been implicated in the pathogenesis of some immunodeficiencies in some circumstances. These include human T lymphotropic virus type III (HTLV-III), rubella virus, cytomegalovirus, and Epstein-Barr virus. Several infectious syndromes in specific immunodeficiencies have been identified. Examples include enteric cytopathic human orphan (ECHO) virus encephalitis in agammaglobulinemia, and meningococcal meningitis in C6 deficiency. Infections can also be induced by live vaccines given in immunodeficiency (e.g., paralytic polio in agammaglobulinemia.) Unusual infectious syndromes will be illustrated including parainfluenza infection in severe combined and immunodeficiency, Legionella pneumonia in chronic granulomatous disease, and Cryptosporidium infection in hyper-IgM immunodeficiency.

Effects of mycobacteria on regulation of apoptosis in mononuclear phagocytes.

PubMed Central

Klingler, K; Tchou-Wong, K M; Brändli, O; Aston, C; Kim, R; Chi, C; Rom, W N

1997-01-01

Since apoptosis is observed in tuberculous granulomata, we investigated the molecular mechanisms underlying the apoptotic pathway in an in vitro model of mycobacterial infection of mononuclear phagocytes. We postulated that Mycobacterium tuberculosis could trigger the apoptotic pathway in macrophages, resulting in death of the microorganism by modulating the expression of bcl-2, bax, bcl-xL, and bcl-xS. We found that the mRNA of bcl-2, an inhibitor of apoptosis, was downregulated in peripheral blood monocytes (PBM) between 2 and 6 h following infection with M. bovis BCG or induction with heat-killed M. tuberculosis H37Ra. Western analysis showed a downregulation of the Bcl-2 protein, with a half-life of 24 h. At the same time points, there was no change in the expression of Bax or Bcl-xS, inducers of apoptosis, but Bcl-xL, another inhibitor of apoptosis, was minimally upregulated by BCG. To determine if apoptosis could be a mechanism for growth inhibition in vivo, we obtained alveolar macrophages by bronchoalveolar lavage from involved sites in patients with active pulmonary tuberculosis. Using the TUNEL (terminal deoxynucleotidyltransferase mediated nick end labeling) technique, we observed significantly more apoptosis in involved segments of five tuberculosis patients (14.8 +/- 1.9%) than in those of normal controls (<1%, P = 0.02) or in uninvolved segments (4.3 +/- 0.9%, P < 0.05). We conclude that apoptosis of mononuclear phagocytes induced by M. tuberculosis occurs in vivo and that in an in vitro model of mycobacterial infection, apoptosis may be mediated by downregulation of Bcl-2. PMID:9393826

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

PubMed Central

Walker, Naomi F.; Clark, Simon O.; Oni, Tolu; Andreu, Nuria; Tezera, Liku; Singh, Shivani; Saraiva, Luísa; Pedersen, Bernadette; Kelly, Dominic L.; Tree, Julia A.; D'Armiento, Jeanine M.; Meintjes, Graeme; Mauri, Francesco A.; Williams, Ann; Wilkinson, Robert J.; Friedland, Jon S.

2012-01-01

Rationale: Tuberculosis kills more than 1.5 million people per year, and standard treatment has remained unchanged for more than 30 years. Tuberculosis (TB) drives matrix metalloproteinase (MMP) activity to cause immunopathology. In advanced HIV infection, tissue destruction is reduced, but underlying mechanisms are poorly defined and no current antituberculous therapy reduces host tissue damage. Objectives: To investigate MMP activity in patients with TB with and without HIV coinfection and to determine the potential of doxycycline to inhibit MMPs and decrease pathology. Methods: Concentrations of MMPs and cytokines were analyzed by Luminex array in a prospectively recruited cohort of patients. Modulation of MMP secretion and Mycobacterium tuberculosis growth by doxycycline was studied in primary human cells and TB-infected guinea pigs. Measurements and Main Results: HIV coinfection decreased MMP concentrations in induced sputum of patients with TB. MMPs correlated with clinical markers of tissue damage, further implicating dysregulated protease activity in TB-driven pathology. In contrast, cytokine concentrations were no different. Doxycycline, a licensed MMP inhibitor, suppressed TB-dependent MMP-1 and -9 secretion from primary human macrophages and epithelial cells by inhibiting promoter activation. In the guinea pig model, doxycycline reduced lung TB colony forming units after 8 weeks in a dose-dependent manner compared with untreated animals, and in vitro doxycycline inhibited mycobacterial proliferation. Conclusions: HIV coinfection in patients with TB reduces concentrations of immunopathogenic MMPs. Doxycycline decreases MMP activity in a cellular model and suppresses mycobacterial growth in vitro and in guinea pigs. Adjunctive doxycycline therapy may reduce morbidity and mortality in TB. PMID:22345579

[Evaluation of mycobacterial microscopy and culture results of Sureyyapasa Chest Diseases and Chest Surgery Training and Research Hospital: A 3-year analysis].

PubMed

Akduman Alaşehir, Elçin; Balıkçı, Ahmet; Partal, Mualla; Çatmabacak, Gülay; Yaman, Görkem

2016-09-01

Effective diagnosis of tuberculosis is of great importance for transmission control and treatment success. The purpose of this study is to evaluate microscopic examination results of Ehrlich-Ziehl Neelsen (EZN) and Auramine-Rhodamine staining methods and automated BACTEC MGIT 960™ system and Löwenstein-Jensen (L-J) culture results of various clinical samples in the light of recent data from the world and Turkey. Specimens that were sent from various clinics to Sureyyapasa Chest Diseases and Chest Surgery Training and Research Hospital Microbiology Laboratory from January 2012 to December 2015 were evaluated retrospectively. From a total of 62456 samples; 60923 (97.5%) were pulmonary and 1533 (2.5%) were non-pulmonary samples, especially pleura. 2853 (4.6%) Acid-resistant bacilli (ARB) positivity was detected and mycobacterial culture positivity was in total 12.2%. 7076 (93%) and 535 (7%) mycobacteria other than tuberculosis (MOTT) strains were isolated. In 356 specimens the cultures were negative in despite the positive ARB results. Considering mycobacterial culture as the gold standard; the sensitivity, specificity, positive and negative predictive values of ARB microscopy were 32.8%, 99.4%, 87.5% and 91.4%, respectively. The contamination rates in total were within acceptable limits being 2.7% for L-J and 3.8% for MGIT. Analysis of our data indicated that the sensitivity of microscopy is low and it should be evaluated together with the mycobacterial culture to rule out tuberculosis infection. With the use of fluorescent staining and also L-J and MGIT broth together for routine culture since 2013; ARB false negativity rate was observed to fall to 51.7% from 74.1% compared to the years. The follow-up of data such as the sensitivity of microscopy, culture positivity, false-positivity and false-negativity rates and contamination values is of great importance in terms of assessing compliance with laboratory quality standards and contributing to the surveillance studies.

The Burden of Pulmonary Nontuberculous Mycobacterial Disease in the United States

PubMed Central

Strollo, Sara E.; Adjemian, Jennifer; Adjemian, Michael K.

2015-01-01

Rationale: State-specific case numbers and costs are critical for quantifying the burden of pulmonary nontuberculous mycobacterial disease in the United States. Objectives: To estimate and project national and state annual cases of nontuberculous mycobacterial disease and associated direct medical costs. Methods: Available direct cost estimates of nontuberculous mycobacterial disease medical encounters were applied to nontuberculous mycobacterial disease prevalence estimates derived from Medicare beneficiary data (2003–2007). Prevalence was adjusted for International Classification of Diseases, 9th Revision, undercoding and the inclusion of persons younger than 65 years of age. U.S. Census Bureau data identified 2010 and 2014 population counts and 2012 primary insurance-type distribution. Medical costs were reported in constant 2014 dollars. Projected 2014 estimates were adjusted for population growth and assumed a previously published 8% annual growth rate of nontuberculous mycobacterial disease prevalence. Measurements and Main Results: In 2010, we estimated 86,244 national cases, totaling to $815 million, of which 87% were inpatient related ($709 million) and 13% were outpatient related ($106 million). Annual state estimates varied from 48 to 12,544 cases ($503,000–$111 million), with a median of 1,208 cases ($11.5 million). Oceanic coastline states and Gulf States comprised 70% of nontuberculous mycobacterial disease cases but 60% of the U.S. population. Medical encounters among individuals aged 65 years and older ($562 million) were twofold higher than those younger than 65 years of age ($253 million). Of all costs incurred, medications comprised 76% of nontuberculous mycobacterial disease expenditures. Projected 2014 estimates resulted in 181,037 national annual cases ($1.7 billion). Conclusions: For a relatively rare disease, the financial cost of nontuberculous mycobacterial disease is substantial, particularly among older adults. Better data on disease dynamics and more recent prevalence estimates will generate more robust estimates. PMID:26214350

Reversible Lipid Accumulation and Associated Division Arrest of Mycobacterium avium in Lipoprotein-Induced Foamy Macrophages May Resemble Key Events during Latency and Reactivation of Tuberculosis

PubMed Central

Caire-Brändli, Irène; Papadopoulos, Alexia; Malaga, Wladimir; Marais, David; Canaan, Stéphane; Thilo, Lutz

2014-01-01

During the dormant phase of tuberculosis, Mycobacterium tuberculosis persists in lung granulomas by residing in foamy macrophages (FM) that contain abundant lipid bodies (LB) in their cytoplasm, allowing bacilli to accumulate lipids as intracytoplasmic lipid inclusions (ILI). An experimental model of FM is presented where bone marrow-derived mouse macrophages are infected with M. avium and exposed to very-low-density lipoprotein (VLDL) as a lipid source. Quantitative analysis of detailed electron microscope observations showed the following results. (i) Macrophages became foamy, and mycobacteria formed ILI, for which host triacylglycerides, rather than cholesterol, was essential. (ii) Lipid transfer occurred via mycobacterium-induced fusion between LB and phagosomes. (iii) Mycobacteria showed a thinned cell wall and became elongated but did not divide. (iv) Upon removal of VLDL, LB and ILI declined within hours, and simultaneous resumption of mycobacterial division restored the number of mycobacteria to the same level as that found in untreated control macrophages. This showed that the presence of ILI resulted in a reversible block of division without causing a change in the mycobacterial replication rate. Fluctuation between ILI either partially or fully extending throughout the mycobacterial cytoplasm was suggestive of bacterial cell cycle events. We propose that VLDL-driven FM constitute a well-defined cellular system in which to study changed metabolic states of intracellular mycobacteria that may relate to persistence and reactivation of tuberculosis. PMID:24478064

Epidural mass due to aspergillus flavus causing spinal cord compression--a case report and brief update.

PubMed

Tendolkar, U; Sharma, A; Mathur, M; Ranadive, N; Sachdev, M

2005-07-01

Aspergillus infection of the central nervous system (CNS) is an uncommon disease. Most of the reported cases are of sinocranial spread and cases with contiguous spread to spinal cord from lung and other organs are uncommon. A case of pulmonary aspergillosis with extension to thoracic vertebrae forming a paraspinal mass resulting in neurological deficit due to Aspergillus flavus, is reported. The 43 year old patient did not have any obvious predisposing condition. He presented with loss of motor function and succumbed to the infection despite operative intervention and antifungal therapy. A brief update on CNS aspergillosis is presented along with detailed clinical, radiological and laboratory work up of the patient.

Badger macrophages fail to produce nitric oxide, a key anti-mycobacterial effector molecule.

PubMed

Bilham, Kirstin; Boyd, Amy C; Preston, Stephen G; Buesching, Christina D; Newman, Chris; Macdonald, David W; Smith, Adrian L

2017-04-06

The European badger is recognised as a wildlife reservoir for bovine tuberculosis (bTB); the control of which is complex, costly and controversial. Despite the importance of badgers in bTB and the well-documented role for macrophages as anti-mycobacterial effector cells, badger macrophage (bdMφ) responses remain uncharacterised. Here, we demonstrate that bdMφ fail to produce nitric oxide (NO) or upregulate inducible nitric oxide synthase (iNOS) mRNA following Toll-like receptor (TLR) agonist treatment. BdMφ also failed to make NO after stimulation with recombinant badger interferon gamma (bdIFNγ) or a combination of bdIFNγ and lipopolysaccharide. Exposure of bdMφ to TLR agonists and/or bdIFNγ resulted in upregulated cytokine (IL1β, IL6, IL12 and TNFα) mRNA levels indicating that these critical pathways were otherwise intact. Although stimulation with most TLR agonists resulted in strong cytokine mRNA responses, weaker responses were evident after exposure to TLR9 agonists, potentially due to very low expression of TLR9 in bdMφ. Both NO and TLR9 are important elements of innate immunity to mycobacteria, and these features of bdMφ biology would impair their capacity to resist bTB infection. These findings have significant implications for the development of bTB management strategies, and support the use of vaccination to reduce bTB infection in badgers.

MRP8/14 induces autophagy to eliminate intracellular Mycobacterium bovis BCG.

PubMed

Wang, Jinli; Huang, Chunyu; Wu, Minhao; Zhong, Qiu; Yang, Kun; Li, Miao; Zhan, Xiaoxia; Wen, Jinsheng; Zhou, Lin; Huang, Xi

2015-04-01

To explore the role of myeloid-related protein 8/14 in mycobacterial infection. The mRNA and protein expression levels of MRP8 or MRP14 were measured by real-time PCR and flow cytometry, respectively. Role of MRP8/14 was tested by overexpression or RNA interference assays. Flow cytometry and colony forming unit were used to test the phagocytosis and the survival of intracellular Mycobacterium bovis BCG (BCG), respectively. Autophagy mediated by MRP8/14 was detected by Western blot and immunofluorescence. The colocalization of BCG phagosomes with autophagosomes or lysosomes was by detected by confocal microscopy. ROS production was detected by flow cytometry. MRP8/14 expressions were up-regulated in human monocytic THP1 cells and primary macrophages after mycobacterial challenge. Silencing of MRP8/14 suppressed bacterial killing, but had no influence on the phagocytosis of BCG. Importantly, silencing MRP8/14 decreased autophagy and BCG phagosome maturation in THP1-derived macrophages, thereby increasing the BCG survival. Additionally, we demonstrated that MRP8/14 promoted autophagy in a ROS-dependent manner. The present study revealed a novel role of MRP8/14 in the autophagy-mediated elimination of intracellular BCG by promoting ROS generation, which may provide a promising therapeutic target for tuberculosis and other intracellular bacterial infectious diseases. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Structural Biology and the Design of New Therapeutics: From HIV and Cancer to Mycobacterial Infections: A Paper Dedicated to John Kendrew.

PubMed

Thomas, Sherine E; Mendes, Vitor; Kim, So Yeon; Malhotra, Sony; Ochoa-Montaño, Bernardo; Blaszczyk, Michal; Blundell, Tom L

2017-08-18

Interest in applications of protein crystallography to medicine was evident, as the first high-resolution structures emerged in the 50s and 60s. In Cambridge, Max Perutz and John Kendrew sought to understand mutations in sickle cell and other genetic diseases related to hemoglobin, while in Oxford, the group of Dorothy Hodgkin became interested in long-lasting zinc-insulin crystals for treatment of diabetes and later considered insulin redesign, as synthetic insulins became possible. The use of protein crystallography in structure-guided drug discovery emerged as enzyme structures allowed the identification of potential inhibitor-binding sites and optimization of interactions of hits using the structure of the target protein. Early examples of this approach were the use of the structure of renin to design antihypertensives and the structure of HIV protease in design of AIDS antivirals. More recently, use of structure-guided design with fragment-based drug discovery, which reduces the size of screening libraries by decreasing complexity, has improved ligand efficiency in drug design and has been used to progress three oncology drugs through clinical trials to FDA approval. We exemplify current developments in structure-guided target identification and fragment-based lead discovery with efforts to develop new antimicrobials for mycobacterial infections. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

The management of non-tuberculous cervicofacial lymphadenitis in children: A systematic review and meta-analysis.

PubMed

Zimmermann, Petra; Tebruegge, Marc; Curtis, Nigel; Ritz, Nicole

2015-07-01

Cervicofacial lymphadenitis is the most common manifestation of infection with non-tuberculous mycobacteria (NTM) in immunocompetent children. Although complete excision is considered standard management, the optimal treatment remains controversial. This study reviews the evidence for different management options for NTM lymphadenitis. A systematic literature review and meta-analysis were performed including 1951 children from sixty publications. Generalised linear mixed model regressions were used to compare treatment modalities. The adjusted mean cure rate was 98% (95% CI 97.0-99.5%) for complete excision, 73.1% (95% CI 49.6-88.3%) for anti-mycobacterial antibiotics, and 70.4% (95% CI 49.6-88.3%) for 'no intervention'. Compared to 'no intervention', only complete excision was significantly associated with cure (OR 33.1; 95% CI 10.8-102.9; p < 0.001). Complete excision was associated with a 10% risk of facial nerve palsy (2% permanent). 'No intervention' was associated with delayed resolution. Complete excision is associated with the highest cure rate in NTM cervicofacial lymphadenitis, but also had the highest risk of facial nerve palsy. In the absence of large, well-designed RCTs, the choice between surgical excision, anti-mycobacterial antibiotics and 'no intervention' should be based on the location and extent of the disease, and acceptability of prolonged time to resolution. Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

High Mortality and Coinfection in a Prospective Cohort of Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome Patients with Histoplasmosis in Guatemala.

PubMed

Samayoa, Blanca; Roy, Monika; Cleveland, Angela Ahlquist; Medina, Narda; Lau-Bonilla, Dalia; Scheel, Christina M; Gomez, Beatriz L; Chiller, Tom; Arathoon, Eduardo

2017-07-01

Histoplasmosis is one of the most common and deadly opportunistic infections among persons living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome in Latin America, but due to limited diagnostic capacity in this region, few data on the burden and clinical characteristics of this disease exist. Between 2005 and 2009, we enrolled patients ≥ 18 years of age with suspected histoplasmosis at a hospital-based HIV clinic in Guatemala City. A case of suspected histoplasmosis was defined as a person presenting with at least three of five clinical or radiologic criteria. A confirmed case of histoplasmosis was defined as a person with a positive culture or urine antigen test for Histoplasma capsulatum . Demographic and clinical data were also collected and analyzed. Of 263 enrolled as suspected cases of histoplasmosis, 101 (38.4%) were confirmed cases. Median time to diagnosis was 15 days after presentation (interquartile range [IQR] = 5-23). Crude overall mortality was 43.6%; median survival time was 19 days (IQR = 4-69). Mycobacterial infection was diagnosed in 70 (26.6%) cases; 26 (25.7%) histoplasmosis cases were coinfected with mycobacteria. High mortality and short survival time after initial symptoms were observed in patients with histoplasmosis. Mycobacterial coinfection diagnoses were frequent, highlighting the importance of pursuing diagnoses for both diseases.

Sophora flavescens protects against mycobacterial Trehalose Dimycolate-induced lung granuloma by inhibiting inflammation and infiltration of macrophages.

PubMed

Liu, Dehua; Chan, Ben Chung-Lap; Cheng, Ling; Tsang, Miranda Sin-Man; Zhu, Jing; Wong, Chun-Wai; Jiao, Delong; Chan, Helen Yau-Tsz; Leung, Ping Chung; Lam, Christopher Wai-Kei; Wong, Chun Kwok

2018-03-02

The immune system responds to Mycobacterium tuberculosis (MTB) infection by forming granulomas to quarantine the bacteria from spreading. Granuloma-mediated inflammation is a cause of lung destruction and disease transmission. Sophora flavescens (SF) has been demonstrated to exhibit bactericidal activities against MTB. However, its immune modulatory activities on MTB-mediated granulomatous inflammation have not been reported. In the present study, we found that flavonoids from Sophora flavescens (FSF) significantly suppressed the pro-inflammatory mediators released from mouse lung alveolar macrophages (MH-S) upon stimulation by trehalose dimycolate (TDM), the most abundant lipoglycan on MTB surface. Moreover, FSF reduced adhesion molecule (LFA-1) expression on MH-S cells after TDM stimulation. Furthermore, FSF treatment on TDM-activated lung epithelial (MLE-12) cells significantly downregulated macrophage chemoattractant protein (MCP-1/CCL2) expression, which in turn reduced the in vitro migration of MH-S to MLE-12 cells. In addition, FSF increased the clearance of mycobacterium bacteria (Mycobacterium aurum) in macrophages. FSF mainly affected the Mincle-Syk-Erk signaling pathway in TDM-activated MH-S cells. In TDM-induced mouse granulomas model, oral administration with FSF significantly suppressed lung granulomas formation and inflammation. These findings collectively implicated an anti-inflammatory role of FSF on MTB-mediated granulomatous inflammation, thereby providing evidence of FSF as an efficacious adjunct treatment during mycobacterial infection.

Killing of Mycobacterium avium by Lactoferricin Peptides: Improved Activity of Arginine- and d-Amino-Acid-Containing Molecules

PubMed Central

Silva, Tânia; Magalhães, Bárbara; Maia, Sílvia; Gomes, Paula; Nazmi, Kamran; Bolscher, Jan G. M.; Rodrigues, Pedro N.; Bastos, Margarida

2014-01-01

Mycobacterium avium causes respiratory disease in susceptible individuals, as well as disseminated infections in immunocompromised hosts, being an important cause of morbidity and mortality among these populations. Current therapies consist of a combination of antibiotics taken for at least 6 months, with no more than 60% overall clinical success. Furthermore, mycobacterial antibiotic resistance is increasing worldwide, urging the need to develop novel classes of antimicrobial drugs. One potential and interesting alternative strategy is the use of antimicrobial peptides (AMP). These are present in almost all living organisms as part of their immune system, acting as a first barrier against invading pathogens. In this context, we investigated the effect of several lactoferrin-derived AMP against M. avium. Short peptide sequences from both human and bovine lactoferricins, namely, hLFcin1-11 and LFcin17-30, as well as variants obtained by specific amino acid substitutions, were evaluated. All tested peptides significantly inhibited the axenic growth of M. avium, the bovine peptides being more active than the human. Arginine residues were found to be crucial for the display of antimycobacterial activity, whereas the all-d-amino-acid analogue of the bovine sequence displayed the highest mycobactericidal activity. These findings reveal the promising potential of lactoferricins against mycobacteria, thus opening the way for further research on their development and use as a new weapon against mycobacterial infections. PMID:24709266

Radiology of pneumonia.

PubMed

Gharib, A M; Stern, E J

2001-11-01

Infection of the lower respiratory tract, acquired by way of the airways and confined to the lung parenchyma and airways, typically presents radiologically as one of three patterns: (1) focal nonsegmental or lobar pneumonia, (2) multifocal bronchopneumonia or lobular pneumonia, and (3) focal or diffuse "interstitial" pneumonia. These patterns can be useful in identifying the etiological organism in the appropriate clinical setting. To serve the purpose of this article, these patterns are used as the primary method of classification of pulmonary infections caused by different organisms. Mycobacterial and fungal pulmonary infections are reviewed separately because of their wide range of radiographic appearance that depend on the stage of the disease at presentation. This article discusses the clinical and radiographic features of the most common causes of pneumonia, primarily in the adult population of the United States.

Mycobacterium tuberculosis promotes genomic instability in macrophages

PubMed Central

Castro-Garza, Jorge; Luévano-Martínez, Miriam Lorena; Villarreal-Treviño, Licet; Gosálvez, Jaime; Fernández, José Luis; Dávila-Rodríguez, Martha Imelda; García-Vielma, Catalina; González-Hernández, Silvia; Cortés-Gutiérrez, Elva Irene

2018-01-01

BACKGROUND Mycobacterium tuberculosis is an intracellular pathogen, which may either block cellular defensive mechanisms and survive inside the host cell or induce cell death. Several studies are still exploring the mechanisms involved in these processes. OBJECTIVES To evaluate the genomic instability of M. tuberculosis-infected macrophages and compare it with that of uninfected macrophages. METHODS We analysed the possible variations in the genomic instability of Mycobacterium-infected macrophages using the DNA breakage detection fluorescence in situ hybridisation (DBD-FISH) technique with a whole human genome DNA probe. FINDINGS Quantitative image analyses showed a significant increase in DNA damage in infected macrophages as compared with uninfected cells. DNA breaks were localised in nuclear membrane blebs, as confirmed with DNA fragmentation assay. Furthermore, a significant increase in micronuclei and nuclear abnormalities were observed in infected macrophages versus uninfected cells. MAIN CONCLUSIONS Genomic instability occurs during mycobacterial infection and these data may be seminal for future research on host cell DNA damage in M. tuberculosis infection. PMID:29412354

Melanized Fungi in Human Disease

PubMed Central

Revankar, Sanjay G.; Sutton, Deanna A.

2010-01-01

Summary: Melanized or dematiaceous fungi are associated with a wide variety of infectious syndromes. Many are soil organisms and are generally distributed worldwide, though certain species appear to have restricted geographic ranges. Though they are uncommon causes of disease, melanized fungi have been increasingly recognized as important pathogens, with most reports occurring in the past 20 years. The spectrum of diseases with which they are associated has also broadened and includes allergic disease, superficial and deep local infections, pneumonia, brain abscess, and disseminated infection. For some infections in immunocompetent individuals, such as allergic fungal sinusitis and brain abscess, they are among the most common etiologic fungi. Melanin is a likely virulence factor for these fungi. Diagnosis relies on careful microscopic and pathological examination, as well as clinical assessment of the patient, as these fungi are often considered contaminants. Therapy varies depending upon the clinical syndrome. Local infection may be cured with excision alone, while systemic disease is often refractory to therapy. Triazoles such as voriconazole, posaconazole, and itraconazole have the most consistent in vitro activity. Further studies are needed to better understand the pathogenesis and optimal treatment of these uncommon infections. PMID:20930077

Leishmania (Viannia) naiffi: rare enough to be neglected?

PubMed

Fagundes-Silva, Giselle Aparecida; Romero, Gustavo Adolfo Sierra; Cupolillo, Elisa; Yamashita, Ellen Priscila Gadelha; Gomes-Silva, Adriano; Guerra, Jorge Augusto de Oliveira; Da-Cruz, Alda Maria

2015-09-01

In the Brazilian Amazon, American tegumentary leishmaniasis (ATL) is endemic and presents a wide spectrum of clinical manifestations due, in part, to the circulation of at least seven Leishmania species. Few reports of Leishmania (Viannia) naiffi infection suggest that its occurrence is uncommon and the reported cases present a benign clinical course and a good response to treatment. This study aimed to strengthen the clinical and epidemiological importance of L. (V.) naiffi in the Amazon Region (Manaus, state of Amazonas) and to report therapeutic failure in patients infected with this species. Thirty Leishmania spp samples isolated from cutaneous lesions were characterised by multilocus enzyme electrophoresis. As expected, the most common species was Leishmania (V.) guyanensis (20 cases). However, a relevant number of L. (V.) naiffi patients (8 cases) was observed, thus demonstrating that this species is not uncommon in the region. No patient infected with L. (V.) naiffi evolved to spontaneous cure until the start of treatment, which indicated that this species may not have a self-limiting nature. In addition, two of the patients experienced a poor response to antimonial or pentamidine therapy. Thus, either ATL cases due to L. (V.) naiffi cannot be as uncommon as previously thought or this species is currently expanding in this region.

Differential Trafficking of TLR1 I602S Underlies Host Protection Against Pathogenic Mycobacteria§

PubMed Central

Hart, Bryan E.; Tapping, Richard I.

2012-01-01

We have recently identified I602S as a frequent single nucleotide polymorphism of human TLR1 which greatly inhibits cell surface trafficking, confers hyporesponsiveness to TLR1 agonists, and protects against the mycobacterial diseases leprosy and tuberculosis. Since mycobacteria are known to manipulate the TLR system to their advantage, we hypothesize that the hyporesponsive 602S variant may confer protection by enabling the host to overcome this immune subversion. We report that primary human monocytes and macrophages from homozygous TLR1 602S individuals are resistant to mycobacterial-induced downregulation of macrophage MHCII, CD64, and IFNγ responses compared to individuals who harbor the TLR1 602I variant. Additionally, when challenged with mycobacterial agonists, macrophages from TLR1 602S/S individuals resist induction of host arginase-1; an enzyme that depletes cellular arginine stores required for production of antimicrobial reactive nitrogen intermediates. The differences in cell activation mediated by TLR1 602S and TLR1 602I are observed upon stimulation with soluble mycobacterial-derived agonists but not with whole mycobacterial cells. Taken together, these results suggest that the TLR1 602S variant protects against mycobacterial disease by preventing soluble mycobacterial products, perhaps released from granulomas, from disarming myeloid cells prior to their encounter with whole mycobacteria. PMID:23105135

Looking within the zebrafish to understand the tuberculous granuloma.

PubMed

Ramakrishnan, Lalita

2013-01-01

Tuberculosis is characterized by the formation of complex immune cell aggregates called granulomas, which for nearly a century have been viewed as critical host-beneficial structures to restrict bacterial growth and spread. A different view has now emerged from real-time visualization of granuloma formation and its consequences in the optically transparent and genetically tractable zebrafish larva. Pathogenic mycobacteria have developed mechanisms to use host granulomas for their expansion and dissemination, at least during the innate phases of infection. Host processes that are intended to be beneficial-death of infected macrophages and their subsequent phagocytosis by macrophages that are newly recruited to the growing granuloma-are harnessed by mycobacteria for their own benefit. Mycobacteria can also render the granuloma a safe-haven in the more advanced stages of infection. An understanding of the host and bacterial pathways involved in tuberculous granuloma formation may suggest new ways to combat mycobacterial infection.

DISSEMINATED FUNGAL INFECTION WITH ADRENAL INVOLVEMENT: REPORT OF TWO HIV NEGATIVE BRAZILIAN PATIENTS.

PubMed

Pereira, Graziella Hanna; Lanzoni, Valéria Pereira Barbosa; Beirão, Elisa Maria; Timerman, Artur; Melhem, Marcia de Souza Carvalho

2015-12-01

Paracoccidioidomycosis and histoplasmosis are systemic fungal infections endemic in Brazil. Disseminated clinical forms are uncommon in immunocompetent individuals. We describe two HIV-negative patients with disseminated fungal infections, paracoccidioidomycosis and histoplasmosis, who were diagnosed by biopsies of suprarenal lesions. Both were treated for a prolonged period with oral antifungal agents, and both showed favorable outcomes.

DISSEMINATED FUNGAL INFECTION WITH ADRENAL INVOLVEMENT: REPORT OF TWO HIV NEGATIVE BRAZILIAN PATIENTS

PubMed Central

PEREIRA, Graziella Hanna; LANZONI, Valéria Pereira Barbosa; BEIRÃO, Elisa Maria; TIMERMAN, Artur; MELHEM, Marcia de Souza Carvalho

2015-01-01

Paracoccidioidomycosis and histoplasmosis are systemic fungal infections endemic in Brazil. Disseminated clinical forms are uncommon in immunocompetent individuals. We describe two HIV-negative patients with disseminated fungal infections, paracoccidioidomycosis and histoplasmosis, who were diagnosed by biopsies of suprarenal lesions. Both were treated for a prolonged period with oral antifungal agents, and both showed favorable outcomes. PMID:27049710

Silicone in HIV-1-infected patients: a cause of misdiagnosed granulomatous disease.

PubMed

Males, Sylvia; Joly, Veronique; Adle-Biassette, Homa; Abgrall, Sophie; Lariven, Sylvie; Leboulanger, Nicolas; Yeni, Patrick

2010-09-01

Granulomatous diseases are common in HIV-infected patients and are usually related to opportunistic infectious or tumoral conditions. We report three cases of uncommon granulomatous disease in HIV-infected patients who had previously received silicone and for which diagnostic investigations remained negative. Copyright © 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Leaderless Transcripts and Small Proteins Are Common Features of the Mycobacterial Translational Landscape

PubMed Central

Lapierre, Pascal; Mir, Mushtaq; Chase, Michael R.; Pyle, Margaret M.; Gawande, Richa; Ahmad, Rushdy; Sarracino, David A.; Ioerger, Thomas R.; Fortune, Sarah M.; Derbyshire, Keith M.; Wade, Joseph T.; Gray, Todd A.

2015-01-01

RNA-seq technologies have provided significant insight into the transcription networks of mycobacteria. However, such studies provide no definitive information on the translational landscape. Here, we use a combination of high-throughput transcriptome and proteome-profiling approaches to more rigorously understand protein expression in two mycobacterial species. RNA-seq and ribosome profiling in Mycobacterium smegmatis, and transcription start site (TSS) mapping and N-terminal peptide mass spectrometry in Mycobacterium tuberculosis, provide complementary, empirical datasets to examine the congruence of transcription and translation in the Mycobacterium genus. We find that nearly one-quarter of mycobacterial transcripts are leaderless, lacking a 5’ untranslated region (UTR) and Shine-Dalgarno ribosome-binding site. Our data indicate that leaderless translation is a major feature of mycobacterial genomes and is comparably robust to leadered initiation. Using translational reporters to systematically probe the cis-sequence requirements of leaderless translation initiation in mycobacteria, we find that an ATG or GTG at the mRNA 5’ end is both necessary and sufficient. This criterion, together with our ribosome occupancy data, suggests that mycobacteria encode hundreds of small, unannotated proteins at the 5’ ends of transcripts. The conservation of small proteins in both mycobacterial species tested suggests that some play important roles in mycobacterial physiology. Our translational-reporter system further indicates that mycobacterial leadered translation initiation requires a Shine Dalgarno site in the 5’ UTR and that ATG, GTG, TTG, and ATT codons can robustly initiate translation. Our combined approaches provide the first comprehensive view of mycobacterial gene structures and their non-canonical mechanisms of protein expression. PMID:26536359

Leaderless Transcripts and Small Proteins Are Common Features of the Mycobacterial Translational Landscape.

PubMed

Shell, Scarlet S; Wang, Jing; Lapierre, Pascal; Mir, Mushtaq; Chase, Michael R; Pyle, Margaret M; Gawande, Richa; Ahmad, Rushdy; Sarracino, David A; Ioerger, Thomas R; Fortune, Sarah M; Derbyshire, Keith M; Wade, Joseph T; Gray, Todd A

2015-11-01

RNA-seq technologies have provided significant insight into the transcription networks of mycobacteria. However, such studies provide no definitive information on the translational landscape. Here, we use a combination of high-throughput transcriptome and proteome-profiling approaches to more rigorously understand protein expression in two mycobacterial species. RNA-seq and ribosome profiling in Mycobacterium smegmatis, and transcription start site (TSS) mapping and N-terminal peptide mass spectrometry in Mycobacterium tuberculosis, provide complementary, empirical datasets to examine the congruence of transcription and translation in the Mycobacterium genus. We find that nearly one-quarter of mycobacterial transcripts are leaderless, lacking a 5' untranslated region (UTR) and Shine-Dalgarno ribosome-binding site. Our data indicate that leaderless translation is a major feature of mycobacterial genomes and is comparably robust to leadered initiation. Using translational reporters to systematically probe the cis-sequence requirements of leaderless translation initiation in mycobacteria, we find that an ATG or GTG at the mRNA 5' end is both necessary and sufficient. This criterion, together with our ribosome occupancy data, suggests that mycobacteria encode hundreds of small, unannotated proteins at the 5' ends of transcripts. The conservation of small proteins in both mycobacterial species tested suggests that some play important roles in mycobacterial physiology. Our translational-reporter system further indicates that mycobacterial leadered translation initiation requires a Shine Dalgarno site in the 5' UTR and that ATG, GTG, TTG, and ATT codons can robustly initiate translation. Our combined approaches provide the first comprehensive view of mycobacterial gene structures and their non-canonical mechanisms of protein expression.

Over-Expression of the Mycobacterial Trehalose-Phosphate Phosphatase OtsB2 Results in a Defect in Macrophage Phagocytosis Associated with Increased Mycobacterial-Macrophage Adhesion

PubMed Central

Li, Hao; Wu, Mei; Shi, Yan; Javid, Babak

2016-01-01

Trehalose-6-phosphate phosphatase (OtsB2) is involved in the OtsAB trehalose synthesis pathway to produce free trehalose and is strictly essential for mycobacterial growth. We wished to determine the effects of OtsB2 expression on mycobacterial phenotypes such as growth, phagocytosis and survival in macrophages. Mycobacterium bovis-bacillus calmette-guerin (BCG) over-expressing OtsB2 were able to better survive in stationary phase. Over-expression of OtsB2 led to a decrease in phagocytosis but not survival in THP-1 macrophage-like cells, and this was not due to a decrease in general macrophage phagocytic activity. Surprisingly, when we investigated macrophage–mycobacterial interactions by flow cytometry and atomic force microscopy, we discovered that BCG over-expressing OtsB2 have stronger binding to THP-1 cells than wild-type BCG. These results suggest that altering OtsB2 expression has implications for mycobacterial host–pathogen interactions. Macrophage–mycobacteria phagocytic interactions are complex and merit further study. PMID:27867377

Mycobacterium marinum infection in a blue-fronted Amazon parrot (Amazona aestiva).

PubMed

Hannon, David E; Bemis, David A; Garner, Michael M

2012-12-01

A blue-fronted Amazon parrot (Amazona aestiva) was presented with a granuloma involving the proximal rhinotheca and extending into the rostral sinuses. Mycobacterium marinum was diagnosed based on results of biopsy and culture. Treatment was initiated with clarithromycin, rifampin, and ethambutol, but the bird died 4 months after the onset of antimicrobial therapy. Additional granulomas were found in the left lung and liver on postmortem examination. Mycobacterial isolation on postmortem samples was unsuccessful. This is the first report of Mycobacterium marinum in a bird.

Mycobacterium intracellulare Pleurisy Identified on Liquid Cultures of the Pleural Fluid and Pleural Biopsy.

PubMed

Lim, Jong Gu; O, Sei Won; Lee, Ki Dong; Suk, Dong Keun; Jung, Tae Young; Shim, Tae Sun; Chon, Gyu Rak

2013-03-01

Pleural effusion is a rare complication in non-tuberculous mycobacterial infection. We report a case of Mycobacterium intracellulare pleuritis with idiopathic pulmonary fibrosis in a 69-year-old man presenting with dyspnea. Pleural effusion revealed lymphocyte dominant exudate. M. intracellulare was identified using a polymerase chain reaction-restriction fragment length polymorphism method and liquid cultures of pleural effusion and pleural biopsy. After combination therapy for M. intracellulare pulmonary disease, the patient was clinically well at a 1-month follow-up.

An outbreak of salmonella chester infection in Canada: rare serotype, uncommon exposure, and unusual population demographic facilitate rapid identification of food vehicle.

PubMed

Taylor, John; Galanis, Eleni; Wilcott, Lynn; Hoang, Linda; Stone, Jason; Ekkert, Judi; Quibell, Doug; Huddleston, Mark; McCormick, Rachel; Whitfield, Yvonne; Adhikari, Bijay; Grant, Christopher C R; Sharma, Davendra

2012-04-01

Salmonella Chester infection has rarely been reported in the literature. In 2010, 33 case patients were reported in 2 months in four Canadian provinces. We conducted an outbreak investigation in collaboration with public health agencies, food safety specialists, regulatory agencies, grocery store chains, and the product distributor. We used case patient interviews, customer loyalty cards, and microbiological testing of clinical and food samples to identify nationally distributed head cheese as the food vehicle responsible for the outbreak. The rare serotype, a limited affected demographic group, and an uncommon exposure led to the rapid identification of the source. Control measures were implemented within 9 days of notification of the outbreak.

The reliability of diagnostic coding and laboratory data to identify tuberculosis and nontuberculous mycobacterial disease among rheumatoid arthritis patients using anti-tumor necrosis factor therapy.

PubMed

Winthrop, Kevin L; Baxter, Roger; Liu, Liyan; McFarland, Bentson; Austin, Donald; Varley, Cara; Radcliffe, LeAnn; Suhler, Eric; Choi, Dongsoek; Herrinton, Lisa J

2011-03-01

Anti-tumor necrosis factor-alpha (anti-TNF) therapies are associated with severe mycobacterial infections in rheumatoid arthritis patients. We developed and validated electronic record search algorithms for these serious infections. The study used electronic clinical, microbiologic, and pharmacy records from Kaiser Permanente Northern California (KPNC) and the Portland Veterans Affairs Medical Center (PVAMC). We identified suspect tuberculosis and nontuberculous mycobacteria (NTM) cases using inpatient and outpatient diagnostic codes, culture results, and anti-tuberculous medication dispensing. We manually reviewed records to validate our case-finding algorithms. We identified 64 tuberculosis and 367 NTM potential cases, respectively. For tuberculosis, diagnostic code positive predictive value (PPV) was 54% at KPNC and 9% at PVAMC. Adding medication dispensings improved these to 87% and 46%, respectively. Positive tuberculosis cultures had a PPV of 100% with sensitivities of 79% (KPNC) and 55% (PVAMC). For NTM, the PPV of diagnostic codes was 91% (KPNC) and 76% (PVAMC). At KPNC, ≥ 1 positive NTM culture was sensitive (100%) and specific (PPV, 74%) if non-pathogenic species were excluded; at PVAMC, ≥1 positive NTM culture identified 76% of cases with PPV of 41%. Application of the American Thoracic Society NTM microbiology criteria yielded the highest PPV (100% KPNC, 78% PVAMC). The sensitivity and predictive value of electronic microbiologic data for tuberculosis and NTM infections is generally high, but varies with different facilities or models of care. Unlike NTM, tuberculosis diagnostic codes have poor PPV, and in the absence of laboratory data, should be combined with anti-tuberculous therapy dispensings for pharmacoepidemiologic research. Copyright © 2010 John Wiley & Sons, Ltd.

Development of an in vitro model of the early-stage bovine tuberculous granuloma using Mycobacterium bovis-BCG.

PubMed

Garza-Cuartero, Laura; McCarthy, Elaine; Brady, Joseph; Cassidy, Joseph; Hamilton, Clare; Sekiya, Mary; NcNair, Jim; Mulcahy, Grace

2015-12-15

Mycobacterium bovis causes 3.1% of human tuberculosis cases, as described by the World Health Organisation. In cattle, this organism causes bovine tuberculosis (BTB) which can have a prevalence of up to 39.5% in some developing countries. In developed countries, although the prevalence of BTB has been reduced through eradication programmes, complete eradication has in some cases proved elusive, with prevalences in cattle of 0.5% in the Republic of Ireland and of 4.3% in the UK. As the tuberculous granuloma is the fundamental lesion that reflects the pathogenesis, immune control and progression of BTB, we aimed to develop an in vitro model of the early-stage bovine tuberculous granuloma, in order to model the early stages of BTB, while also reducing the use of experimentally infected animals. In vitro models of human and ovine mycobacterial granulomas have previously been developed; however, so far, there is no model for the BTB granuloma. As the disease in cattle differs in a number of ways from that in other species, we consider this to be a significant gap in the tools available to study the pathogenesis of BTB. By combining bovine monocyte-derived macrophages infected with M. bovis-BCG and autologous lymphocytes we have developed an early-stage tuberculous bovine granuloma model. In the model, 3D cell aggregations formed a spherical-shape that grew for up to 11 days post-infection. This bovine tuberculous granuloma model can aid in the study of such lesion development, and in comparative studies of pathogenesis, such as, for example, the question of mycobacterial latency in bovine tuberculosis. Copyright © 2015 Elsevier B.V. All rights reserved.

Febrile urticaria in a family: uncommon manifestation of a common disease.

PubMed

Sharma, Vishal; Singhal, Mayank; Sharma, Alka; Kumar, Vivek

2012-12-15

Cutaneous manifestations are uncommon with malaria. These include urticaria, purpura fulminans, and petechial rash. We report on a series of three patients from a single family who had an urticarial rash with fever that was subsequently diagnosed to be caused by malaria. Urticarial rash has been previously reported with both falciparum and vivax malaria infections. Although the exact pathogenesis is not clear urticarial rash might be related with IgE mediated mast cell degranulation.

Multistate US Outbreak of Rapidly Growing Mycobacterial Infections Associated with Medical Tourism to the Dominican Republic, 2013–20141

PubMed Central

Esposito, Douglas H.; Gaines, Joanna; Ridpath, Alison; Barry, M. Anita; Feldman, Katherine A.; Mullins, Jocelyn; Burns, Rachel; Ahmad, Nina; Nyangoma, Edith N.; Nguyen, Duc B.; Perz, Joseph F.; Moulton-Meissner, Heather A.; Jensen, Bette J.; Lin, Ying; Posivak-Khouly, Leah; Jani, Nisha; Morgan, Oliver W.; Brunette, Gary W.; Pritchard, P. Scott; Greenbaum, Adena H.; Rhee, Susan M.; Blythe, David; Sotir, Mark

2016-01-01

During 2013, the Maryland Department of Health and Mental Hygiene in Baltimore, MD, USA, received report of 2 Maryland residents whose surgical sites were infected with rapidly growing mycobacteria after cosmetic procedures at a clinic (clinic A) in the Dominican Republic. A multistate investigation was initiated; a probable case was defined as a surgical site infection unresponsive to therapy in a patient who had undergone cosmetic surgery in the Dominican Republic. We identified 21 case-patients in 6 states who had surgery in 1 of 5 Dominican Republic clinics; 13 (62%) had surgery at clinic A. Isolates from 12 (92%) of those patients were culture-positive for Mycobacterium abscessus complex. Of 9 clinic A case-patients with available data, all required therapeutic surgical intervention, 8 (92%) were hospitalized, and 7 (78%) required ≥3 months of antibacterial drug therapy. Healthcare providers should consider infection with rapidly growing mycobacteria in patients who have surgical site infections unresponsive to standard treatment. PMID:27434822

Remote transient Lactobacillus animalis bacteremia causing prosthetic hip joint infection: a case report.

PubMed

Somayaji, R; Lynch, T; Powell, J N; Gregson, D

2016-11-04

Lactobacillus spp. are uncommon pathogens in immunocompetent hosts, and even rarer causes of prosthetic device infections. A case of chronic hip prosthetic joint infection (PJI) caused by L. animalis is described. This occurred 5 years after a transient bacteremia with the same organism. Whole genome sequencing of both isolates proved this PJI infection resulted from this remote bacteremia. We document that prosthetic joint infections may be a consequence of bacteremia as much as 3 years before the onset of symptoms.

Endogenous lipoid pneumonia associated with Legionella pneumophila serogroup 1.

PubMed

Hui, Chee-Kin

2013-03-01

Endogenous lipoid pneumonia is an uncommon condition. This is a report of a 29-year-old woman diagnosed with endogenous lipoid pneumonia associated with Legionella pneumophila serogroup 1 infection. The patient's endogenous lipoid pneumonia resolved completely after treatment for Legionella pneumophila infection. This suggests that early diagnosis and aggressive treatment of the underlying infection may prevent any long-term sequelae of lipoid pneumonia.

Antemortem diagnosis of Mycobacterium bovis infection in free-ranging African lions (Panthera leo) and implications for transmission.

PubMed

Miller, Michele; Buss, Peter; Hofmeyr, Jennifer; Olea-Popelka, Francisco; Parsons, Sven; van Helden, Paul

2015-04-01

Diagnosis of tuberculosis in wildlife often relies on postmortem samples because of logistical challenges and lack of field-friendly techniques for live animal testing. Confirmation of infection through detection of infectious organisms is essential for studying the pathogenesis and epidemiology of disease. We describe the application of a technique to obtain respiratory samples from free-ranging living lions to facilitate detection of viable Mycobacterium bovis under field conditions. We identified M. bovis by mycobacterial culture and PCR in tracheobronchial lavage samples from 8/134 (6.0%) lions tested in Kruger National Park, South Africa. This confirms the respiratory shedding of viable M. bovis in living lions. The implications of these results are that infected lions have the potential to transmit this disease and serve as maintenance hosts.

Modulation of autophagy as a strategy for development of new vaccine candidates against tuberculosis.

PubMed

Flores-Valdez, Mario Alberto; Segura-Cerda, Cristian Alfredo; Gaona-Bernal, Jorge

2018-05-01

Effective prevention of tuberculosis (Tb) would undoubtedly be of paramount relevance in the control of its global burden, which resulted in more than 6 million new cases in 2016. Research aimed to improve the current vaccine, Bacillus Calmette- Guérin (BCG), or directed to develop new candidates, has taken into account the interaction between the host and Mycobacterium tuberculosis (Mtb). Recently, autophagy, an intracellular process of the host, has been shown to act as a mechanism that contributes to bacilli clearance in vitro and in vivo. Stimulation of autophagy, if correctly balanced, is an approach that has the potential to enhance the immune response of the host, and offers new avenues for developing immunogens that may give an improved protection upon immunization, given that in fact, some recent rBCG vaccine candidates have been shown to modulate autophagy. In this Discussion, we analyze the role of autophagy in the context of mycobacterial infection, its modulation via mycobacterial elements, and the management of host response as an alternative to develop new, hopefully improved, Tb-vaccine candidates. Copyright © 2018 Elsevier Ltd. All rights reserved.

BALB/c mice display more enhanced BCG vaccine induced Th1 and Th17 response than C57BL/6 mice but have equivalent protection.

PubMed

Garcia-Pelayo, M Carmen; Bachy, Véronique S; Kaveh, Daryan A; Hogarth, Philip J

2015-01-01

It is generally assumed that the inbred mouse strains BALB/c (H-2(d)) and C57BL/6 (H-2(b)) respond to mycobacterial infection with distinct polarisation of T helper responses, with C57BL/6 predisposed to Th1 and BALB/c to Th2. We investigated this in a BCG-immunisation, Mycobacterium bovis challenge model. Following immunisation, lung and spleen cell cytokine responses to in vitro re-stimulation with a cocktail of seven secreted, immunogenic, recombinant mycobacterial proteins were determined. In both lung and spleen, BALB/c cells produced at least 2-fold more IFN-γ, and up to 7-fold more IL-2 and IL-17 than C57BL/6 cells, whereas IL-10 production was reciprocally increased in C57BL/6 mice. These data suggest that, contrary to reports in the literature, specific mycobacterial antigens are able to induce strong Th1 and Th17 responses in BALB/c mice following BCG vaccination, whilst in C57BL/6 mice, the Th1 response is partly counterbalanced by IL-10. After subsequent M. bovis low dose challenge, protection, as measured in the lungs and dissemination to the spleen, was equivalent in BALB/c and C57BL/6 mice, indicating that BCG-induced immunity was equivalent in both strains. Thus, the differential immune responses do not appear to have a role in protection, but further, as yet unidentified, specific immune responses play a significant role. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

Evolutionary interpretations of mycobacteriophage biodiversity and host-range through the analysis of codon usage bias.

PubMed

Esposito, Lauren A; Gupta, Swati; Streiter, Fraida; Prasad, Ashley; Dennehy, John J

2016-10-01

In an genomics course sponsored by the Howard Hughes Medical Institute (HHMI), undergraduate students have isolated and sequenced the genomes of more than 1,150 mycobacteriophages, creating the largest database of sequenced bacteriophages able to infect a single host, Mycobacterium smegmatis , a soil bacterium. Genomic analysis indicates that these mycobacteriophages can be grouped into 26 clusters based on genetic similarity. These clusters span a continuum of genetic diversity, with extensive genomic mosaicism among phages in different clusters. However, little is known regarding the primary hosts of these mycobacteriophages in their natural habitats, nor of their broader host ranges. As such, it is possible that the primary host of many newly isolated mycobacteriophages is not M. smegmatis , but instead a range of closely related bacterial species. However, determining mycobacteriophage host range presents difficulties associated with mycobacterial cultivability, pathogenicity and growth. Another way to gain insight into mycobacteriophage host range and ecology is through bioinformatic analysis of their genomic sequences. To this end, we examined the correlations between the codon usage biases of 199 different mycobacteriophages and those of several fully sequenced mycobacterial species in order to gain insight into the natural host range of these mycobacteriophages. We find that UPGMA clustering tends to match, but not consistently, clustering by shared nucleotide sequence identify. In addition, analysis of GC content, tRNA usage and correlations between mycobacteriophage and mycobacterial codon usage bias suggests that the preferred host of many clustered mycobacteriophages is not M. smegmatis but other, as yet unknown, members of the mycobacteria complex or closely allied bacterial species.

Evolutionary interpretations of mycobacteriophage biodiversity and host-range through the analysis of codon usage bias

PubMed Central

Esposito, Lauren A.; Gupta, Swati; Streiter, Fraida; Prasad, Ashley

2016-01-01

In an genomics course sponsored by the Howard Hughes Medical Institute (HHMI), undergraduate students have isolated and sequenced the genomes of more than 1,150 mycobacteriophages, creating the largest database of sequenced bacteriophages able to infect a single host, Mycobacterium smegmatis, a soil bacterium. Genomic analysis indicates that these mycobacteriophages can be grouped into 26 clusters based on genetic similarity. These clusters span a continuum of genetic diversity, with extensive genomic mosaicism among phages in different clusters. However, little is known regarding the primary hosts of these mycobacteriophages in their natural habitats, nor of their broader host ranges. As such, it is possible that the primary host of many newly isolated mycobacteriophages is not M. smegmatis, but instead a range of closely related bacterial species. However, determining mycobacteriophage host range presents difficulties associated with mycobacterial cultivability, pathogenicity and growth. Another way to gain insight into mycobacteriophage host range and ecology is through bioinformatic analysis of their genomic sequences. To this end, we examined the correlations between the codon usage biases of 199 different mycobacteriophages and those of several fully sequenced mycobacterial species in order to gain insight into the natural host range of these mycobacteriophages. We find that UPGMA clustering tends to match, but not consistently, clustering by shared nucleotide sequence identify. In addition, analysis of GC content, tRNA usage and correlations between mycobacteriophage and mycobacterial codon usage bias suggests that the preferred host of many clustered mycobacteriophages is not M. smegmatis but other, as yet unknown, members of the mycobacteria complex or closely allied bacterial species. PMID:28348827

The role of alveolar epithelial cells in initiating and shaping pulmonary immune responses: communication between innate and adaptive immune systems.

PubMed

Chuquimia, Olga D; Petursdottir, Dagbjort H; Rahman, Muhammad J; Hartl, Katharina; Singh, Mahavir; Fernández, Carmen

2012-01-01

Macrophages and dendritic cells have been recognized as key players in the defense against mycobacterial infection. However, more recently, other cells in the lungs such as alveolar epithelial cells (AEC) have been found to play important roles in the defense and pathogenesis of infection. In the present study we first compared AEC with pulmonary macrophages (PuM) isolated from mice in their ability to internalize and control Bacillus Calmette-Guérin (BCG) growth and their capacity as APCs. AEC were able to internalize and control bacterial growth as well as present antigen to primed T cells. Secondly, we compared both cell types in their capacity to secrete cytokines and chemokines upon stimulation with various molecules including mycobacterial products. Activated PuM and AEC displayed different patterns of secretion. Finally, we analyzed the profile of response of AEC to diverse stimuli. AEC responded to both microbial and internal stimuli exemplified by TLR ligands and IFNs, respectively. The response included synthesis by AEC of several factors, known to have various effects in other cells. Interestingly, TNF could stimulate the production of CCL2/MCP-1. Since MCP-1 plays a role in the recruitment of monocytes and macrophages to sites of infection and macrophages are the main producers of TNF, we speculate that both cell types can stimulate each other. Also, another cell-cell interaction was suggested when IFNs (produced mainly by lymphocytes) were able to induce expression of chemokines (IP-10 and RANTES) by AEC involved in the recruitment of circulating lymphocytes to areas of injury, inflammation, or viral infection. In the current paper we confirm previous data on the capacity of AEC regarding internalization of mycobacteria and their role as APC, and extend the knowledge of AEC as a multifunctional cell type by assessing the secretion of a broad array of factors in response to several different types of stimuli.

Whole genome sequencing reveals mycobacterial microevolution among concurrent isolates from sputum and blood in HIV infected TB patients.

PubMed

Ssengooba, Willy; de Jong, Bouke C; Joloba, Moses L; Cobelens, Frank G; Meehan, Conor J

2016-08-05

In the context of advanced immunosuppression, M. tuberculosis is known to cause detectable mycobacteremia. However, little is known about the intra-patient mycobacterial microevolution and the direction of seeding between the sputum and blood compartments. From a diagnostic study of HIV-infected TB patients, 51 pairs of concurrent blood and sputum M. tuberculosis isolates from the same patient were available. In a previous analysis, we identified a subset with genotypic concordance, based on spoligotyping and 24 locus MIRU-VNTR. These paired isolates with identical genotypes were analyzed by whole genome sequencing and phylogenetic analysis. Of the 25 concordant pairs (49 % of the 51 paired isolates), 15 (60 %) remained viable for extraction of high quality DNA for whole genome sequencing. Two patient pairs were excluded due to poor quality sequence reads. The median CD4 cell count was 32 (IQR; 16-101)/mm(3) and ten (77 %) patients were on ART. No drug resistance mutations were identified in any of the sequences analyzed. Three (23.1 %) of 13 patients had SNPs separating paired isolates from blood and sputum compartments, indicating evidence of microevolution. Using a phylogenetic approach to identify the ancestral compartment, in two (15 %) patients the blood isolate was ancestral to the sputum isolate, in one (8 %) it was the opposite, and ten (77 %) of the pairs were identical. Among HIV-infected patients with poor cellular immunity, infection with multiple strains of M. tuberculosis was found in half of the patients. In those patients with identical strains, whole genome sequencing indicated that M. tuberculosis intra-patient microevolution does occur in a few patients, yet did not reveal a consistent direction of spread between sputum and blood. This suggests that these compartments are highly connected and potentially seed each other repeatedly.

Low serum vitamin D levels in type 2 diabetes patients are associated with decreased mycobacterial activity.

PubMed

Herrera, María Teresa; Gonzalez, Yolanda; Hernández-Sánchez, Fernando; Fabián-San Miguel, Guadalupe; Torres, Martha

2017-09-07

Concurrent diabetes mellitus and tuberculosis represent a significant health problem worldwide. Patients with diabetes mellitus have a high risk of tuberculosis, which may be mediated by an abnormal innate immune response due to hyperglycaemia or low vitamin D levels. In the present study, we evaluated inactive vitamin D serum levels and the monocyte response to infection with M. tuberculosis, including phagocytosis of M. tuberculosis, antimycobacterial activity, LL-37, human β defensin-2 and IL-10 gene expression and nitric oxide production, between type 2 diabetes mellitus patients (n = 51) and healthy volunteers (n = 38). Twenty-seven type 2 diabetes mellitus patients had inadequate inactive vitamin D levels (<50 nM). The percentages of M. tuberculosis phagocytosis between monocytes were similar across groups according to microscopy. Intracellular mycobacterial growth was similar in infected monocytes from both groups. However, M. tuberculosis growth was significantly higher in monocytes obtained from type 2 diabetes mellitus patients and lower vitamin D levels after 1-h (D0) and 72-h (D3) post-infection (p ≤ 0.05). LL-37, human β defensin-2 and IL-10 mRNA expression were similar between monocytes across groups; vitamin D serum levels and LL-37, human β defensin-2 and IL-10 expression were not correlated. Nitric oxide production was significantly higher in healthy volunteers than in type 2 diabetes mellitus patients with low vitamin D serum levels at D3 post-infection (p ≤ 0.05). Our results show that monocytes from type 2 diabetes mellitus patients and low vitamin D serum levels show an impaired ability to control the intracellular growth of M. tuberculosis, which is not associated with significant decrease of LL-37 or human β defensin-2 expression. Vitamin D could be the link between diabetes and tuberculosis susceptibility.

Fine-tuning the space, time, and host distribution of mycobacteria in wildlife

PubMed Central

2011-01-01

Background We describe the diversity of two kinds of mycobacteria isolates, environmental mycobacteria and Mycobacterium bovis collected from wild boar, fallow deer, red deer and cattle in Doñana National Park (DNP, Spain), analyzing their association with temporal, spatial and environmental factors. Results High diversity of environmental mycobacteria species and M. bovis typing patterns (TPs) were found. When assessing the factors underlying the presence of the most common types of both environmental mycobacteria and M. bovis TPs in DNP, we evidenced (i) host species differences in the occurrence, (ii) spatial structuration and (iii) differences in the degree of spatial association of specific types between host species. Co-infection of a single host by two M. bovis TPs occurred in all three wild ungulate species. In wild boar and red deer, isolation of one group of mycobacteria occurred more frequently in individuals not infected by the other group. While only three TPs were detected in wildlife between 1998 and 2003, up to 8 different ones were found during 2006-2007. The opposite was observed in cattle. Belonging to an M. bovis-infected social group was a significant risk factor for mycobacterial infection in red deer and wild boar, but not for fallow deer. M. bovis TPs were usually found closer to water marshland than MOTT. Conclusions The diversity of mycobacteria described herein is indicative of multiple introduction events and a complex multi-host and multi-pathogen epidemiology in DNP. Significant changes in the mycobacterial isolate community may have taken place, even in a short time period (1998 to 2007). Aspects of host social organization should be taken into account in wildlife epidemiology. Wildlife in DNP is frequently exposed to different species of non-tuberculous, environmental mycobacteria, which could interact with the immune response to pathogenic mycobacteria, although the effects are unknown. This research highlights the suitability of molecular typing for surveys at small spatial and temporal scales. PMID:21288321

Bacteraemia and breast abscess: unusual extra-intestinal manifestations of Clostridium difficile infection.

PubMed

Durojaiye, Oyewole; Gaur, Soma; Alsaffar, Layth

2011-03-01

Extra-intestinal manifestations of Clostridium difficile infection are uncommon. Most cases are associated with gastrointestinal disease and often occur as a mixed infection with other gut flora. We report a case of breast abscess following monomicrobial C. difficile bacteraemia in a female with background chronic hepatitis C infection and alcoholic liver disease. No evidence of colitis was found. Our case shows that C. difficile is indeed capable of spreading from the gastrointestinal tract.

A case of cutaneous Rhodotorula infection mimicking cryptococcosis.

PubMed

George, S M C; Quante, M; Cubbon, M D; MacDiarmaid-Gordon, A R; Topham, E J

2016-12-01

Rhodotorula is a ubiquitous environmental and commensal yeast, and an emerging opportunistic pathogen, particularly in immunocompromised individuals. Clinical infections with Rhodotorula have been increasingly recognized over the past 30 years; however, infections in solid-organ transplant recipients are uncommon, and cutaneous manifestations have rarely been reported. We describe a 59-year-old male renal transplant recipient, who developed cutaneous infection with Rhodotorula upon failure of his graft and commencement of haemodialysis. © 2016 British Association of Dermatologists.

Bacterial reproductive pathogens of cats and dogs.

PubMed

Graham, Elizabeth M; Taylor, David J

2012-05-01

With the notable exception of Brucella canis, exogenous bacterial pathogens are uncommon causes of reproductive disease in cats and dogs. Most bacterial reproductive infections are endogenous, and predisposing factors for infection are important. This article reviews the etiology, pathogenesis, clinical presentation, diagnosis, treatment, and public health significance of bacterial reproductive pathogens in cats and dogs.

[Frontier of mycobacterium research--host vs. mycobacterium].

PubMed

Okada, Masaji; Shirakawa, Taro

2005-09-01

During the past decade, we have observed advance in tuberculosis research including novel vaccines, innate immunity (TLR), SNIP analysis and molecular mechanism of drug resistance. Worldwide genome project enabled the whole genome sequence of host resistant against tuberculosis as well as the whole genome sequence of M. tuberculosis H37Rv. DNA technology has also provided a great impact on the development of novel vaccine against TB. In this symposium, we have invited leading researchers in the field of the frontier study of Mycobacterium research in order to provide general overview of the cutting edge of frontier research. Molecular mechanism of drug resistance of M. tuberculosis has been clarified. On the other hand, molecular mechanism of host-defence (insusceptibility of host) against M. tuberculosis has not yet elucidated. Dr. Taro Shirakawa (Kyoto University) reviewed the susceptibility genes of host in TB infection and presented candidate genes associated with multi-drug resistant tuberculosis. Dr. Naoto Keicho (International Medical Center of Japan) tried to identify host genetic factors involved in susceptibility to pulmonary Mycobacterium avium complex (MAC) infection by candidate gene approach and genome-wide approach. In Japan, Dr. Masaji Okada (National Hospital Organization Kinki-Chuo Chest Medical Center) has been engaged actively in the development of new tuberculosis vaccines (HVJ-liposome/Hsp65 DNA + IL-12 DNA vaccine and recombinant 72f BCG vaccine). He showed basic strategy for construction of new candidate vaccines and also showed significant efficacy on the protection of tuberculosis infection using cynomolgus monkeys, which are very similar to human tuberculosis. Dr. Hatsumi Taniguchi (University of Occupational and Environmental Health) presented that M. tuberculosis mIHF and the neighbor genes went into a dormacy-like state of M. smegmatis in J774 macrophage cells. This study might provide a weapon for elucidating the mechanism of dormacy of M. tuberculosis and the development of novel therapy. Dr. Chiyoji Abe (Nippon Becton Dickinson Co.) reviewed the molecular basis of the resistance to anti-tuberculosis drugs. Most cases of resistance are related to simple nucleotide substitutions rather than to acquisition of new elements. Dr. Kiyoshi Takeda (Kyushu University) showed interesting finding. He analyzed whether Toll-like receptor (TLR)-mediated activation of innate immunity in host defense against mycobacterial infection. MyD88/TRIF double defi-indicating that innate immunity is involved in anti-mycobacterial infection. (1) SNP (single nucleotide polymorphism) analysis in association with Mycobacterium tuberculosis: Taro SHIRAKAWA (Department of Health Promotion & Human Behavior, Kyoto University Medical School, and RIKEN SRC Center) Candidate gene approach was made on 18 SNPs in 11 genes in association with M. tuberculosis. Patients with multi-drug resistance against M. tuberculosis are also subjected. SNPs in NRAMP1 gene were associated with the disease, and drug resistance, its mechanisms remain unknown. (2) Search for genes susceptible to pulmonary Mycobacterium avium complex infection: Naoto KEICHO (Department of Respiratory Diseases, Research Institute, International Medical Center of Japan) Interaction among pathogens and host factors is important for development of infectious diseases. We are trying to identify host genetic factors involved in susceptibility to nonimmunocompromized pulmonary Mycobacterium avium complex (MAC) infection by candidate gene approach and genome-wide approach. Elucidation of functional significance of susceptibility gene polymorphisms will lead to a new strategy for control and prevention of the disease. (3) T cell immunity against Tuberculosis in host and the establishment of novel vaccine: Masaji OKADA (Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center) T cell (CTL, Th1) immunity including granulysin play an important role in host defense against tuberculosis (TB) in human. Patients with TB or Multi-drug resistant TB showed suppression of all these immunities. HVJ-liposome/Hsp65 DNA + IL-12 DNA vaccination was 100 fold more efficient than BCG on the elimination of Mycobacterium tuberculosis (M.TB) in the BALB/c mice. Cytotoxic T cells activity against M. TB was augmented. By using these new vaccines (Hsp 65 DNA + IL-12 DNA, recombinant 72f BCG) and the cynomolgus monkey models which are very similar to human tuberculosis, the prophylactic effect of vaccines was observed. Thus, these novel vaccines should provide a useful tool for the prevention of human TB infection. (4) Mycobacterium tuberculosis mIHF and the neighbor genes go into a dormancy-like state of M. smegmatis J15CS in J774 cells: Hatsumi TANIGUCHI (Department of Microbiology, School of Medicine, University of Occupational and Environmental Health) Mycobacterium smegmatis J15CS transformants harboring the mIHF gene or the mIHF-gmk-Rv1390 genes showed no difference in in vitro growth and acid-fastness. However, transformants harboring mIHF-gmk-Rv1390 formed short-rod cell morphology and decreased acid-fastness in the mouse macrophage-like cell line J774 compared to those of the other transformants, and the nuclei of the infected J774 cells also changed. Nevertheless, the colony forming units were similar. These indicate that mIHF and the neighbor genes of M. tuberculosis might regulate a growth of mycobacteria in macrophages. (5) Molecular basis of the resistance to anti-tuberculosis drugs: Chiyoji ABE (Nippon Becton Dickinson Company, Ltd.) Considerable progress has been made toward understanding the molecular basis of the resistance to anti-tuberculosis drugs. Most cases of resistance are related usually to simple nucleotide substitutions rather than to acquisition of new elements. Multi-drug resistant isolates of Mycobacterium tuberculosis arise a consequence of sequential accumulation of mutation conferring resistance to single therapeutic agents. The basis of resistance is not able to be explained yet in a substantial percentage of strains for other anti-tuberculosis drugs than rifampin and pyrazinamide. Further studies are required to fully understand the molecular mechanisms of resistance. (6) Toll-like receptors in anti-mycobacterial immune responses: Kiyoshi TAKEDA (Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University) Toll-like receptors (TLRs) play an essential role in the recognition of specific patterns of microbial components. TLRs mediate activation of innate immunity and further development of antigen-specific adaptive immunity. In TLR signaling pathways, Toll/IL-1 receptor (TIR) domain-containing adaptors, such as MyD88, TIRAP, TRIF, and TRAM, have been shown to play pivotal roles. Thus, the molecular mechanisms for TLR-mediated activation of innate immunity have been largely understood. We analyzed whether TLR-mediated activation of innate immunity is involved in host defense against mycobacterial infection. MyD88/TRIF double deficient mice, in which TLR-dependent activation of innate immunity is abolished, showed high sensitivity to mycobacterial infection, indicating that innate immunity is critically involved in anti-mycobacterial responses.

Nonrheumatic myopericarditis post acute streptococcal pharyngitis: An uncommon cause of sore throat with ST segment elevation.

PubMed

Pourmand, Ali; Gelman, Daniel; Davis, Steven; Shokoohi, Hamid

2017-05-01

Nonrheumatic myopericarditis is an uncommon complication of acute pharyngitis caused by Group A Streptococcal infection (GAS). While the natural history of carditis complicating acute rheumatic fever is well established, the incidence, pathophysiology and clinical course of nonrheumatic myopericarditis are ill defined. Advances in rapid bedside testing for both myocardial injury and GAS pharyngitis have allowed for increasing recognition of this uncommon complication in patients presenting with a sore throat with associated chest discomfort. We describe a case of a 34years old man with GAS pharyngitis complicated by acute myopericarditis who presented with chest pain, ST segment elevation on electrocardiogram, and elevated cardiac biomarkers. Copyright © 2016 Elsevier Inc. All rights reserved.

[Meningococcal vulvovaginitis in a prepubertal girl].

PubMed

Nathanson, M; Tisseron, B; de Pontual, L

2005-12-01

Neisseria meningitidis is an uncommon cause of vulvovaginitis in the prepubertal girl. The microorganism must not be mistaken for Neisseria gonorrhoeae, as the consequences of such an error may be serious. Colonization or infection by Neisseria meningitis is not uncommon in adolescents and adults. Vulvitis, even when it is recurrent, is not per se a good indicator of sexual abuse, but some microorganisms found by vaginal swab can make it possible, likely or certain. Sexual transmission of N. meningitidis has not been described in the prepubertal child.

Mycobacterial Antigen Driven Activation of CD14++CD16− Monocytes Is a Predictor of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

PubMed Central

Andrade, Bruno B.; Singh, Amrit; Narendran, Gopalan; Schechter, Melissa E.; Nayak, Kaustuv; Subramanian, Sudha; Anbalagan, Selvaraj; Jensen, Stig M. R.; Porter, Brian O.; Antonelli, Lis R.; Wilkinson, Katalin A.; Wilkinson, Robert J.; Meintjes, Graeme; van der Plas, Helen; Follmann, Dean; Barber, Daniel L.; Swaminathan, Soumya; Sher, Alan; Sereti, Irini

2014-01-01

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co-infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa. Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14++CD16− monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment. PMID:25275318

Outbreak of primary inoculation tuberculosis in an acupuncture clinic in southeastern China.

PubMed

Wang, J; Zhu, M Y; Li, C; Zhang, H B; Zuo, G B; Wang, M H; Teng, H L

2015-04-01

Outbreak of Mycobacterium tuberculosis infections associated with acupuncture has not been reported. Thirteen patients with a painful swollen lump were referred to our hospital. The index patient received acupuncture and paraspinal muscular injection at a local acupuncture clinic in April 2011 and was diagnosed with M. tuberculosis 1 month later. From May 2011 to August 2011, 12 more patients with a swollen lump on the nuchal region or in the lower back or the buttocks region were referred to our hospital. Tuberculin skin test (TST), T-SPOT.TB, acid-fast stain, M. tuberculosis culture, chest radiograph, and lump magnetic resonance imaging (MRI) were performed and the patients were diagnosed with tuberculous abscess of the lump. All 13 patients received intramuscular injection at the paraspinal muscle by two acupuncturists at a local clinic and reported a swollen lump at the injection site. The needles and syringes were reused after autoclave sterilization. The TST was positive in all patients. Twelve patients had positive acid-fast stains. Mycobacterial cultures of abscess specimens were positive in all 13 patients. T-SPOT.TB tests were positive in all patients who underwent the test. The lesions and biopsies were subjected to polymerase chain reaction (PCR) and gene sequencing by the Disease Control Center of Zhejiang Province, China and the causative agent was identified as M. tuberculosis, Beijing type. In conclusion, physicians should consider the possibility of mycobacterial infections, apart from other bacterial agents, in patients with a swollen paraspinal lump following intramuscular injection.

Killing of Mycobacterium avium by lactoferricin peptides: improved activity of arginine- and D-amino-acid-containing molecules.

PubMed

Silva, Tânia; Magalhães, Bárbara; Maia, Sílvia; Gomes, Paula; Nazmi, Kamran; Bolscher, Jan G M; Rodrigues, Pedro N; Bastos, Margarida; Gomes, Maria Salomé

2014-06-01

Mycobacterium avium causes respiratory disease in susceptible individuals, as well as disseminated infections in immunocompromised hosts, being an important cause of morbidity and mortality among these populations. Current therapies consist of a combination of antibiotics taken for at least 6 months, with no more than 60% overall clinical success. Furthermore, mycobacterial antibiotic resistance is increasing worldwide, urging the need to develop novel classes of antimicrobial drugs. One potential and interesting alternative strategy is the use of antimicrobial peptides (AMP). These are present in almost all living organisms as part of their immune system, acting as a first barrier against invading pathogens. In this context, we investigated the effect of several lactoferrin-derived AMP against M. avium. Short peptide sequences from both human and bovine lactoferricins, namely, hLFcin1-11 and LFcin17-30, as well as variants obtained by specific amino acid substitutions, were evaluated. All tested peptides significantly inhibited the axenic growth of M. avium, the bovine peptides being more active than the human. Arginine residues were found to be crucial for the display of antimycobacterial activity, whereas the all-d-amino-acid analogue of the bovine sequence displayed the highest mycobactericidal activity. These findings reveal the promising potential of lactoferricins against mycobacteria, thus opening the way for further research on their development and use as a new weapon against mycobacterial infections. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Mycobacterium bovis infections in slaughter pigs in Mubende district, Uganda: a public health concern.

PubMed

Muwonge, Adrian; Johansen, Tone B; Vigdis, Edvardsen; Godfroid, Jacques; Olea-Popelka, Francisco; Biffa, Demelash; Skjerve, Eystein; Djønne, Berit

2012-09-21

Bovine tuberculosis (TB) caused by Mycobacterium bovis is primarily a disease of ruminants, particularly cattle (Bos primigenius) and buffalo (Syncerus caffer), and is endemic in most developing countries. To date, studies done in Uganda have documented the prevalence of M. bovis in cattle, humans and wild life, in addition to non-tuberculous mycobacteria in pigs. Pigs are increasingly becoming an important component of the livestock sector and share the human ecosystem in rural Uganda. It is therefore of public health interest that they are not a source of human infections. As a follow up to previously published findings on mycobacteria in pigs, this study was aimed at investigating the occurrence and molecular characteristics of M. bovis detected in slaughter pigs in Mubende district, Uganda. One hundred fifty mesenteric lymph nodes with lesions suggestive of mycobacterial infections were collected from approximately one thousand slaughtered pigs in Mubende district over a period of five months. The isolation and identification of M. bovis was done using conventional mycobacteriological methods. Mycobacteria belonging to the Mycobacterium tuberculosis complex (MTC) were identified to species level using deletion analysis. Molecular typing was done using Spoligotyping and MIRU-VNTR analysis. Molecular data were analysed and interpreted using MIRU-VNTR plus, SpolDB4.0 and the Mycobacterium bovis spoligo database. Of the examined animals, one boar and two sows from Madudu Sub County were infected with M. bovis which presented as lesions of a deep yellow colour and a grit-like texture in the mesenteric lymph nodes. This represents 2% (3/150) of the lymph nodes where lesions suggestive of mycobacterial infections were detected. Molecular analysis revealed that the isolates from the infected pigs showed identical MIRU-VNTR profile and spoligotype (SB1469). This is the first study documenting the occurrence of M. bovis in slaughter pigs in Uganda, revealing that one in fifty slaughter pigs with suspected lesions in mesenteric lymph nodes were infected. Molecular analysis revealed that the isolates were identical, showing a spoligotype previously reported from humans and cattle in the north eastern part of the Uganda cattle corridor. This finding is of public health importance, therefore there is a need for close cooperation between medical and veterinary professionals in designing and implementing control and prevention measures that safeguard the public from this potential source of zoonotic TB in Uganda.

Pleural fluid culture

MedlinePlus

... Risks of thoracentesis are: Collapsed lung ( pneumothorax ) Excessive loss of blood Fluid reaccumulation Infection Pulmonary edema Respiratory distress Serious complications are uncommon Alternative Names Culture - pleural fluid Images Pleural culture References Chernecky CC, ...

Detection of Mycobacteria by Culture and DNA-Based Methods in Animal-Derived Food Products Purchased at Spanish Supermarkets

PubMed Central

Sevilla, Iker A.; Molina, Elena; Tello, Maitane; Elguezabal, Natalia; Juste, Ramón A.; Garrido, Joseba M.

2017-01-01

Mycobacteria include obligate and opportunistic pathogens that cause significant human and animal disease. The burden of tuberculosis has been largely reduced in developed territories but remains a huge problem worldwide. The significance of nontuberculous mycobacteria is growing considerably, especially in developed regions with higher life expectancy and more therapy-related immunosuppressed individuals. Due to their robustness mycobacteria can contaminate animal products by direct transmission from infected individuals or by environmental contamination during processing. The situation at market level is poorly known. Most studies analyzing commercially available foods are limited to a small or local scale and mainly focused on a particular mycobacterial species. There is a need to investigate if animal products that have passed the established controls to be for sale at main supermarkets could represent a route of contact with any mycobacteria. Thus, our goal was to study the prevalence of mycobacteria in these foods to assess if this could represent a source of human exposure. Five stores from the main supermarket chains in Spain were selected. 138 dairy and 119 meat products were purchased. All were processed using culture and multiplex real-time PCR methods. Additional molecular methods were used to specifically identify any positive result. Mycobacterium avium subsp. hominissuis (2), M. avium subsp. avium (1), and M. fortuitum (1) were isolated from powdered infant formula and ground beef, chicken sausage, and mortadella cold cut, respectively. Mycobacterial DNA (M. avium, M. tuberculosis complex and other nontuberculous mycobacteria) was detected in 15% of dairy products and 2% of meat products. These results show that the prevalence of viable mycobacteria in foods of animal origin obtained at the supermarket was not substantial although a considerable proportion of them contained mycobacterial DNA. Contact with mycobacteria through this route could be ensured over time. Further investigation is necessary to determine the real impact of foodborne mycobacterial exposure on human health and identify critical points in the food production system to enable setting up more stringent control measures. PMID:28649235

Shigella Phages Isolated during a Dysentery Outbreak Reveal Uncommon Structures and Broad Species Diversity.

PubMed

Doore, Sarah M; Schrad, Jason R; Dean, William F; Dover, John A; Parent, Kristin N

2018-04-15

In 2016, Michigan experienced the largest outbreak of shigellosis, a type of bacillary dysentery caused by Shigella spp., since 1988. Following this outbreak, we isolated 16 novel Shigella -infecting bacteriophages (viruses that infect bacteria) from environmental water sources. Most well-known bacteriophages infect the common laboratory species Escherichia coli and Salmonella enterica , and these phages have built the foundation of molecular and bacteriophage biology. Until now, comparatively few bacteriophages were known to infect Shigella spp., which are close relatives of E. coli We present a comprehensive analysis of these phages' host ranges, genomes, and structures, revealing genome sizes and capsid properties that are shared by very few previously described phages. After sequencing, a majority of the Shigella phages were found to have genomes of an uncommon size, shared by only 2% of all reported phage genomes. To investigate the structural implications of this unusual genome size, we used cryo-electron microscopy to resolve their capsid structures. We determined that these bacteriophage capsids have similarly uncommon geometry. Only two other viruses with this capsid structure have been described. Since most well-known bacteriophages infect Escherichia or Salmonella , our understanding of bacteriophages has been limited to a subset of well-described systems. Continuing to isolate phages using nontraditional strains of bacteria can fill gaps that currently exist in bacteriophage biology. In addition, the prevalence of Shigella phages during a shigellosis outbreak may suggest a potential impact of human health epidemics on local microbial communities. IMPORTANCE Shigella spp. bacteria are causative agents of dysentery and affect more than 164 million people worldwide every year. Despite the need to combat antibiotic-resistant Shigella strains, relatively few Shigella -infecting bacteriophages have been described. By specifically looking for Shigella -infecting phages, this work has identified new isolates that (i) may be useful to combat Shigella infections and (ii) fill gaps in our knowledge of bacteriophage biology. The rare qualities of these new isolates emphasize the importance of isolating phages on "nontraditional" laboratory strains of bacteria to more fully understand both the basic biology and diversity of bacteriophages. Copyright © 2018 American Society for Microbiology.

Preventing herpes simplex virus in the newborn.

PubMed

Pinninti, Swetha G; Kimberlin, David W

2014-12-01

Genital herpes simplex virus (HSV) infections are very common worldwide. Approximately 22% of pregnant women are infected genitally with HSV, and most of them are unaware of this. The most devastating consequence of maternal genital herpes is HSV disease in the newborn. Although neonatal HSV infections remain uncommon, due to the significant morbidity and mortality associated with the infection, HSV infection in the newborn is often considered in the differential diagnosis of ill neonates. This review summarizes the epidemiology and management of neonatal HSV infections and discusses strategies to prevent HSV infection in the newborn. Copyright © 2014 Elsevier Inc. All rights reserved.

Rituximab Restores IFN-γ-STAT1 Function and Ameliorates Disseminated Mycobacterium avium Infection in a Patient with Anti-Interferon-γ Autoantibody.

PubMed

Koizumi, Yusuke; Sakagami, Takuro; Nishiyama, Naoya; Hirai, Jun; Hayashi, Yuta; Asai, Nobuhiro; Yamagishi, Yuka; Kato, Hideo; Hagihara, Mao; Sakanashi, Daisuke; Suematsu, Hiroyuki; Ogawa, Kenji; Mikamo, Hiroshige

2017-10-01

A 67-year-old Japanese female with back pain and severe cachexia visited our hospital. The diagnosis was disseminated Mycobacterium avium complex infection (dMAC) with multiple bone involvement. Anti-mycobacterial chemotherapy was started, but fever persisted and dislocation of cervical vertebrae has made her bedridden. Because anti-interferon (IFN)-γ autoantibody was positive, four doses of rituximab 375 mg/m 2 , every 7 day, were administered. Soon after treatment, progression of osteolytic lesions and wasting has stopped. We proved that rituximab has recovered IFN-γ signaling as shown by IFN-γ-induced STAT1 phosphorylation. It can be a promising option for dMAC cases with anti-IFN-γ autoantibody.

Cerebrospinal Fluid HIV Escape from Antiretroviral Therapy.

PubMed

Ferretti, Francesca; Gisslen, Magnus; Cinque, Paola; Price, Richard W

2015-06-01

CNS infection is a nearly constant facet of systemic CNS infection and is generally well controlled by suppressive systemic antiretroviral therapy (ART). However, there are instances when HIV can be detected in the cerebrospinal fluid (CSF) despite suppression of plasma viruses below the clinical limits of measurement. We review three types of CSF viral escape: asymptomatic, neuro-symptomatic, and secondary. The first, asymptomatic CSF escape, is seemingly benign and characterized by lack of discernable neurological deterioration or subsequent CNS disease progression. Neuro-symptomatic CSF escape is an uncommon, but important, entity characterized by new or progressive CNS disease that is critical to recognize clinically because of its management implications. Finally, secondary CSF escape, which may be even more uncommon, is defined by an increase of CSF HIV replication in association with a concomitant non-HIV infection, as a consequence of the local inflammatory response. Understanding these CSF escape settings not only is important for clinical diagnosis and management but also may provide insight into the CNS HIV reservoir.

Spondylodiskitis secondary to Streptococcus equi subspecies zooepidemicus.

PubMed

Bhatia, Ravi; Bhanot, Nitin

2012-01-01

Streptococcus equi subspecies zooepidemicus, traditionally classified under Group C Streptococci, is primarily a veterinary pathogen. Rarely, it may cause infections such as bacteremia, meningitis, endocarditis and pneumonia in humans. Musculoskeletal infections secondary to this pathogen are very uncommon. The authors present the first case of osteomyelitis due to S. zooepidemicus in a farmer who had close contact with a dead horse. The authors review all cases of osteoarticular infections secondary to this microbe, in addition to providing an overview of clinical manifestations, treatment and outcome of this infection.

Cutaneous protothecosis in a patient with previously undiagnosed HIV infection.

PubMed

Fong, Kenneth; Tee, Shang-Ian; Ho, Madeline S L; Pan, Jiun Yit

2015-08-01

Protothecosis is an uncommon condition resulting from infection by achlorophyllous algae of the Prototheca species. Immunocompromised individuals are generally most susceptible to protothecal infection and tend to develop severe and disseminated disease. However, the association between protothecosis and HIV-induced immunosuppression is not clear, with only a handful of cases having been described to date. Here we report a case of cutaneous protothecosis in a Chinese man with previously undiagnosed HIV infection that responded well to oral itraconazole. © 2014 The Australasian College of Dermatologists.

Early recognition of serious infections in obstetrics and gynecology.

PubMed

Soper, David E

2012-12-01

Pelvic infections commonly occur in pregnant and postoperative women. Most of these infections are readily diagnosed because of their typical clinical manifestations and prompt antimicrobial therapy that leads to the resolution of disease. However, uncommon cases may escape detection and the severity of the process may also go unrecognized without a careful assessment of clues available through physical examination and laboratory testing. In some cases a particularly virulent pathogen can lead to severe infection, septic shock and its consequences, even death, despite clinicians acting appropriately.

Measuring the Global Substrate Specificity of Mycobacterial Serine Hydrolases Using a Library of Fluorogenic Ester Substrates.

PubMed

Bassett, Braden; Waibel, Brent; White, Alex; Hansen, Heather; Stephens, Dominique; Koelper, Andrew; Larsen, Erik M; Kim, Charles; Glanzer, Adam; Lavis, Luke D; Hoops, Geoffrey C; Johnson, R Jeremy

2018-04-16

Among the proteins required for lipid metabolism in Mycobacterium tuberculosis are a significant number of uncharacterized serine hydrolases, especially lipases and esterases. Using a streamlined synthetic method, a library of immolative fluorogenic ester substrates was expanded to better represent the natural lipidomic diversity of Mycobacterium. This expanded fluorogenic library was then used to rapidly characterize the global structure activity relationship (SAR) of mycobacterial serine hydrolases in M. smegmatis under different growth conditions. Confirmation of fluorogenic substrate activation by mycobacterial serine hydrolases was performed using nonspecific serine hydrolase inhibitors and reinforced the biological significance of the SAR. The hydrolases responsible for the global SAR were then assigned using gel-resolved activity measurements, and these assignments were used to rapidly identify the relative substrate specificity of previously uncharacterized mycobacterial hydrolases. These measurements provide a global SAR of mycobacterial hydrolase activity, a picture of cycling hydrolase activity, and a detailed substrate specificity profile for previously uncharacterized hydrolases.

High prevalence of Mycobacterium tuberculosis bacteraemia among a cohort of HIV-infected patients with severe sepsis in Lusaka, Zambia.

PubMed

Muchemwa, Levy; Shabir, Lakhi; Andrews, Ben; Bwalya, Mwango

2017-05-01

Tuberculosis is recognised as one of the leading causes of severe sepsis among HIV-infected patients. Most patients with Mycobacterium tuberculosis bacteraemia have advanced HIV disease with CD4 counts less than 100 cells/μl and its presentation is non-specific in most instances. This was a cross-sectional study which was done by analyzing data from 201 adult HIV-infected patients who met the inclusion criteria for severe sepsis. The prevalence of Mycobacterium tuberculosis bactraemia in the study population was 34.8%. Severe sepsis caused by other etiologies was observed in 33 (16.4%) of the participants. Concomitant infection of Mycobacterium tuberculosis bactraemia with other organisms is not uncommon in patients with severe sepsis. This cohort of HIV-infected patients had severe immunosuppression with a median CD4 count of 51 (20-136) cells/μl with moderate anaemia, mean haemoglobin 8.0 (3.0) g/dl, and were generally underweight with a mean mid upper arm circumference (MUAC) of 21.0 (3.4) cm. Mycobacterium tuberculosis bacteraemia is very common in HIV-infected patients with advanced HIV disease who present with severe sepsis. Mycobacterium tuberculosis bacteraemia co-infection with aerobic organisms is not uncommon. Factors that were independently associated with Mycobacterium tuberculosis bacteraemia in our study population were MUAC and sodium level.

Zygomycotic infective endocarditis in pregnancy.

PubMed

Vaideeswar, Pradeep; Shah, Rushabh

Under the circumstances of cardiovascular adaptations and immunomodulation, an uncommon but disastrous complication of infective endocarditis (IE) can occur in pregnancy. Almost all the cases reported earlier were caused by bacteria. We report a fatal case of zygomycotic valvular and mural endocarditis in a young non-diabetic primigravida with a positive hepatitis B serology. Copyright © 2017 Elsevier Inc. All rights reserved.

Deep vein thrombosis associated with dengue fever.

PubMed

Roy, Amrita; Chaudhuri, Jasodhara; Chakraborty, Swapna

2013-11-08

Hemorrhagic manifestations are common with Dengue but thrombotic events are uncommonly reported. 11-year-old boy who presented with ileo-femoral deep vein thrombosis associated with serologically confirmed infection with DEN1 dengue virus. There was no other history or investigation suggestive of a procoagulant state. Successfully treated with enoxaparin and warfarin. Thrombotic complications are possible with dengue infection.

Mycobacterium chimaera colonisation of heater–cooler units (HCU) in Western Australia, 2015: investigation of possible iatrogenic infection using whole genome sequencing

PubMed Central

Robinson, James Owen; Coombs, Geoffrey Wallace; Speers, David John; Keehner, Terillee; Keil, Anthony David; D’Abrera, Victoria; Boan, Peter; Pang, Stanley

2016-01-01

Following the reported link between heater–cooler unit (HCU) colonisation with Mycobacterium chimaera and endocarditis, mycobacterial sampling of all HCUs in use in Western Australia was initiated from August 2015, revealing M. chimaera colonisation in 10 of 15 HCUs. After M. chimaera was isolated from a pleural biopsy from a cardiothoracic patient who may have been exposed to a colonised HCU, a whole genome sequencing investigation was performed involving 65 specimens from 15 HCUs across five hospitals to assess if this infection was related to the HCU. Genetic relatedness was found between the 10 HCU M. chimaera isolates from four hospitals. However the M. chimaera isolate from the cardiothoracic patient was not genetically related to the HCU M. chimaera isolates from that hospital, nor to the other HCU isolates, indicating that the HCUs were not the source of the infection in this patient. PMID:27918263

Genetic Diversity of Toll-Like Receptors and Immunity to M. leprae Infection

PubMed Central

Hart, Bryan E.; Tapping, Richard I.

2012-01-01

Genetic association studies of leprosy cohorts across the world have identified numerous polymorphisms which alter susceptibility and outcome to infection with Mycobacterium leprae. As expected, many of the polymorphisms reside within genes that encode components of the innate and adaptive immune system. Despite the preponderance of these studies, our understanding of the mechanisms that underlie these genetic associations remains sparse. Toll-like receptors (TLRs) have emerged as an essential family of innate immune pattern recognition receptors which play a pivotal role in host defense against microbes, including pathogenic strains of mycobacteria. This paper will highlight studies which have uncovered the association of specific TLR gene polymorphisms with leprosy or tuberculosis: two important diseases resulting from mycobacterial infection. This analysis will focus on the potential influence these polymorphic variants have on TLR expression and function and how altered TLR recognition or signaling may contribute to successful antimycobacterial immunity. PMID:22529866

Use of Testing for West Nile Virus and Other Arboviruses.

PubMed

Vanichanan, Jakapat; Salazar, Lucrecia; Wootton, Susan H; Aguilera, Elizabeth; Garcia, Melissa N; Murray, Kristy O; Hasbun, Rodrigo

2016-09-01

In the United States, the most commonly diagnosed arboviral disease is West Nile virus (WNV) infection. Diagnosis is made by detecting WNV IgG or viral genomic sequences in serum or cerebrospinal fluid. To determine frequency of this testing in WNV-endemic areas, we examined the proportion of tests ordered for patients with meningitis and encephalitis at 9 hospitals in Houston, Texas, USA. We identified 751 patients (567 adults, 184 children), among whom 390 (52%) experienced illness onset during WNV season (June-October). WNV testing was ordered for 281 (37%) of the 751; results indicated acute infection for 32 (11%). Characteristics associated with WNV testing were acute focal neurologic deficits; older age; magnetic resonance imaging; empirically prescribed antiviral therapy; worse clinical outcomes: and concomitant testing for mycobacterial, fungal, or other viral infections. Testing for WNV is underutilized, and testing of patients with more severe disease raises the possibility of diagnostic bias in epidemiologic studies.

Mycobacterium tuberculosis Metabolism

PubMed Central

Warner, Digby F.

2015-01-01

Metabolism underpins the physiology and pathogenesis of Mycobacterium tuberculosis. However, although experimental mycobacteriology has provided key insights into the metabolic pathways that are essential for survival and pathogenesis, determining the metabolic status of bacilli during different stages of infection and in different cellular compartments remains challenging. Recent advances—in particular, the development of systems biology tools such as metabolomics—have enabled key insights into the biochemical state of M. tuberculosis in experimental models of infection. In addition, their use to elucidate mechanisms of action of new and existing antituberculosis drugs is critical for the development of improved interventions to counter tuberculosis. This review provides a broad summary of mycobacterial metabolism, highlighting the adaptation of M. tuberculosis as specialist human pathogen, and discusses recent insights into the strategies used by the host and infecting bacillus to influence the outcomes of the host–pathogen interaction through modulation of metabolic functions. PMID:25502746

An unusual renal manifestation of chronic HBV infection.

PubMed

Aravindan, Ananthakrishnapuram; Yong, Jim; Killingsworth, Murray; Strasser, Simone; Suranyi, Michael

2010-08-01

Hepatitis B viral infection is usually a self-limiting disease in immunocompetent individuals. Chronic infection can be seen in up to 5% of infected patients. Renal manifestations of chronic HBV infection are usually glomerular. We describe here an uncommon presentation of a patient with chronic HBV infection with very high viral load and rapidly progressive renal failure. Renal biopsy showed features of tubulointerstitial nephritis and tubular epithelial inclusion bodies suggestive of HBV infection. Entecavir treatment slowed down the progression of his renal disease. Tubulointerstitial nephritis should be considered as a part of the differential diagnosis in patients with HBV infection. Early antiviral treatment may halt the progression of renal disease.

A macrophage response to Mycobacterium leprae phenolic glycolipid initiates nerve damage in leprosy

PubMed Central

Madigan, Cressida A.; Cambier, C.J.; Kelly-Scumpia, Kindra M.; Scumpia, Philip O.; Cheng, Tan-Yun; Zailaa, Joseph; Bloom, Barry R.; Moody, D. Branch; Smale, Stephen T.; Sagasti, Alvaro; Modlin, Robert L.; Ramakrishnan, Lalita

2018-01-01

SUMMARY Mycobacterium leprae causes leprosy, and is unique among mycobacterial diseases in producing peripheral neuropathy. This debilitating morbidity is attributed to axon demyelination resulting from direct interactions of the M. leprae-specific phenolic glycolipid 1 (PGL-1) with myelinating glia, and their subsequent infection. Here, we use transparent zebrafish larvae to visualize the earliest events of M. leprae-induced nerve damage. We find that demyelination and axonal damage are not directly initiated by M. leprae but by infected macrophages that patrol axons; demyelination occurs in areas of intimate contact. PGL-1 confers this neurotoxic response on macrophages: macrophages infected with M. marinum expressing PGL-1 also damage axons. PGL-1 induces nitric oxide synthase in infected macrophages, and the resultant increase in reactive nitrogen species damages axons by injuring their mitochondria and inducing demyelination. Our findings implicate the response of innate macrophages to M. leprae PGL-1 in initiating nerve damage in leprosy. PMID:28841420

Mycobacterium chimaera pulmonary infection complicating cystic fibrosis: a case report.

PubMed

Cohen-Bacrie, Stéphan; David, Marion; Stremler, Nathalie; Dubus, Jean-Christophe; Rolain, Jean-Marc; Drancourt, Michel

2011-09-22

Mycobacterium chimaera is a recently described species within the Mycobacterium avium complex. Its pathogenicity in respiratory tract infection remains disputed. It has never been isolated during cystic fibrosis respiratory tract infection. An 11-year-old boy of Asian ethnicity who was born on Réunion Island presented to our hospital with cystic fibrosis after a decline in his respiratory function over the course of seven years. We found that the decline in his respiratory function was correlated with the persistent presence of a Mycobacterium avium complex organism further identified as M. chimaera. Using sequencing-based methods of identification, we observed that M. chimaera organisms contributed equally to respiratory tract infections in patients with cystic fibrosis when compared with M. avium subsp. hominissuis isolates. We believe that M. chimaera should be regarded as an emerging opportunistic respiratory pathogen in patients with cystic fibrosis, including young children, and that its detection warrants long-lasting appropriate anti-mycobacterial treatment to eradicate it.

A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy.

PubMed

Madigan, Cressida A; Cambier, C J; Kelly-Scumpia, Kindra M; Scumpia, Philip O; Cheng, Tan-Yun; Zailaa, Joseph; Bloom, Barry R; Moody, D Branch; Smale, Stephen T; Sagasti, Alvaro; Modlin, Robert L; Ramakrishnan, Lalita

2017-08-24

Mycobacterium leprae causes leprosy and is unique among mycobacterial diseases in producing peripheral neuropathy. This debilitating morbidity is attributed to axon demyelination resulting from direct interaction of the M. leprae-specific phenolic glycolipid 1 (PGL-1) with myelinating glia and their subsequent infection. Here, we use transparent zebrafish larvae to visualize the earliest events of M. leprae-induced nerve damage. We find that demyelination and axonal damage are not directly initiated by M. leprae but by infected macrophages that patrol axons; demyelination occurs in areas of intimate contact. PGL-1 confers this neurotoxic response on macrophages: macrophages infected with M. marinum-expressing PGL-1 also damage axons. PGL-1 induces nitric oxide synthase in infected macrophages, and the resultant increase in reactive nitrogen species damages axons by injuring their mitochondria and inducing demyelination. Our findings implicate the response of innate macrophages to M. leprae PGL-1 in initiating nerve damage in leprosy. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

A catheter-related bloodstream infection caused by Chryseobacterium indologenes successfully treated with antibiotic-lock rescue therapy.

PubMed

Corbella, Marta; Brandolini, Micaela; Cambieri, Patrizia; Decembrino, Nunzia; Pagani, Michele; Bottazzi, Andrea; Muzzi, Alba; Zecca, Marco; Mariani, Bianca; Marone, Piero

2017-07-01

We report the case of a catheter-related bloodstream infection caused by Chryseobacterium indologenes, an uncommon and multi-resistant pathogen, in a pediatric patient with a long-term vascular access device placed for chemotherapy treatment. The infection was successfully treated with ciprofloxacin antibiotic-lock therapy. This is the first report on successful salvage of a long-term device colonized by multi-resistant Chryseobacterium indologenes.

[Competitive karate and the risk of HIV infection--review, risk analysis and risk minimizing strategies].

PubMed

Müller-Rath, R; Mumme, T; Miltner, O; Skobel, E

2004-03-01

Bleeding facial injuries are not uncommon in competitive karate. Nevertheless, the risk of an infection with HIV is extremely low. Guidelines about the prevention of HIV infections are presented. Especially in contact sports and martial arts the athletes, judges and staff have to recognize and employ these recommendations. Bleeding wounds of the hands due to contact with the opponents teeth can be minimized by fist padding.

Management of Prosthetic Joint Infection.

PubMed

Tande, Aaron J; Gomez-Urena, Eric O; Berbari, Elie F; Osmon, Douglas R

2017-06-01

Although uncommon, prosthetic joint infection is a devastating complication. This challenging condition requires a coordinated management approach to achieve good patient outcomes. This review details the general principles to consider when managing patients with prosthetic joint infection. The different medical/surgical treatment strategies and how to appropriately select a strategy are discussed. The data to support each strategy are presented, along with discussion of antimicrobial strategies in specific situations. Copyright © 2017 Elsevier Inc. All rights reserved.

Chemiluminescence of neutrophils from patients with Behçet's disease and its correlation with an increased proportion of uncommon serotypes of Streptococcus sanguis in the oral flora.

PubMed

Isogai, E; Ohno, S; Kotake, S; Isogai, H; Tsurumizu, T; Fujii, N; Yokota, K; Syuto, B; Yamaguchi, M; Matsuda, H

1990-01-01

Zymosan-induced chemiluminescence was investigated in whole blood and in neutrophils: in both, the peak count was frequently elevated in Behçet's disease, and was significantly higher than in healthy controls; similarly the peak time was shorter. There were more uncommon serotypes of Streptococcus sanguis in the oral flora of patients with Behçet's disease. Common serotypes were present in the flora of healthy controls, but not in patients with the disease. The percentage of Strep. sanguis in the oral flora was significantly correlated with the level of chemiluminescence response. Thus infection with uncommon serotypes of Strep. sanguis may play a role in the aetiology of Behçet's disease.

Synergistic Response of Rifampicin with Hydroperoxides on Mycobacterium: A Mechanistic Study

PubMed Central

Patel, Yesha S.; Mehra, Sarika

2017-01-01

Prolonged chemotherapy as well as rapid development of antimicrobial resistance are two of the major concerns for treatment of mycobacterial infections. To enhance the effectiveness of current drug regimens, search for compounds having synergistic interaction with anti-mycobacterial drugs has become indispensable. Here, we have investigated the intervention by oxidative stress, a major factor in mycobacterial pathogenesis, in combination with rifampicin (RIF), a first-line drug used against Mycobacterium tuberculosis. We have observed that a sub-inhibitory concentration of cumene hydroperoxide (CHP), a hydrophobic oxidant, synergistically reduced the minimum inhibitory concentration of RIF by fourfold, with a Fractional Inhibitory Concentration Index (FICI) of 0.45. Also, this interaction was found to be robust and synergistic against different strains of M. smegmatis as well as on M. bovis BCG, with FICI ranging from 0.3 to 0.6. Various physiological, biochemical and molecular parameters were explored to understand the mechanism of synergy. It was observed that increased membrane permeability owing to the presence of the oxidant, led to higher uptake of the drug. Moreover, downregulation of the hydroperoxide reductases by RIF, a transcriptional inhibitor, prevented quenching of the reactive oxygen species produced in the presence of CHP. The lipid soluble reactive species triggered autocatalytic lipid peroxidation (LPO), observed here as extensive membrane damage eventually leading to growth inhibition. Furthermore, it was seen that in combination with hydrogen peroxide (H2O2), the effect was only additive, establishing LPO as a key aspect leading toward synergism. To conclude, this work suggests that targeting the bacterial membrane by a radical species can have a significant impact on the treatment of tuberculosis. PMID:29163385

Cooling towers--a potential environmental source of slow-growing mycobacterial species.

PubMed

Black, Walter C; Berk, Sharon G

2003-01-01

Over the last decade a rise in the frequency of disease caused by nontuberculous mycobacteria (NTM) has occurred, especially among AIDS patients. The lack of evidence for person-to-person transmission indicates the environment is a source of infection. The ecology and environmental sources of NTMs are poorly understood, and many pathogenic strains have not been observed outside of clinical cases. Several species of NTMs have been reported from treated water distribution systems; however, one type of manmade environment that has not been examined for mycobacteria is that of cooling towers of air-conditioning systems. Such environments not only harbor a variety of microbial species, they also disseminate them in aerosols. The present investigation examined nine cooling towers from various locations in the United States. Cooling tower water was concentrated, treated with cetylpyridinium chloride, and plated onto Middlebrook 7H10 agar supplemented with OADC and cycloheximide. Colonies presumed to be mycobacterial species were isolated and acid-fast stained. Identification was made by amplifying and sequencing 1450 bp fragments of the 16S rRNA gene in both directions, and comparing resulting sequences with those in GenBank. Results showed that at least 75% of tower samples contained NTMs, and most of the isolates closely matched known mycobacterial pathogens. Isolates most closely matched the following GenBank sequences: Mycobacterium intracellulare, M. szulgai, M. bohemicum, M. gordonae, M. nonchromogenicum, and M. n. sp. "Fuerth 1999." This is the first report of specific NTMs in cooling tower water, and the first report of M. n. sp. "Fuerth 1999" from any environmental sample. Although cooling towers have a relatively high pH, they may favor the growth and dissemination of such potential pathogens, and future epidemiologic investigations should consider cooling towers as possible environmental sources of mycobacteria.

Determining the mode of action of anti-mycobacterial C17 diyne natural products using expression profiling: evidence for fatty acid biosynthesis inhibition.

PubMed

Li, Haoxin; Cowie, Andrew; Johnson, John A; Webster, Duncan; Martyniuk, Christopher J; Gray, Christopher A

2016-08-11

The treatment of microbial infections is becoming increasingly challenging because of limited therapeutic options and the growing number of pathogenic strains that are resistant to current antibiotics. There is an urgent need to identify molecules with novel modes of action to facilitate the development of new and more effective therapeutic agents. The anti-mycobacterial activity of the C17 diyne natural products falcarinol and panaxydol has been described previously; however, their mode of action remains largely undetermined in microbes. Gene expression profiling was therefore used to determine the transcriptomic response of Mycobacterium smegmatis upon treatment with falcarinol and panaxydol to better characterize the mode of action of these C17 diynes. Our analyses identified 704 and 907 transcripts that were differentially expressed in M. smegmatis after treatment with falcarinol and panaxydol respectively. Principal component analysis suggested that the C17 diynes exhibit a mode of action that is distinct to commonly used antimycobacterial drugs. Functional enrichment analysis and pathway enrichment analysis revealed that cell processes such as ectoine biosynthesis and cyclopropane-fatty-acyl-phospholipid synthesis were responsive to falcarinol and panaxydol treatment at the transcriptome level in M. smegmatis. The modes of action of the two C17 diynes were also predicted through Prediction of Activity Spectra of Substances (PASS). Based upon convergence of these three independent analyses, we hypothesize that the C17 diynes inhibit fatty acid biosynthesis, specifically phospholipid synthesis, in mycobacteria. Based on transcriptomic responses, it is suggested that the C17 diynes act differently than other anti-mycobacterial compounds in M. smegmatis, and do so by inhibiting phospholipid biosynthesis.

Mycobacterial Nucleoside Diphosphate Kinase Blocks Phagosome Maturation in Murine Raw 264.7 Macrophages

PubMed Central

Sun, Jim; Wang, Xuetao; Lau, Alice; Liao, Ting-Yu Angela; Bucci, Cecilia; Hmama, Zakaria

2010-01-01

Background Microorganisms capable of surviving within macrophages are rare, but represent very successful pathogens. One of them is Mycobacterium tuberculosis (Mtb) whose resistance to early mechanisms of macrophage killing and failure of its phagosomes to fuse with lysosomes causes tuberculosis (TB) disease in humans. Thus, defining the mechanisms of phagosome maturation arrest and identifying mycobacterial factors responsible for it are key to rational design of novel drugs for the treatment of TB. Previous studies have shown that Mtb and the related vaccine strain, M. bovis bacille Calmette-Guérin (BCG), disrupt the normal function of host Rab5 and Rab7, two small GTPases that are instrumental in the control of phagosome fusion with early endosomes and late endosomes/lysosomes respectively. Methodology/Principal Findings Here we show that recombinant Mtb nucleoside diphosphate kinase (Ndk) exhibits GTPase activating protein (GAP) activity towards Rab5 and Rab7. Then, using a model of latex bead phagosomes, we demonstrated that Ndk inhibits phagosome maturation and fusion with lysosomes in murine RAW 264.7 macrophages. Maturation arrest of phagosomes containing Ndk-beads was associated with the inactivation of both Rab5 and Rab7 as evidenced by the lack of recruitment of their respective effectors EEA1 (early endosome antigen 1) and RILP (Rab7-interacting lysosomal protein). Consistent with these findings, macrophage infection with an Ndk knocked-down BCG strain resulted in increased fusion of its phagosome with lysosomes along with decreased survival of the mutant. Conclusion Our findings provide evidence in support of the hypothesis that mycobacterial Ndk is a putative virulence factor that inhibits phagosome maturation and promotes survival of mycobacteria within the macrophage. PMID:20098737

Multifocal Tubercular Dactylitis: A Rare Presentation of Skeletal Tuberculosis in an Adult.

PubMed

Thatoi, Pravat; Parida, Manoj; Barik, Rakesh; Das, Bidyut

2017-06-01

Tubercular dactylitis is an uncommon form of osteo-articular tuberculosis seen in children. Multifocal involvement, simultaneously involving hands and feet is extremely uncommon. Here we report an adult patient with tubercular dactylitis involving multiple digits of both hands and second digit of right foot in absence of any risk factors like immunodeficiency or any debilitating condition. The patient was successfully treated with anti-tubercular drugs for six months. Mycobacterium tuberculosis infection of bones and joints can present in an unusual way but early diagnosis and treatment caries a good prognosis.

One Not to Miss: Ovarian Vein Thrombosis Causing Pulmonary Embolism with Literature Review

PubMed Central

Verde, Franco; Johnson, Pamela T.

2012-01-01

Ovarian vein thrombosis (OVT) is an uncommon entity typically seen in the post-partum, patients with pelvic surgery, infection, or inflammation, and hypercoagulabilty. Concurrent pulmonary embolism (PE) may occur in these patients; however, is an uncommon complication. Treatment commonly involves anti-coagulation and antibiotics in the setting of pelvic inflammatory disease. Presented is a case report of ovarian vein thrombosis leading to pulmonary embolism in the setting of malignancy, underscoring the importance of inspecting the gonadal vein during interpretation, particularly in the emergency setting. PMID:23378885

Heme Catabolism by Heme Oxygenase-1 Confers Host Resistance to Mycobacterium Infection

PubMed Central

Silva-Gomes, Sandro; Appelberg, Rui; Larsen, Rasmus; Soares, Miguel Parreira

2013-01-01

Heme oxygenases (HO) catalyze the rate-limiting step of heme degradation. The cytoprotective action of the inducible HO-1 isoform, encoded by the Hmox1 gene, is required for host protection against systemic infections. Here we report that upregulation of HO-1 expression in macrophages (Mϕ) is strictly required for protection against mycobacterial infection in mice. HO-1-deficient (Hmox1−/−) mice are more susceptible to intravenous Mycobacterium avium infection, failing to mount a protective granulomatous response and developing higher pathogen loads, than infected wild-type (Hmox1+/+) controls. Furthermore, Hmox1−/− mice also develop higher pathogen loads and ultimately succumb when challenged with a low-dose aerosol infection with Mycobacterium tuberculosis. The protective effect of HO-1 acts independently of adaptive immunity, as revealed in M. avium-infected Hmox1−/− versus Hmox1+/+ SCID mice lacking mature B and T cells. In the absence of HO-1, heme accumulation acts as a cytotoxic pro-oxidant in infected Mϕ, an effect mimicked by exogenous heme administration to M. avium-infected wild-type Mϕ in vitro or to mice in vivo. In conclusion, HO-1 prevents the cytotoxic effect of heme in Mϕ, contributing critically to host resistance to Mycobacterium infection. PMID:23630967

Substrate-bound Crystal Structures Reveal Features Unique to Mycobacterium tuberculosis N-Acetyl-glucosamine 1-Phosphate Uridyltransferase and a Catalytic Mechanism for Acetyl Transfer

PubMed Central

Jagtap, Pravin Kumar Ankush; Soni, Vijay; Vithani, Neha; Jhingan, Gagan Deep; Bais, Vaibhav Singh; Nandicoori, Vinay Kumar; Prakash, Balaji

2012-01-01

N-Acetyl-glucosamine-1-phosphate uridyltransferase (GlmU), a bifunctional enzyme involved in bacterial cell wall synthesis is exclusive to prokaryotes. GlmU, now recognized as a promising target to develop new antibacterial drugs, catalyzes two key reactions: acetyl transfer and uridyl transfer at two independent domains. Hitherto, we identified GlmU from Mycobacterium tuberculosis (GlmUMtb) to be unique in possessing a 30-residue extension at the C terminus. Here, we present the crystal structures of GlmUMtb in complex with substrates/products bound at the acetyltransferase active site. Analysis of these and mutational data, allow us to infer a catalytic mechanism operative in GlmUMtb. In this SN2 reaction, His-374 and Asn-397 act as catalytic residues by enhancing the nucleophilicity of the attacking amino group of glucosamine 1-phosphate. Ser-416 and Trp-460 provide important interactions for substrate binding. A short helix at the C-terminal extension uniquely found in mycobacterial GlmU provides the highly conserved Trp-460 for substrate binding. Importantly, the structures reveal an uncommon mode of acetyl-CoA binding in GlmUMtb; we term this the U conformation, which is distinct from the L conformation seen in the available non-mycobacterial GlmU structures. Residues, likely determining U/L conformation, were identified, and their importance was evaluated. In addition, we identified that the primary site for PknB-mediated phosphorylation is Thr-418, near the acetyltransferase active site. Down-regulation of acetyltransferase activity upon Thr-418 phosphorylation is rationalized by the structures presented here. Overall, this work provides an insight into substrate recognition, catalytic mechanism for acetyl transfer, and features unique to GlmUMtb, which may be exploited for the development of inhibitors specific to GlmU. PMID:22969087

Anti-mycobacterial screening of five Indian medicinal plants and partial purification of active extracts of Cassia sophera and Urtica dioica.

PubMed

Singh, Rambir; Hussain, Shariq; Verma, Rajesh; Sharma, Poonam

2013-05-13

To find out the anti-mycobacterial potential of Cassia sophera (C. sophera), Urtica dioica (U. dioica), Momordica dioica, Tribulus terrestris and Coccinia indica plants against multi-drug resistant (MDR) strain of Mycobacterium tuberculosis (M. tuberculosis). Plant materials were extracted successively with solvents of increasing polarity. Solvent extracts were screened for anti-mycobacterial activity against fast growing, non-pathogenic mycobacterium strain, Mycobacterium semegmatis, by disk diffusion method. The active extracts were tested against MDR and clinical isolates of M. tuberculosis by absolute concentration and proportion methods. The active extracts were subjected to bio-autoassay on TLC followed by silica column chromatography for isolation of potential drug leads. Hexane extract of U. dioica (HEUD) and methanol extract of C. sophera (MECS) produced inhibition zone of 20 mm in disc diffusion assay and MIC of 250 and 125 μ g/mL respectively in broth dilution assay against Mycobacterium semegmatis. Semipurified fraction F2 from MECS produced 86% inhibition against clinical isolate and 60% inhibition against MDR strain of M. tuberculosis. F18 from HEUD produced 81% inhibition against clinical isolate and 60% inhibition against MDR strain of M. tuberculosis. Phytochemical analysis indicated that anti-mycobacterial activity of MECS may be due to presence of alkaloids or flavonoids and that of HEUD due to terpenoids. C. sophera and U. dioica plant extracts exhibited promising anti-mycobacterial activity against MDR strain of M. tuberculosis. This is the first report of anti-mycobacterial activity form C. sophera. This study showed possibility of purifying novel anti-mycobacterial compound(s) from C. sophera and U. dioica. Copyright © 2013 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Specific detection of the cleavage activity of mycobacterial enzymes using a quantum dot based DNA nanosensor

NASA Astrophysics Data System (ADS)

Jepsen, Morten Leth; Harmsen, Charlotte; Godbole, Adwait Anand; Nagaraja, Valakunja; Knudsen, Birgitta R.; Ho, Yi-Ping

2015-12-01

We present a quantum dot based DNA nanosensor specifically targeting the cleavage step in the reaction cycle of the essential DNA-modifying enzyme, mycobacterial topoisomerase I. The design takes advantages of the unique photophysical properties of quantum dots to generate visible fluorescence recovery upon specific cleavage by mycobacterial topoisomerase I. This report, for the first time, demonstrates the possibility to quantify the cleavage activity of the mycobacterial enzyme without the pre-processing sample purification or post-processing signal amplification. The cleavage induced signal response has also proven reliable in biological matrices, such as whole cell extracts prepared from Escherichia coli and human Caco-2 cells. It is expected that the assay may contribute to the clinical diagnostics of bacterial diseases, as well as the evaluation of treatment outcomes.We present a quantum dot based DNA nanosensor specifically targeting the cleavage step in the reaction cycle of the essential DNA-modifying enzyme, mycobacterial topoisomerase I. The design takes advantages of the unique photophysical properties of quantum dots to generate visible fluorescence recovery upon specific cleavage by mycobacterial topoisomerase I. This report, for the first time, demonstrates the possibility to quantify the cleavage activity of the mycobacterial enzyme without the pre-processing sample purification or post-processing signal amplification. The cleavage induced signal response has also proven reliable in biological matrices, such as whole cell extracts prepared from Escherichia coli and human Caco-2 cells. It is expected that the assay may contribute to the clinical diagnostics of bacterial diseases, as well as the evaluation of treatment outcomes. Electronic supplementary information (ESI) available: Characterization of the QD-based DNA Nanosensor. See DOI: 10.1039/c5nr06326d

The use of light-emitting diode fluorescence to diagnose mycobacterial lymphadenitis in fine-needle aspirates from children

PubMed Central

van Wyk, A. C.; Marais, B. J.; Warren, R. M.; van Wyk, S. S.; Wright, C. A.

2011-01-01

SUMMARY BACKGROUND Fine-needle aspiration biopsy (FNAB) is a simple, safe and effective method for investigating suspected mycobacterial lymphadenitis in children. Fluorescence microscopy can provide rapid mycobacterial confirmation. Light-emitting diodes (LEDs) provide a cheap and robust excitation light source, making fluorescence microscopy feasible in resource-limited settings. OBJECTIVE To compare the diagnostic performance of LED fluorescence microscopy on Papanicolaou (PAP) stained smears with the conventional mercury vapour lamp (MVL). METHODS FNAB smears routinely collected from palpable lymph nodes in children with suspected mycobacterial disease were PAP-stained and evaluated by two independent microscopists using different excitatory light sources (MVL and LED). Mycobacterial culture results provided the reference standard. A manually rechargeable battery-powered LED power source was evaluated in a random subset. RESULTS We evaluated 182 FNAB smears from 121 children (median age 31 months, interquartile range 10–67). Mycobacterial cultures were positive in 84 of 121 (69%) children. The mean sensitivity with LED (mains-powered), LED (rechargeable battery-powered) and MVL was respectively 48.2%, 50.0% and 51.8% (specificity 78.4%, 86.7% and 78.4%). Inter-observer variation was similar for LED and MVL (κ = 0.5). CONCLUSION LED fluorescence microscopy provides a reliable alternative to conventional methods and has many favourable attributes that would facilitate improved, decentralised diagnostic services. PMID:21276297

The alternate effects of anti-TNFα therapeutics and their role in mycobacterial granulomatous infection in Crohn's disease.

PubMed

Qasem, Ahmad; Naser, Abed Elrahman; Naser, Saleh A

2017-07-01

Crohn's disease is an inflammatory bowel disease that has been debated to be associated with bacterial triggers such as Mycobacterium avium subspecies paratuberculosis (MAP). Standard treatment of Crohn's disease (CD) patients includes a family of immunomodulators and biologics such as Anti-Tumor Necrosis Factor alpha (Anti-TNFα). This cytokine in particular has been known to play vital roles in fighting microbial infections through formation and maintenance of granulomas. Areas covered: This perspective is focused on elucidating the negative effects of using Anti-TNFα therapeutic agents as a treatment option in CD patients who are more likely suspected to have MAP infection, and the role of other immunomodulators in MAP infection. Expert commentary: While treatment with Anti-TNFα is beneficial to reduce inflammation and to provide short term relief to the patients, it also compromises the immune system causing susceptibility to microbial infection. More than 50% of CD patients have shown no response to Anti-TNFα treatment which indicates a demand for introducing novel CD treatment in combination with antibiotics as a future CD treatment plan.

Expression of cathelicidin LL-37 during Mycobacterium tuberculosis infection in human alveolar macrophages, monocytes, neutrophils, and epithelial cells.

PubMed

Rivas-Santiago, Bruno; Hernandez-Pando, Rogelio; Carranza, Claudia; Juarez, Esmeralda; Contreras, Juan Leon; Aguilar-Leon, Diana; Torres, Martha; Sada, Eduardo

2008-03-01

The innate immune response in human tuberculosis is not completely understood. To improve our knowledge regarding the role of cathelicidin hCAP-18/LL37 in the innate immune response to tuberculosis infection, we used immunohistochemistry, immunoelectron microscopy, and gene expression to study the induction and production of the antimicrobial peptide in A549 epithelial cells, alveolar macrophages (AM), neutrophils, and monocyte-derived macrophages (MDM) after infection with Mycobacterium tuberculosis. We demonstrated that mycobacterial infection induced the expression and production of LL-37 in all cells studied, with AM being the most efficient. We did not detect peptide expression in tuberculous granulomas, suggesting that LL-37 participates only during early infection. Through the study of Toll-like receptors (TLR) in MDM, we showed that LL-37 can be induced by stimulation through TLR-2, TLR-4, and TLR-9. This last TLR was strongly stimulated by M. tuberculosis DNA. We concluded that LL-37 may have an important role in the innate immune response against M. tuberculosis.

Expression of Cathelicidin LL-37 during Mycobacterium tuberculosis Infection in Human Alveolar Macrophages, Monocytes, Neutrophils, and Epithelial Cells▿

PubMed Central

Rivas-Santiago, Bruno; Hernandez-Pando, Rogelio; Carranza, Claudia; Juarez, Esmeralda; Contreras, Juan Leon; Aguilar-Leon, Diana; Torres, Martha; Sada, Eduardo

2008-01-01

The innate immune response in human tuberculosis is not completely understood. To improve our knowledge regarding the role of cathelicidin hCAP-18/LL37 in the innate immune response to tuberculosis infection, we used immunohistochemistry, immunoelectron microscopy, and gene expression to study the induction and production of the antimicrobial peptide in A549 epithelial cells, alveolar macrophages (AM), neutrophils, and monocyte-derived macrophages (MDM) after infection with Mycobacterium tuberculosis. We demonstrated that mycobacterial infection induced the expression and production of LL-37 in all cells studied, with AM being the most efficient. We did not detect peptide expression in tuberculous granulomas, suggesting that LL-37 participates only during early infection. Through the study of Toll-like receptors (TLR) in MDM, we showed that LL-37 can be induced by stimulation through TLR-2, TLR-4, and TLR-9. This last TLR was strongly stimulated by M. tuberculosis DNA. We concluded that LL-37 may have an important role in the innate immune response against M. tuberculosis. PMID:18160480

Rapid Identification of Mycobacterial Whole Cells in Solid and Liquid Culture Media by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry ▿

PubMed Central

Lotz, Aurélie; Ferroni, Agnès; Beretti, Jean-Luc; Dauphin, Brunhilde; Carbonnelle, Etienne; Guet-Revillet, Hélène; Veziris, Nicolas; Heym, Béate; Jarlier, Vincent; Gaillard, Jean-Louis; Pierre-Audigier, Catherine; Frapy, Eric; Berche, Patrick; Nassif, Xavier; Bille, Emmanuelle

2010-01-01

Mycobacterial identification is based on several methods: conventional biochemical tests that require several weeks for accurate identification, and molecular tools that are now routinely used. However, these techniques are expensive and time-consuming. In this study, an alternative method was developed using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). This approach allows a characteristic mass spectral fingerprint to be obtained from whole inactivated mycobacterial cells. We engineered a strategy based on specific profiles in order to identify the most clinically relevant species of mycobacteria. To validate the mycobacterial database, a total of 311 strains belonging to 31 distinct species and 4 species complexes grown in Löwenstein-Jensen (LJ) and liquid (mycobacterium growth indicator tube [MGIT]) media were analyzed. No extraction step was required. Correct identifications were obtained for 97% of strains from LJ and 77% from MGIT media. No misidentification was noted. Our results, based on a very simple protocol, suggest that this system may represent a serious alternative for clinical laboratories to identify mycobacterial species. PMID:20943874

Scarlet Fever Upsurge in England and Molecular-Genetic Analysis in North-West London, 2014.

PubMed

Turner, Claire E; Pyzio, Marta; Song, Bonita; Lamagni, Theresa; Meltzer, Margie; Chow, J Yimmy; Efstratiou, Androulla; Curtis, Sally; Sriskandan, Shiranee

2016-06-01

Scarlet fever notifications surged across the United Kingdom in spring 2014. Molecular epidemiologic investigation of Streptococcus pyogenes infections in North-West London highlighted increased emm4 and emm3 infections coincident with the upsurge. Unlike outbreaks in other countries, antimicrobial resistance was uncommon, highlighting an urgent need to better understand the drivers of scarlet fever activity.

Polyradiculoneuropathy associated to human herpesvirus 2 in an HIV-1-infected patient (Elsberg syndrome): case report and literature review.

PubMed

Suarez-Calvet, Marc; Rojas-Garcia, Ricard; Querol, Luís; Sarmiento, Luís M; Domingo, Pere

2010-02-01

Peripheral nerve disorders are a common complication in HIV patients, reaching 15% of them. Several patterns and aetiologies have been described, being lumbosacral poliradiculoneuropathy one of them. We describe an HIV-1-infected patient who developed lumbosacral poliradiculoneuropathy caused by Human herpesvirus 2 and review the literature about this uncommon condition.

Ocular localization of mycobacterial lesions in tank-reared juvenile cobia, Rachycentron canadum.

PubMed

Phillips, A C N; Suepaul, R; Soto, E

2017-12-01

Severe clinical mycobacteriosis with consistent ocular lesion localization was diagnosed in a population of 800 juvenile tank-reared Cobia (Rachycentron canadum) which experienced a sudden increase in mortality approximately 5 months after arriving into Trinidad and Tobago from Florida, USA. Moderate daily mortality (15-20 animals per day) persisted for just over 1 month. Moribund fish displayed circling behaviour and had an open-mouth gape upon death. Fish consistently presented with bilateral exophthalmia, corneal cloudiness and hyphema. Non-branching acid-fast rods were detected in aqueous humour touch preparations. Histological analysis revealed severe bilateral intra-ocular granulomatous responses in all specimens. Mycobacterium sp. was identified using a real-time PCR assay detecting the RNA polymerase β-subunit (rpoB) gene in different tissue samples. Specimens did not present with characteristic granulomatous responses usually seen in viscera. To the best of our knowledge, this represents only the third documentation of piscine mycobacterial infection presenting with only localized ocular lesions, and the second documented case of mycobacteriosis in cobia. It is, however, the first documentation of an ocular presentation of mycobacteriosis in a marine species and is the first documentation of such a presentation in cobia. © 2017 John Wiley & Sons Ltd.

Porins Increase Copper Susceptibility of Mycobacterium tuberculosis

PubMed Central

Speer, Alexander; Rowland, Jennifer L.; Haeili, Mehri; Niederweis, Michael

2013-01-01

Copper resistance mechanisms are crucial for many pathogenic bacteria, including Mycobacterium tuberculosis, during infection because the innate immune system utilizes copper ions to kill bacterial intruders. Despite several studies detailing responses of mycobacteria to copper, the pathways by which copper ions cross the mycobacterial cell envelope are unknown. Deletion of porin genes in Mycobacterium smegmatis leads to a severe growth defect on trace copper medium but simultaneously increases tolerance for copper at elevated concentrations, indicating that porins mediate copper uptake across the outer membrane. Heterologous expression of the mycobacterial porin gene mspA reduced growth of M. tuberculosis in the presence of 2.5 μM copper by 40% and completely suppressed growth at 15 μM copper, while wild-type M. tuberculosis reached its normal cell density at that copper concentration. Moreover, the polyamine spermine, a known inhibitor of porin activity in Gram-negative bacteria, enhanced tolerance of M. tuberculosis for copper, suggesting that copper ions utilize endogenous outer membrane channel proteins of M. tuberculosis to gain access to interior cellular compartments. In summary, these findings highlight the outer membrane as the first barrier against copper ions and the role of porins in mediating copper uptake in M. smegmatis and M. tuberculosis. PMID:24013632

FurA contributes to the oxidative stress response regulation of Mycobacterium avium ssp. paratuberculosis

PubMed Central

Eckelt, Elke; Meißner, Thorsten; Meens, Jochen; Laarmann, Kristin; Nerlich, Andreas; Jarek, Michael; Weiss, Siegfried; Gerlach, Gerald-F.; Goethe, Ralph

2015-01-01

The ferric uptake regulator A (FurA) is known to be involved in iron homeostasis and stress response in many bacteria. In mycobacteria the precise role of FurA is still unclear. In the presented study, we addressed the functional role of FurA in the ruminant pathogen Mycobacterium avium ssp. paratuberculosis (MAP) by construction of a furA deletion strain (MAPΔfurA). RNA deep sequencing revealed that the FurA regulon consists of repressed and activated genes associated to stress response or intracellular survival. Not a single gene related to metal homeostasis was affected by furA deletion. A decisive role of FurA during intracellular survival in macrophages was shown by significantly enhanced survival of MAPΔfurA compared to the wildtype, indicating that a principal task of mycobacterial FurA is oxidative stress response regulation in macrophages. This resistance was not associated with altered survival of mice after long term infection with MAP. Our results demonstrate for the first time, that mycobacterial FurA is not involved in the regulation of iron homeostasis. However, they provide strong evidence that FurA contributes to intracellular survival as an oxidative stress sensing regulator. PMID:25705205

Impaired IFNγ-Signaling and Mycobacterial Clearance in IFNγR1-Deficient Human iPSC-Derived Macrophages.

PubMed

Neehus, Anna-Lena; Lam, Jenny; Haake, Kathrin; Merkert, Sylvia; Schmidt, Nico; Mucci, Adele; Ackermann, Mania; Schubert, Madline; Happle, Christine; Kühnel, Mark Philipp; Blank, Patrick; Philipp, Friederike; Goethe, Ralph; Jonigk, Danny; Martin, Ulrich; Kalinke, Ulrich; Baumann, Ulrich; Schambach, Axel; Roesler, Joachim; Lachmann, Nico

2018-01-09

Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of interferon gamma (IFNγ) immunity and is characterized by severe infections by weakly virulent mycobacteria. Although IFNγ is the macrophage-activating factor, macrophages from these patients have never been studied. We demonstrate the generation of heterozygous and compound heterozygous (iMSMD-cohet) induced pluripotent stem cells (iPSCs) from a single chimeric patient, who suffered from complete autosomal recessive IFNγR1 deficiency and received bone-marrow transplantation. Loss of IFNγR1 expression had no influence on the macrophage differentiation potential of patient-specific iPSCs. In contrast, lack of IFNγR1 in iMSMD-cohet macrophages abolished IFNγ-dependent phosphorylation of STAT1 and induction of IFNγ-downstream targets such as IRF-1, SOCS-3, and IDO. As a consequence, iMSMD-cohet macrophages show impaired upregulation of HLA-DR and reduced intracellular killing of Bacillus Calmette-Guérin. We provide a disease-modeling platform that might be suited to investigate novel treatment options for MSMD and to gain insights into IFNγ signaling in macrophages. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

FurA contributes to the oxidative stress response regulation of Mycobacterium avium ssp. paratuberculosis.

PubMed

Eckelt, Elke; Meißner, Thorsten; Meens, Jochen; Laarmann, Kristin; Nerlich, Andreas; Jarek, Michael; Weiss, Siegfried; Gerlach, Gerald-F; Goethe, Ralph

2015-01-01

The ferric uptake regulator A (FurA) is known to be involved in iron homeostasis and stress response in many bacteria. In mycobacteria the precise role of FurA is still unclear. In the presented study, we addressed the functional role of FurA in the ruminant pathogen Mycobacterium avium ssp. paratuberculosis (MAP) by construction of a furA deletion strain (MAPΔfurA). RNA deep sequencing revealed that the FurA regulon consists of repressed and activated genes associated to stress response or intracellular survival. Not a single gene related to metal homeostasis was affected by furA deletion. A decisive role of FurA during intracellular survival in macrophages was shown by significantly enhanced survival of MAPΔfurA compared to the wildtype, indicating that a principal task of mycobacterial FurA is oxidative stress response regulation in macrophages. This resistance was not associated with altered survival of mice after long term infection with MAP. Our results demonstrate for the first time, that mycobacterial FurA is not involved in the regulation of iron homeostasis. However, they provide strong evidence that FurA contributes to intracellular survival as an oxidative stress sensing regulator.

Targeting Mycobacterium tuberculosis Topoisomerase I by Small-Molecule Inhibitors

PubMed Central

Godbole, Adwait Anand; Ahmed, Wareed; Bhat, Rajeshwari Subray; Bradley, Erin K.; Ekins, Sean

2014-01-01

We describe inhibition of Mycobacterium tuberculosis topoisomerase I (MttopoI), an essential mycobacterial enzyme, by two related compounds, imipramine and norclomipramine, of which imipramine is clinically used as an antidepressant. These molecules showed growth inhibition of both Mycobacterium smegmatis and M. tuberculosis cells. The mechanism of action of these two molecules was investigated by analyzing the individual steps of the topoisomerase I (topoI) reaction cycle. The compounds stimulated cleavage, thereby perturbing the cleavage-religation equilibrium. Consequently, these molecules inhibited the growth of the cells overexpressing topoI at a low MIC. Docking of the molecules on the MttopoI model suggested that they bind near the metal binding site of the enzyme. The DNA relaxation activity of the metal binding mutants harboring mutations in the DxDxE motif was differentially affected by the molecules, suggesting that the metal coordinating residues contribute to the interaction of the enzyme with the drug. Taken together, the results highlight the potential of these small molecules, which poison the M. tuberculosis and M. smegmatis topoisomerase I, as leads for the development of improved molecules to combat mycobacterial infections. Moreover, targeting metal coordination in topoisomerases might be a general strategy to develop new lead molecules. PMID:25534741

Characterization of the receptors for mycobacterial cord factor in Guinea pig.

PubMed

Toyonaga, Kenji; Miyake, Yasunobu; Yamasaki, Sho

2014-01-01

Guinea pig is a widely used animal for research and development of tuberculosis vaccines, since its pathological disease process is similar to that present in humans. We have previously reported that two C-type lectin receptors, Mincle (macrophage inducible C-type lectin, also called Clec4e) and MCL (macrophage C-type lectin, also called Clec4d), recognize the mycobacterial cord factor, trehalose-6,6'-dimycolate (TDM). Here, we characterized the function of the guinea pig homologue of Mincle (gpMincle) and MCL (gpMCL). gpMincle directly bound to TDM and transduced an activating signal through ITAM-bearing adaptor molecule, FcRγ. Whereas, gpMCL lacked C-terminus and failed to bind to TDM. mRNA expression of gpMincle was detected in the spleen, lymph nodes and peritoneal macrophages and it was strongly up-regulated upon stimulation of zymosan and TDM. The surface expression of gpMincle was detected on activated macrophages by a newly established monoclonal antibody that also possesses a blocking activity. This antibody potently suppressed TNF production in BCG-infected macrophages. Collectively, gpMincle is the TDM receptor in the guinea pig and TDM-Mincle axis is involved in host immune responses against mycobacteria.

[Solitary nodular sarcoidosis demonstrating reversed tuberculin skin reaction].

PubMed

Osoreda, Hisayuki; Kobayashi, Hideo; Kanoh, Soichiro; Motoyoshi, Kazuo

2008-08-01

A 29-year-old woman was admitted because of chest radiograph abnormality. She had no respiratory complaints. Chest CT demonstrated an ill-defined nodule of 20mm with the "sarcoid galaxy sign" in the right upper lobe. Transbronchial biopsy (TBB) specimens from right S2 revealed non-caseating epithelioid cell granuloma. Initial clinical findings suggested mycobacterial infection. However, while waiting for the results of mycobacterial cultures in bronchial washing fluid, the tuberculin skin reaction was found to be negative, and enlargement of nodule, mediastinal lymphadenopathy and elevated soluble IL-2R were observed. Cultures for mycobacterium were negative and repeat TBB specimens revealed granulomatous inflammation. We diagnosed with sarcoidosis based on these findings. Solitary nodular sarcoidosis is rare with only 17 cases having been reported. These cases were diagnosed with difficulty because of non-specific clinical findings and of the 17, 16 cases (94%) were diagnosed by surgical procedures. We observed the clinico-radiological course of solitary nodules and the change in tuberculin reaction. Although a negative tuberculin skin reaction was commonly recognized in sarcoidosis patients, we confirmed that initial positive tuberculin reaction changed to negative according to disease progress. To the best of our knowledge, this is the first case report in adults.

Transcriptional Profiling of Mycobacterium tuberculosis Exposed to In Vitro Lysosomal Stress

PubMed Central

Lin, Wenwei; de Sessions, Paola Florez; Teoh, Garrett Hor Keong; Mohamed, Ahmad Naim Nazri; Zhu, Yuan O.; Koh, Vanessa Hui Qi; Ang, Michelle Lay Teng; Dedon, Peter C.; Hibberd, Martin Lloyd

2016-01-01

Increasing experimental evidence supports the idea that Mycobacterium tuberculosis has evolved strategies to survive within lysosomes of activated macrophages. To further our knowledge of M. tuberculosis response to the hostile lysosomal environment, we profiled the global transcriptional activity of M. tuberculosis when exposed to the lysosomal soluble fraction (SF) prepared from activated macrophages. Transcriptome sequencing (RNA-seq) analysis was performed using various incubation conditions, ranging from noninhibitory to cidal based on the mycobacterial replication or killing profile. Under inhibitory conditions that led to the absence of apparent mycobacterial replication, M. tuberculosis expressed a unique transcriptome with modulation of genes involved in general stress response, metabolic reprogramming, respiration, oxidative stress, dormancy response, and virulence. The transcription pattern also indicates characteristic cell wall remodeling with the possible outcomes of increased infectivity, intrinsic resistance to antibiotics, and subversion of the host immune system. Among the lysosome-specific responses, we identified the glgE-mediated 1,4 α-glucan synthesis pathway and a defined group of VapBC toxin/anti-toxin systems, both of which represent toxicity mechanisms that potentially can be exploited for killing intracellular mycobacteria. A meta-analysis including previously reported transcriptomic studies in macrophage infection and in vitro stress models was conducted to identify overlapping and nonoverlapping pathways. Finally, the Tap efflux pump-encoding gene Rv1258c was selected for validation. An M. tuberculosis ΔRv1258c mutant was constructed and displayed increased susceptibility to killing by lysosomal SF and the antimicrobial peptide LL-37, as well as attenuated survival in primary murine macrophages and human macrophage cell line THP-1. PMID:27324481

Coxiella burnetii Infection With Severe Hyperferritinemia in an Asplenic Patient

PubMed Central

Paine, Allison; Miya, Tadashi; Webb, Brandon J.

2015-01-01

Q fever is an uncommon but likely underreported zoonotic infection. Severe hyperferritinemia has been associated with hemophagocytic lymphohistiocytosis and other infectious diseases. In this study, we report a case of Coxiella burnetii infection in an asplenic patient complicated by severe hyperferritinemia and bone marrow infiltration. In this case, the marked ferritin elevation may have been an indicator of profound systemic macrophage activation due to preferential intracellular infection of this cell type by C burnetii, perhaps exacerbated by altered mononuclear phagocyte system function in the setting of asplenia. PMID:26430699

[Dipylidium caninum infection in a 2 year old infant: case report and literature review].

PubMed

Neira O, Patricia; Jofré M, Leonor; Muñoz S, Nelson

2008-12-01

Dipylidiasis is a zoonotic parasitic infection caused by the dog tapeworm Dipylidium caninum; it affects both feline and canine species and accidentally, humans. In Chile, as well as in other countries, it is an uncommon infection. A case of a 2 year old child from Casablanca, (a city located in the Valparaíso Region), with an infection by D. caninum, is presented. Clinical manifestations are reviewed, as well as epidemiology in domestic and wild animals, cases among the published national literature and its treatment and prevention strategies.

Cutaneous Involvement in the Deep Mycoses: A Literature Review. Part I-Subcutaneous Mycoses.

PubMed

Carrasco-Zuber, J E; Navarrete-Dechent, C; Bonifaz, A; Fich, F; Vial-Letelier, V; Berroeta-Mauriziano, D

2016-12-01

The deep mycoses are uncommon in our setting. These fungal infections occur mainly in immunosuppressed patients or in tropical climates, and include subcutaneous infections and systemic infections. The skin is always involved in the former. In the first part of this review, we describe the main subcutaneous mycoses: sporotrichosis, chromoblastomycosis, mycetoma, phaeohyphomycosis, hyalohyphomycosis, and lacaziosis. Early recognition and treatment is important, as these infections are frequently associated with high morbidity. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Mycobacterial biomaterials and resources for researchers.

PubMed

Hazbón, Manzour Hernando; Rigouts, Leen; Schito, Marco; Ezewudo, Matthew; Kudo, Takuji; Itoh, Takashi; Ohkuma, Moriya; Kiss, Katalin; Wu, Linhuan; Ma, Juncai; Hamada, Moriyuki; Strong, Michael; Salfinger, Max; Daley, Charles L; Nick, Jerry A; Lee, Jung-Sook; Rastogi, Nalin; Couvin, David; Hurtado-Ortiz, Raquel; Bizet, Chantal; Suresh, Anita; Rodwell, Timothy; Albertini, Audrey; Lacourciere, Karen A; Deheer-Graham, Ana; Alexander, Sarah; Russell, Julie E; Bradford, Rebecca; Riojas, Marco A

2018-06-01

There are many resources available to mycobacterial researchers, including culture collections around the world that distribute biomaterials to the general scientific community, genomic and clinical databases, and powerful bioinformatics tools. However, many of these resources may be unknown to the research community. This review article aims to summarize and publicize many of these resources, thus strengthening the quality and reproducibility of mycobacterial research by providing the scientific community access to authenticated and quality-controlled biomaterials and a wealth of information, analytical tools and research opportunities.

Childhood parasitic infections endemic to the United States.

PubMed

Barry, Meagan A; Weatherhead, Jill E; Hotez, Peter J; Woc-Colburn, Laila

2013-04-01

Endemic parasitic infections in the United States are more frequent than is commonly perceived. Intestinal parasitic infection with Cryptosporidium, Dientamoeba, and Giardia occurs most often in children in northern states during the summer months. Zoonotic Toxocara and Toxoplasma parasitic infections are more frequent in southern states, in African Americans, and in populations with lower socioeconomic status. Approximately 300, 000 people in the United States have Trypanosoma cruzi infection. Local, vector-borne transmission of T cruzi and Leishmania infections has been documented in southern states. Parasitic diseases endemic to the United States are not uncommon but are understudied. Copyright © 2013 Elsevier Inc. All rights reserved.

Mycobacterium avium subspecies impair dendritic cell maturation.

PubMed

Basler, Tina; Brumshagen, Christina; Beineke, Andreas; Goethe, Ralph; Bäumer, Wolfgang

2013-10-01

Mycobacterium avium ssp. paratuberculosis (MAP) causes Johne's disease, a chronic, granulomatous enteritis of ruminants. Dendritic cells (DC) of the gut are ideally placed to combat invading mycobacteria; however, little is known about their interaction with MAP. Here, we investigated the interaction of MAP and the closely related M. avium ssp. avium (MAA) with murine DC and the effect of infected macrophages on DC maturation. The infection of DC with MAP or MAA induced DC maturation, which differed to that of LPS as maturation was accompanied by higher production of IL-10 and lower production of IL-12. Treatment of maturing DC with supernatants from mycobacteria-infected macrophages resulted in impaired DC maturation, leading to a semi-mature, tolerogenic DC phenotype expressing low levels of MHCII, CD86 and TNF-α after LPS stimulation. Though the cells were not completely differentiated they responded with an increased IL-10 and a decreased IL-12 production. Using recombinant cytokines we provide evidence that the semi-mature DC phenotype results from a combination of secreted cytokines and released antigenic mycobacterial components of the infected macrophage. Our results indicate that MAP and MAA are able to subvert DC function directly by infecting and indirectly via the milieu created by infected macrophages.

Notes from the Field: Outbreak of Multidrug-Resistant Salmonella Infections Linked to Pork--Washington, 2015.

PubMed

Kawakami, Vance M; Bottichio, Lyndsay; Angelo, Kristina; Linton, Natalie; Kissler, Bonnie; Basler, Colin; Lloyd, Jennifer; Inouye, Wendy; Gonzales, Elysia; Rietberg, Krista; Melius, Beth; Oltean, Hanna; Wise, Matthew; Sinatra, Jennifer; Marsland, Paula; Li, Zhen; Meek, Roxanne; Kay, Meagan; Duchin, Jeff; Lindquist, Scott

2016-04-15

During June-July 2015, Public Health-Seattle & King County (PHSKC) and Washington State Department of Health (WADOH) investigated 22 clusters of Salmonella serotype I 4,[5], 12:i:- infections. Serotype I 4,[5], 12:i:- is the fifth most frequently reported Salmonella serotype in the United States, but is uncommon in Washington. On July 29, 2015, WADOH and PHSKC requested assistance from CDC to identify the infection source, determine risk factors, and make recommendations for prevention.

Bedside ultrasound of the soft tissue of the face: a case of early Ludwig's angina.

PubMed

Gaspari, Romolo J

2006-10-01

A case is reported of a 38-year-old man presenting with early Ludwig's angina. It is difficult to differentiate superficial from deep infections of the face and neck by physical examination alone. The diagnosis of this condition with bedside soft tissue ultrasound of the face is described. Ludwig's angina is an uncommon infection of the deep tissues of the face and neck that usually evolves from more superficial infections such as dental abscesses.

A repeat offender: Recurrent extraintestinal Clostridium difficile infection following fecal microbiota transplantation.

PubMed

Gardiner, Bradley J; Thorpe, Cheleste M; Pinkham, Nicholas V; McDermott, Laura A; Walk, Seth T; Snydman, David R

2018-06-01

Extraintestinal infection with Clostridium difficile has been reported but remains uncommon. Treatment of this unusual complication is complex given the limitations of current therapeutic options. Here we report a novel case of recurrent extraintestinal C. difficile infection that occurred following fecal microbiota transplantation. Using whole genome sequencing, we confirmed recrudescence rather than reinfection was responsible. The patient ultimately responded to prolonged, targeted antimicrobial therapy informed by susceptibility testing. Copyright © 2018 Elsevier Ltd. All rights reserved.

Scarlet Fever Upsurge in England and Molecular-Genetic Analysis in North-West London, 2014

PubMed Central

Turner, Claire E.; Pyzio, Marta; Song, Bonita; Lamagni, Theresa; Meltzer, Margie; Chow, J. Yimmy; Efstratiou, Androulla; Curtis, Sally

2016-01-01

Scarlet fever notifications surged across the United Kingdom in spring 2014. Molecular epidemiologic investigation of Streptococcus pyogenes infections in North-West London highlighted increased emm4 and emm3 infections coincident with the upsurge. Unlike outbreaks in other countries, antimicrobial resistance was uncommon, highlighting an urgent need to better understand the drivers of scarlet fever activity. PMID:27192393

Examining Merkel Cell Polyomavirus Minor Capsid Proteins | Center for Cancer Research

Cancer.gov

Merkel cell polyomavirus (MCV or MCPyV) is a recently discovered member of the viral family Polyomaviridae. It is a skin-dwelling polyomavirus species that appears to cause a rare but highly lethal form of skin cancer called Merkel cell carcinoma (MCC). Despite MCC being uncommon, chronic MCV infection of human skin is widespread, and most infected people have no known

Tuberculosis and non-tuberculous mycobacteria among HIV-infected individuals in Ghana.

PubMed

Bjerrum, Stephanie; Oliver-Commey, Joseph; Kenu, Ernest; Lartey, Margaret; Newman, Mercy Jemima; Addo, Kennedy Kwasi; Hilleman, Doris; Andersen, Aase Bengaard; Johansen, Isik Somuncu

2016-09-01

To assess the prevalence and clinical importance of previously unrecognised tuberculosis (TB) and isolation of non-tuberculous mycobacteria (NTM) among HIV-infected individuals in a teaching hospital in Ghana. Intensified mycobacterial case finding was conducted among HIV-positive individuals before initiation of antiretroviral therapy (ART). Data were collected on socio-demographic characteristics, medical history and TB-related signs and symptoms, and participants were followed for six months to determine treatment and vital status. Two sputum samples were obtained and examined for mycobacteria with smear microscopy, culture and Xpert MTB/RIF assay. NTM species were identified with the GenoType Mycobacterium CM/AS or sequence analysis of 16S rRNA gene. Of 473 participants, 60 (12.7%) had confirmed pulmonary TB, and 38 (8.0%) had positive cultures for NTM. Mycobacterium avium complex was identified in 9/38 (23.7%) of NTM isolates. Participants with NTM isolated were more likely to have CD4 cell count< 100 cells/μL (aOR 2.37; 95% CI: 1.10-5.14), BMI<18.5kg/m(2) (aOR 2.51; 95% CI: 1.15-5.51) and fever ≥2 weeks (aOR 2.76; 95% CI: 1.27-6.03) at baseline than participants with no mycobacteria. By six months, 76 (16.1%) participants had died; 20 (33.3%) with confirmed TB and 9 (23.7%) with NTM-positive culture. Mortality at six months was independently associated with TB diagnosis at enrolment (aHR 1.97; 95% CI 1.09-3.59), but not with NTM isolation after controlling for age, sex, CD4 cell count, BMI, prolonged fever and ART initiation. Intensified mycobacterial screening of HIV-infected individuals revealed a high burden of unrecognised pulmonary TB before ART initiation, which increased risk of death within six months. NTM were frequently isolated and associated with signs of poor clinical status but not with increased mortality. © 2016 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.

Detection of Mycobacterium tuberculosis peptides in the exosomes of patients with active and latent M. tuberculosis infection using MRM-MS.

PubMed

Kruh-Garcia, Nicole A; Wolfe, Lisa M; Chaisson, Lelia H; Worodria, William O; Nahid, Payam; Schorey, Jeff S; Davis, J Lucian; Dobos, Karen M

2014-01-01

The identification of easily measured, accurate diagnostic biomarkers for active tuberculosis (TB) will have a significant impact on global TB control efforts. Because of the host and pathogen complexities involved in TB pathogenesis, identifying a single biomarker that is adequately sensitive and specific continues to be a major hurdle. Our previous studies in models of TB demonstrated that exosomes, such as those released from infected macrophages, contain mycobacterial products, including many Mtb proteins. In this report, we describe the development of targeted proteomics assays employing multiplexed multiple reaction monitoring mass spectrometry (MRM-MS) in order to allow us to follow those proteins previously identified by western blot or shotgun mass spectrometry, and enhance biomarker discovery to include detection of Mtb proteins in human serum exosomes. Targeted MRM-MS assays were applied to exosomes isolated from human serum samples obtained from culture-confirmed active TB patients to detect 76 peptides representing 33 unique Mtb proteins. Our studies revealed the first identification of bacteria-derived biomarker candidates of active TB in exosomes from human serum. Twenty of the 33 proteins targeted for detection were found in the exosomes of TB patients, and included multiple peptides from 8 proteins (Antigen 85B, Antigen 85C, Apa, BfrB, GlcB, HspX, KatG, and Mpt64). Interestingly, all of these proteins are known mycobacterial adhesins and/or proteins that contribute to the intracellular survival of Mtb. These proteins will be included as target analytes in future validation studies as they may serve as markers for persistent active and latent Mtb infection. In summary, this work is the first step in identifying a unique and specific panel of Mtb peptide biomarkers encapsulated in exosomes and reveals complex biomarker patterns across a spectrum of TB disease states.

Detection of Mycobacterium tuberculosis Peptides in the Exosomes of Patients with Active and Latent M. tuberculosis Infection Using MRM-MS

PubMed Central

Kruh-Garcia, Nicole A.; Wolfe, Lisa M.; Chaisson, Lelia H.; Worodria, William O.; Nahid, Payam; Schorey, Jeff S.; Davis, J. Lucian; Dobos, Karen M.

2014-01-01

The identification of easily measured, accurate diagnostic biomarkers for active tuberculosis (TB) will have a significant impact on global TB control efforts. Because of the host and pathogen complexities involved in TB pathogenesis, identifying a single biomarker that is adequately sensitive and specific continues to be a major hurdle. Our previous studies in models of TB demonstrated that exosomes, such as those released from infected macrophages, contain mycobacterial products, including many Mtb proteins. In this report, we describe the development of targeted proteomics assays employing multiplexed multiple reaction monitoring mass spectrometry (MRM-MS) in order to allow us to follow those proteins previously identified by western blot or shotgun mass spectrometry, and enhance biomarker discovery to include detection of Mtb proteins in human serum exosomes. Targeted MRM-MS assays were applied to exosomes isolated from human serum samples obtained from culture-confirmed active TB patients to detect 76 peptides representing 33 unique Mtb proteins. Our studies revealed the first identification of bacteria-derived biomarker candidates of active TB in exosomes from human serum. Twenty of the 33 proteins targeted for detection were found in the exosomes of TB patients, and included multiple peptides from 8 proteins (Antigen 85B, Antigen 85C, Apa, BfrB, GlcB, HspX, KatG, and Mpt64). Interestingly, all of these proteins are known mycobacterial adhesins and/or proteins that contribute to the intracellular survival of Mtb. These proteins will be included as target analytes in future validation studies as they may serve as markers for persistent active and latent Mtb infection. In summary, this work is the first step in identifying a unique and specific panel of Mtb peptide biomarkers encapsulated in exosomes and reveals complex biomarker patterns across a spectrum of TB disease states. PMID:25080351

Non tuberculous mycobacterial lesion of the parotid gland and facial skin in a 4year old girl: A proposed treatment strategy.

PubMed

Berkovic, Juraj; Vanchiere, John A; Gungor, Anil

2016-01-01

We report a case of a parotid-facial caseating granulomatous infection caused by atypical mycobacteria (Mycobacterium avium) in an immuno-competent child. The size and depth of the lesion and its proximity to the facial nerve present a challenge for a purely surgical treatment strategy. An alternative treatment strategy is developed to avoid severe disfigurement. Atypical mycobacterial infection of the parotid region in a 5 year old girl: timeline and definition of a planned combined treatment strategy with antibiotics and surgical excision. Cervicofacial infections caused by non-tuberculous mycobacteria (NTM) may present surgical challenges due to the size and depth of the lesion and its proximity to the facial nerve and major vascular structures. Even minor scars are highly visible and poorly tolerated. Close clinical monitoring combined with judicious treatment strategies is necessary for successful treatment and good cosmesis. Recent literature provides insufficient guidance in formulating the best treatment strategy for the individual patient. Comparisons of antibiotic therapy with variations of surgical excision are abundant but poorly formulated. Our case presented with a lesion involving skin, superficial and deep lobe of the parotid gland. Lesion was in immediate proximity to the distribution of the facial nerve through the parotid gland. The risk of surgical damage to the facial nerve in the acute phase of the inflammation and the required extent of skin excision were significant. We decided to start treatment with combination antimycobacterial antibiotics in close cooperation with the pediatric infectious disease specialists. We observed and documented the regress and executed a delayed surgical excision when the lesion was reduced to skin only. In our opinion this was the best treatment strategy that helped us avoid extensive dissection in the vicinity of the facial nerve as well as a parotidectomy. Excision of the involved skin with the deep portion was performed 6.5 months after initial diagnosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of two line probe assays for rapid detection of Mycobacterium tuberculosis, tuberculosis (TB) drug resistance, and non-TB Mycobacteria in HIV-infected individuals with suspected TB.

PubMed

Luetkemeyer, Anne F; Kendall, Michelle A; Wu, Xingye; Lourenço, Maria Cristina; Jentsch, Ute; Swindells, Susan; Qasba, Sarojini S; Sanchez, Jorge; Havlir, Diane V; Grinsztejn, Beatriz; Sanne, Ian M; Firnhaber, Cynthia

2014-04-01

Limited performance data from line probe assays (LPAs), nucleic acid tests used for the rapid diagnosis of tuberculosis (TB), nontuberculosis mycobacteria (NTM), and Mycobacterium tuberculosis drug resistance are available for HIV-infected individuals, in whom paucibacillary TB is common. In this study, the strategy of testing sputum with GenoType MTBDRplus (MTBDR-Plus) and GenoType Direct LPA (Direct LPA) was compared to a gold standard of one mycobacterial growth indicator tube (MGIT) liquid culture. HIV-positive (HIV(+)) individuals with suspected TB from southern Africa and South America with <7 days of TB treatment had 1 sputum specimen tested with Direct LPA, MTBDR-Plus LPA, smear microscopy, MGIT, biochemical identification of mycobacterial species, and culture-based drug-susceptibility testing (DST). Of 639 participants, 59.3% were MGIT M. tuberculosis culture positive, of which 276 (72.8%) were acid-fast bacillus (AFB) smear positive. MTBDR-Plus had a sensitivity of 81.0% and a specificity of 100%, with sensitivities of 44.1% in AFB smear-negative versus 94.6% in AFB smear-positive specimens. For specimens that were positive for M. tuberculosis by MTBDR-Plus, the sensitivity and specificity for rifampin resistance were 91.7% and 96.6%, respectively, and for isoniazid (INH) they were 70.6% and 99.1%. The Direct LPA had a sensitivity of 88.4% and a specificity of 94.6% for M. tuberculosis detection, with a sensitivity of 72.5% in smear-negative specimens. Ten of 639 MGIT cultures grew Mycobacterium avium complex or Mycobacterium kansasii, half of which were detected by Direct LPA. Both LPA assays performed well in specimens from HIV-infected individuals, including in AFB smear-negative specimens, with 72.5% sensitivity for M. tuberculosis identification with the Direct LPA and 44.1% sensitivity with MTBDR-Plus. LPAs have a continued role for use in settings where rapid identification of INH resistance and clinically relevant NTM are priorities.

Regulatory T Cells Subvert Mycobacterial Containment in Patients Failing Extensively Drug-resistant TB Treatment.

PubMed

Davids, Malika; Pooran, Anil S; Pietersen, Elize; Wainwright, Helen C; Binder, Anke; Warren, Robin; Dheda, Keertan

2018-02-09

The advent of extensively (XDR-TB) and totally drug-resistant TB, with limited or no treatment options, has facilitated renewed interest in host directed immunotherapy, particularly for therapeutically destitute patients. However, the selection and utility of such approaches depend upon understanding the host immune response in XDR-TB, which hitherto remains unexplored. To determine the host immunological profile in patients with XDR-TB, compared to drug-sensitive TB, using peripheral blood and explanted lung tissue. Blood and explanted lung tissue were obtained from patients with XDR-TB (n=31), drug-sensitive TB (DS-TB, n=20) and presumed latent-TB infection (LTBI, n=20). T-cell phenotype (Th1/Th2/Th17/Tregs) was evaluated in all patient groups, and Treg function assessed in XDR-TB non-responders by co-culturing PPD pre-primed effector T-cells with H37Rv-infected monocyte-derived macrophages, with or without autologous Tregs. Mycobacterial containment was evaluated by counting colony-forming units. Patients failing XDR-TB treatment had an altered immuno-phenotype characterized by a substantial increase in the frequency (median; IQR) of CD4+CD25+FoxP3+ regulatory T-cells (11.5; 5.9-15.2) compared to DS-TB (3.4 %; 1.6-5.73; p < 0.001) and presumed LTBI (1.8 % 1.2-2.3; p < 0.001), which was unrelated to disease duration. Tregs isolated from XDR-TB patients suppressed T-cell proliferation (up to 90%) and subverted containment of H37Rv-infected monocyte-derived macrophages (by 30%; p= 0.03) by impairing effector T-cell function through a mechanism independent of direct cell-to-cell contact, IL-10, TGF-beta and CTLA-4. Collectively, these data suggest that Tregs may be contributing to immune dysfunction, and bacterial persistence, in patients with XDR-TB. The relevant cellular pathways may serve as potential targets for immunotherapeutic intervention.

Central nervous system involvement in adult patients with invasive infection caused by Streptococcus agalactiae.

PubMed

Oyanguren, B; Esteban, L; Guillán, M; de Felipe, A; Alonso Cánovas, A; Navas, E; Quereda, C; Corral, I

2015-04-01

Streptococcus agalactiae is frequently an asymptomatic coloniser and a cause of neonatal and puerperal sepsis. Infections in nonpregnant adults are uncommon. The frequency of neurological complications caused by invasive infection with this microorganism in adults remains unknown. Here, we study the frequency and characteristics of central nervous system (CNS) involvement in adults with invasive S. agalactiae infection. Review of all adults with invasive S. agalactiae infection between 2003 and 2011 in a tertiary hospital. S. agalactiae was isolated from blood, CSF or synovial fluid in 75 patients. Among them, 7 (9,3%) displayed neurological involvement: 5 men and 2 nonpregnant women, aged between 20 and 62 years. Diagnoses were spinal epidural abscess due to spondylodiscitis with spinal cord compression; acute bacterial meningitis; ischemic stroke as presentation of bacterial endocarditis (2 patients each); and meningoventriculitis after neurosurgery and ventricular shunting. One patient with endocarditis caused by S. agalactiae and S. aureus died in the acute phase, and another died 3 months later from metastatic cancer. The other patients recovered without sequelae. All patients had systemic predisposing factors for infection and 5 (71,4%) had experienced disruption of the mucocutaneous barrier as a possible origin of the infection. CNS involvement is not uncommon in adult patients with invasive infection caused by S. agalactiae. Isolating S. agalactiae, especially in cases of meningitis, should lead doctors to search for predisposing systemic disease and causes of mucocutaneous barrier disruption. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Therapeutic efficacy of liposomes containing 4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine in a murine model of progressive pulmonary tuberculosis.

PubMed

Mata-Espinosa, Dulce; Molina-Salinas, Gloria María; Barrios-Payán, Jorge; Navarrete-Vázquez, Gabriel; Marquina, Brenda; Ramos-Espinosa, Octavio; Bini, Estela Isabel; Baeza, Isabel; Hernández-Pando, Rogelio

2015-06-01

Tuberculosis (TB) is one of the deadliest infectious diseases and comprises a global public health concern because co-infection with Human immunodeficiency virus (HIV) and, in particular, the continuous isolation of new Multidrug-resistant strains (MDR), rendering the discovery of novel anti-TB agents a strategic priority. One of the most effective first-line mycobactericidal drugs is Isoniazid (INH). Previously, we reported in vitro anti-mycobacterial activity against sensitive and MDR Mycobacterium tuberculosis strains of a new oxadiazole obtained from the hybridization of INH and palmitic acid. The present study evaluated the therapeutic potential of liposomes including Phosphatidylcholine (PC) and L-α Phosphatidic acid (PA) or PC and Cholesterol (Chol) containing 4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine in BALB/c male mice infected by intratracheal (i.t.) route with drug-sensitive or MDR M. tuberculosis. The lipophilic 4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine was obtained to mix INH and palmitoyl chloride. The in vivo anti-TB effect of this oxadiazole derivative contained in two different liposomes was tested in BALB/c mice infected with a sensitive strain of M. tuberculosis, initiating treatment 2 months post-infection, by i.t. route, of 50 μg of oxadiazole derivative for 1 month. In a second stage, mice were infected with an MDR (resistant to first-line drugs) and treated with 150 μg of an oxadiazole derivative carried by PC + Chol liposomes for 2 months. The effect of the oxadiazole derivative in vivo was determined by the quantification of lung bacilli loads and histopathology. In comparison with control animals, drug-sensitive, strain-infected mice treated for 1 month with 50 μg of this oxadiazole derivative contained in the liposomes of PC + Chol showed a significant, 80% decrease of live bacilli in lungs, which correlated with the morphometric observation, and the group of MDR clinical isolate-infected mice treated with 150 μg of the oxadiazole derivative contained in the same type of liposome showed significantly lower lung bacillary loads than control mice, producing 90% of bacilli burden reduction after 2 months of treatment. These results confirm and extend the reported highly efficient anti-mycobacterial activity of this lipophilic oxidazole derivative when it is carried by liposomes in mice suffering from late progressive pulmonary TB induced by drug-sensitive, and most prominently by, MDR strains. Copyright © 2015 Elsevier Ltd. All rights reserved.

Secondary metabolites from Tetracera potatoria stem bark with anti-mycobacterial activity.

PubMed

Fomogne-Fodjo, M C Y; Ndinteh, D T; Olivier, D K; Kempgens, P; van Vuuren, S; Krause, R W M

2017-01-04

Tetracera potatoria Afzel. Exg. Don (Dilleniaceae) is a medicinal plant used traditionally in Africa for the treatment of tuberculosis related ailments and respiratory infections. The antibacterial activity of the medium polar extracts of T. potatoria leaves and stem bark was recently reported against Mycobacterium smegmatis (MIC 25µg/mL) and M. aurum (65µg/mL), two fast-growing Mycobacterium strains used as model micro-organisms for the more pathogenic strain Mycobacterium tuberculosis (Fomogne-Fodjo et al., 2014). The aim of this study was consequently to isolate the compounds possibly contributing to this activity, and which may therefore be promising precursors to be used for the development of novel anti-TB drugs. T. potatoria medium polar extract [MeOH/DCM (1:1, v/v)] was fractionated sequentially with petroleum ether to which EtOAC and MeOH were gradually added to increase the polarity. The examination of T. potatoria extract and its fractions was guided by bioassays for anti-mycobacterial activity against M. smegmatis (ATCC 23246) and M. aurum (NCTC 10437) using the minimum inhibitory concentration (MIC) method. All the isolated compounds were structurally elucidated using spectroscopic techniques and evaluated for their anti-mycobacterial activity. Two novel secondary metabolites (1, 2) named tetraceranoate and N-hydroxy imidate-tetracerane, together with five known compounds [β-stigmasterol (3), stigmast-5-en-3β-yl acetate (4), betulinic acid (5), betulin (6) and lupeol (7)] were isolated and identified. Tetraceranoate exhibited the best activity against M. smegmatis with a minimum inhibitory concentration (MIC) of 7.8µg/mL, while β-stigmasterol, betulinic acid and betulin showed appreciable anti-mycobacterial activity against both strains (MIC 15µg/mL). Seven compounds were isolated from the medium polar extract [MeOH/DCM (1:1, v/v)] of T. potatoria stem bark. Only tetraceranoate one of the isolated compounds showed antibacterial activity against M. smegmatis having efficacy as high as rifampicin (one of a three drug regimen recommended in the initial phase short-course anti-tuberculosis therapy). Thus, tetraceranoate might be an interesting target for systematic testing of anti-TB treatment and management. This research supports the use of T. potatoria in African traditional medicine for the treatment of tuberculosis related symptoms. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Multiple Periprosthetic Joint Infections: Evidence for Decreasing Prevalence.

PubMed

Haverstock, John P; Somerville, Lyndsa E; Naudie, Douglas D; Howard, James L

2016-12-01

Multiple periprosthetic joint infections (MPJIs) are uncommon. We determine the prevalence of developing a second-site periprosthetic joint infection. Our institutional arthroplasty database was reviewed. Those who developed a second-site infection had a retrospective chart review to determine the pathogen, timing of infection, comorbidities, and results of treatment. Thirteen of 206 (6.3%) patients at-risk for MPJI experienced a second periprosthetic joint infection. Mode of the second infection was hematogenous in 6, all of whom were being treated for the index periprosthetic joint infection. Seven secondary infections did not relate to the index infection. Two patients were lost to follow-up, 5 continued on suppressive antibiotics, and 6 successfully cleared infection. The prevalence of MPJI has decreased compared with previous reports. Copyright © 2016 Elsevier Inc. All rights reserved.

Mycobacterium tuberculosis and non-tuberculous mycobacteria isolates from HIV-infected patients in Guangxi, China.

PubMed

Lan, R; Yang, C; Lan, L; Ou, J; Qiao, K; Liu, F; Gao, Q

2011-12-01

Tuberculosis (TB) remains the leading cause of death among human immunodeficiency virus (HIV) infected persons. The prevalence of infection with Mycobacterium tuberculosis and non-tuberculous mycobacteria (NTM) in HIV-infected patients in China is unknown. To estimate the prevalence of M. tuberculosis and NTM in HIV-infected patients in Guangxi Province, determine their drug resistance profiles, and evaluate the genotype patterns of M. tuberculosis strains. Samples were collected from two HIV designated hospitals in Guangxi Province between 2005 and 2008. HIV-infected patients who were culture-positive for mycobacteria were included. Drug susceptibility testing was performed for mycobacterial isolates. NTM species was identified by sequencing, and M. tuberculosis isolates were genotyped using the variable number of tandem repeats method. M. tuberculosis and NTM were identified in respectively 117 (53%) and 102 (47%) HIV-infected patients. Drug resistance was found in 27% and multi-drug-resistant TB (MDR-TB) in 11% of the patients with TB. Previous treatment for TB was significantly associated with MDR-TB. Twenty (17%) TB patients belonged to eight VNTR-defined clusters. The high frequency of NTM among HIV-infected patients raises concerns about accurate species identification before the determination of appropriate treatment. The potential for TB transmission exists among HIV-infected patients. Intensified screening and effective treatment of TB-HIV co-infected patients is urgently needed.

Extracellular Vesicles Released from Mycobacterium tuberculosis-Infected Neutrophils Promote Macrophage Autophagy and Decrease Intracellular Mycobacterial Survival

PubMed Central

Alvarez-Jiménez, Violeta D.; Leyva-Paredes, Kahiry; García-Martínez, Mariano; Vázquez-Flores, Luis; García-Paredes, Víctor Gabriel; Campillo-Navarro, Marcia; Romo-Cruz, Israel; Rosales-García, Víctor Hugo; Castañeda-Casimiro, Jessica; González-Pozos, Sirenia; Hernández, José Manuel; Wong-Baeza, Carlos; García-Pérez, Blanca Estela; Ortiz-Navarrete, Vianney; Estrada-Parra, Sergio; Serafín-López, Jeanet; Wong-Baeza, Isabel; Chacón-Salinas, Rommel; Estrada-García, Iris

2018-01-01

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb). In the lungs, macrophages and neutrophils are the first immune cells that have contact with the infecting mycobacteria. Neutrophils are phagocytic cells that kill microorganisms through several mechanisms, which include the lytic enzymes and antimicrobial peptides that are found in their lysosomes, and the production of reactive oxygen species. Neutrophils also release extracellular vesicles (EVs) (100–1,000 nm in diameter) to the extracellular milieu; these EVs consist of a lipid bilayer surrounding a hydrophilic core and participate in intercellular communication. We previously demonstrated that human neutrophils infected in vitro with Mtb H37Rv release EVs (EV-TB), but the effect of these EVs on other cells relevant for the control of Mtb infection, such as macrophages, has not been completely analyzed. In this study, we characterized the EVs produced by non-stimulated human neutrophils (EV-NS), and the EVs produced by neutrophils stimulated with an activator (PMA), a peptide derived from bacterial proteins (fMLF) or Mtb, and observed that the four EVs differed in their size. Ligands for toll-like receptor (TLR) 2/6 were detected in EV-TB, and these EVs favored a modest increase in the expression of the co-stimulatory molecules CD80, a higher expression of CD86, and the production of higher amounts of TNF-α and IL-6, and of lower amounts of TGF-β, in autologous human macrophages, compared with the other EVs. EV-TB reduced the amount of intracellular Mtb in macrophages, and increased superoxide anion production in these cells. TLR2/6 ligation and superoxide anion production are known inducers of autophagy; accordingly, we found that EV-TB induced higher expression of the autophagy-related marker LC3-II in macrophages, and the co-localization of LC3-II with Mtb inside infected macrophages. The intracellular mycobacterial load increased when autophagy was inhibited with wortmannin in these cells. In conclusion, our results demonstrate that neutrophils produce different EVs in response to diverse activators, and that EV-TB activate macrophages and promote the clearance of intracellular Mtb through early superoxide anion production and autophagy induction, which is a novel role for neutrophil-derived EVs in the immune response to Mtb. PMID:29520273

Extracellular Vesicles Released from Mycobacterium tuberculosis-Infected Neutrophils Promote Macrophage Autophagy and Decrease Intracellular Mycobacterial Survival.

PubMed

Alvarez-Jiménez, Violeta D; Leyva-Paredes, Kahiry; García-Martínez, Mariano; Vázquez-Flores, Luis; García-Paredes, Víctor Gabriel; Campillo-Navarro, Marcia; Romo-Cruz, Israel; Rosales-García, Víctor Hugo; Castañeda-Casimiro, Jessica; González-Pozos, Sirenia; Hernández, José Manuel; Wong-Baeza, Carlos; García-Pérez, Blanca Estela; Ortiz-Navarrete, Vianney; Estrada-Parra, Sergio; Serafín-López, Jeanet; Wong-Baeza, Isabel; Chacón-Salinas, Rommel; Estrada-García, Iris

2018-01-01

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb). In the lungs, macrophages and neutrophils are the first immune cells that have contact with the infecting mycobacteria. Neutrophils are phagocytic cells that kill microorganisms through several mechanisms, which include the lytic enzymes and antimicrobial peptides that are found in their lysosomes, and the production of reactive oxygen species. Neutrophils also release extracellular vesicles (EVs) (100-1,000 nm in diameter) to the extracellular milieu; these EVs consist of a lipid bilayer surrounding a hydrophilic core and participate in intercellular communication. We previously demonstrated that human neutrophils infected in vitro with Mtb H37Rv release EVs (EV-TB), but the effect of these EVs on other cells relevant for the control of Mtb infection, such as macrophages, has not been completely analyzed. In this study, we characterized the EVs produced by non-stimulated human neutrophils (EV-NS), and the EVs produced by neutrophils stimulated with an activator (PMA), a peptide derived from bacterial proteins (fMLF) or Mtb, and observed that the four EVs differed in their size. Ligands for toll-like receptor (TLR) 2/6 were detected in EV-TB, and these EVs favored a modest increase in the expression of the co-stimulatory molecules CD80, a higher expression of CD86, and the production of higher amounts of TNF-α and IL-6, and of lower amounts of TGF-β, in autologous human macrophages, compared with the other EVs. EV-TB reduced the amount of intracellular Mtb in macrophages, and increased superoxide anion production in these cells. TLR2/6 ligation and superoxide anion production are known inducers of autophagy; accordingly, we found that EV-TB induced higher expression of the autophagy-related marker LC3-II in macrophages, and the co-localization of LC3-II with Mtb inside infected macrophages. The intracellular mycobacterial load increased when autophagy was inhibited with wortmannin in these cells. In conclusion, our results demonstrate that neutrophils produce different EVs in response to diverse activators, and that EV-TB activate macrophages and promote the clearance of intracellular Mtb through early superoxide anion production and autophagy induction, which is a novel role for neutrophil-derived EVs in the immune response to Mtb.

Mycobacterium avium ss. paratuberculosis Zoonosis – The Hundred Year War – Beyond Crohn’s Disease

PubMed Central

Sechi, Leonardo A.; Dow, Coad Thomas

2015-01-01

The factitive role of Mycobacterium avium ss. paratuberculosis (MAP) in Crohn’s disease has been debated for more than a century. The controversy is due to the fact that Crohn’s disease is so similar to a disease of MAP-infected ruminant animals, Johne’s disease; and, though MAP can be readily detected in the infected ruminants, it is much more difficult to detect in humans. Molecular techniques that can detect MAP in pathologic Crohn’s specimens as well as dedicated specialty labs successful in culturing MAP from Crohn’s patients have provided strong argument for MAP’s role in Crohn’s disease. Perhaps more incriminating for MAP as a zoonotic agent is the increasing number of diseases with which MAP has been related: Blau syndrome, type 1 diabetes, Hashimoto thyroiditis, and multiple sclerosis. In this article, we debate about genetic susceptibility to mycobacterial infection and human exposure to MAP; moreover, it suggests that molecular mimicry between protein epitopes of MAP and human proteins is a likely bridge between infection and these autoimmune disorders. PMID:25788897

Mycobacterium tuberculosis exploits the formation of new blood vessels for its dissemination

PubMed Central

Polena, Helena; Boudou, Frédéric; Tilleul, Sylvain; Dubois-Colas, Nicolas; Lecointe, Cécile; Rakotosamimanana, Niaina; Pelizzola, Mattia; Andriamandimby, Soa Fy; Raharimanga, Vaomalala; Charles, Patricia; Herrmann, Jean-Louis; Ricciardi-Castagnoli, Paola; Rasolofo, Voahangy; Gicquel, Brigitte; Tailleux, Ludovic

2016-01-01

The mechanisms by which the airborne pathogen Mycobacterium tuberculosis spreads within the lung and leaves its primary niche to colonize other organs, thus inducing extrapulmonary forms of tuberculosis (TB) in humans, remains poorly understood. Herein, we used a transcriptomic approach to investigate the host cell gene expression profile in M. tuberculosis–infected human macrophages (ΜΦ). We identified 33 genes, encoding proteins involved in angiogenesis, for which the expression was significantly modified during infection, and we show that the potent angiogenic factor VEGF is secreted by M. tuberculosis-infected ΜΦ, in an RD1-dependent manner. In vivo these factors promote the formation of blood vessels in murine models of the disease. Inhibiting angiogenesis, via VEGF inactivation, abolished mycobacterial spread from the infection site. In accordance with our in vitro and in vivo results, we show that the level of VEGF in TB patients is elevated and that endothelial progenitor cells are mobilized from the bone marrow. These results strongly strengthen the most recent data suggesting that mycobacteria take advantage of the formation of new blood vessels to disseminate. PMID:27616470

Semiquantitative Culture Analysis during Therapy for Mycobacterium avium Complex Lung Disease.

PubMed

Griffith, David E; Adjemian, Jennifer; Brown-Elliott, Barbara A; Philley, Julie V; Prevots, D Rebecca; Gaston, Christopher; Olivier, Kenneth N; Wallace, Richard J

2015-09-15

Microbiologically based criteria such as sputum culture conversion to negative have traditionally been used to define treatment success for mycobacterial diseases. There are, however, limited data regarding whether nontuberculous mycobacterial sputum culture conversion or semiquantitative culture analysis correlates with subjective or nonmicrobiologic objective indices of treatment response. To determine whether a semiquantitative mycobacterial culture scale correlated with clinical disease status and was predictive of long-term sputum mycobacterial culture conversion to negative in a cohort of patients with nodular/bronchiectatic Mycobacterium avium complex lung disease undergoing therapy. One hundred and eighty patients undergoing standard macrolide-based therapy for M. avium complex lung disease were monitored at standard frequent intervals with symptomatic, radiographic, and microbiologic data collected, including semiquantitative mycobacterial culture analysis. Analyses were used to evaluate clinical and microbiologic predictors of long-term sputum conversion to culture negative. After 12 months of therapy, 148 (82%) patients had sputum conversion to culture negative. Baseline semiquantitative sputum culture scores did not differ between patients with sputum conversion and those without. The change in sputum culture semiquantitative score from baseline to Month 3 was highly predictive of subsequent sputum long-term conversion status indicative of treatment success, as was improvement in cough, and especially early radiographic improvement. Early semiquantitative sputum agar plate culture results can be used to predict symptomatic and radiographic improvement as well as long-term sputum culture conversion to negative in this population. We suggest that semiquantitative sputum culture scores can be a useful tool for evaluating new nontuberculous mycobacterial lung disease therapies.

Pulmonary tuberculosis and disease-related pulmonary apical fibrosis in ankylosing spondylitis.

PubMed

Ho, Huei-Huang; Lin, Meng-Chih; Yu, Kuang-Hui; Wang, Chin-Man; Wu, Yeong-Jian Jan; Chen, Ji-Yih

2009-02-01

We investigated the etiological association and clinical characteristics of apical pulmonary fibrosis in ankylosing spondylitis (AS). We reviewed medical records of 2136 consecutive patients diagnosed with AS at a tertiary medical center. Clinical and radiographic characteristics were analyzed for evidence of apical lung fibrosis on chest radiographs. Of 2136 patients with AS, 63 (2.9%) developed apical lung fibrosis, of which chronic infections were the cause in 41 and AS inflammation predisposed the fibrosis in 22 patients. Tuberculosis (TB) infection was considered to be the cause of apical lung fibrosis in 40 patients (63.5%) including 19 with bacteriologically-proven TB and 21 with chest radiographs suggestive of TB. Two were identified as having non-TB mycobacterial infection and one as Aspergillus infection. Lung cavity lesion appeared to be a crucial differentiator (p = 0.009, odds ratio 7.4, 95% CI 1.5-36.0) between TB infection and AS inflammation-induced apical fibrosis. Our study suggests that TB, instead of Aspergillus, is the most common pulmonary infection in patients with AS presenting with apical lung fibrosis. AS-associated apical lung fibrosis may mimic pulmonary TB infection. Thus, bacteriological survey and serial radiological followup of lung fibrocavitary lesions are critical for accurate diagnosis and treatment.

Nontuberculous mycobacterial infection with concurrent IgG4-related lymphadenopathy.

PubMed

Liu, Ting-Ting; Weng, Shao-Wen; Wang, Ming-Chung; Huang, Wan-Ting

2016-03-01

Disseminated nontuberculous mycobacteria (NTM) infection with concurrent IgG4-related lymphadenopathy has not been reported. We described a patient with neutralizing autoantibodies to interferon-gamma (IFN-γ) and elevated levels of serum IgG4 presenting with generalized lymphadenopathy and reactive dermatosis. Histologically, lymph nodes (LNs) showed effaced nodal architecture with polymorphic infiltrates, mimicking angioimmunoblastic T-cell lymphoma. Both the absolute number and the ratio of IgG4+ plasma cells to IgG+ plasma cells were increased. Mycobacterium abscessus was isolated from cultures of LNs, and demonstrated by polymerase chain reaction-restriction fragment length polymorphism. The skin biopsy showed neutrophilic dermatosis, consistent with Sweet syndrome. The patient met the criteria of both adult-onset immunodeficiency syndrome and IgG4-related lymphadenopathy. This case provides evidence of disseminated NTM infection with concurrent type III IgG4-related lymphadenopathy in the patient with anti-IFN-γ autoantibodies. © 2015 APMIS. Published by John Wiley & Sons Ltd.

Atypical mycobacterial infection presenting as persistent skin lesion in a patient with ulcerative colitis.

PubMed

Bamias, Giorgos; Daikos, George L; Siakavellas, Spyros I; Kaltsa, Garyfallia; Smilakou, Stavroula; Katsogridakis, Ioannis; Vafiadis-Zouboulis, Irene; Ladas, Spiros D

2011-01-01

Immunosuppressive drugs are commonly used for the treatment of inflammatory bowel disease. Patients receiving immunosuppressants are susceptible to a variety of infections with opportunistic pathogens. We present a case of skin infection with Mycobacterium chelonae in a 60-year-old Caucasian woman with ulcerative colitis who had been treated with corticosteroids and azathioprine. The disease manifested with fever and rash involving the right leg. Infliximab was administered due to a presumptive diagnosis of pyoderma gangrenosum, leading to worsening of the clinical syndrome and admission to our hospital. Routine cultures from various sites were all negative. However, Ziehl-Neelsen staining of pus from the lesions revealed acid-fast bacilli, and culture yielded a rapidly growing mycobacterium further identified as M. chelonae. The patient responded to a clarithromycin-based regimen. Clinicians should be aware of skin lesions caused by atypical mycobacteria in immunocompromised patients with inflammatory bowel disease. Furthermore, they should be able to thoroughly investigate and promptly treat these conditions.

Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists.

PubMed

Le, Jennifer; Ashley, Elizabeth Dodds; Neuhauser, Melinda M; Brown, Jack; Gentry, Chris; Klepser, Michael E; Marr, Ann Marie; Schiller, Daryl; Schwiesow, Joshua N; Tice, Sally; VandenBussche, Heather L; Wood, G Christopher

2010-06-01

Aerosolized delivery of antimicrobial agents is an attractive option for management of pulmonary infections, as this is an ideal method of providing high local drug concentrations while minimizing systemic exposure. With the paucity of consensus regarding the safety, efficacy, and means with which to use aerosolized antimicrobials, a task force was created by the Society of Infectious Diseases Pharmacists to critically review and evaluate the literature on the use of aerosolized antiinfective agents. This article summarizes key findings and statements for preventing or treating a variety of infectious diseases, including cystic fibrosis, bronchiecstasis, hospital-acquired pneumonia, fungal infections, nontuberculosis mycobacterial infection, and Pneumocystis jiroveci pneumonia. Our intention was to provide guidance for clinicians on the use of aerosolized antibiotics through evidence-based pharmacotherapy. Further research with well-designed clinical trials is necessary to elucidate the optimal dosage and duration of therapy and, of equal importance, to appreciate the true risks associated with the use of aerosolized delivery systems.

Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1

PubMed Central

Qualls, Joseph E.; Subramanian, Chitra; Rafi, Wasiulla; Smith, Amber M.; Balouzian, Liza; DeFreitas, Ashley A.; Shirey, Kari Ann; Reutterer, Benjamin; Kernbauer, Elisabeth; Stockinger, Silvia; Decker, Thomas; Miyairi, Isao; Vogel, Stefanie N.; Salgame, Padmini; Rock, Charles O.; Murray, Peter J.

2012-01-01

Nitric oxide (NO) defends against intracellular pathogens but its synthesis must be regulated due to cell and tissue toxicity. During infection, macrophages import extracellular arginine to synthesize NO, generating the byproduct citrulline. Accumulated intracellular citrulline is thought to fuel arginine synthesis catalyzed by argininosuccinate synthase (Ass1) and argininosuccinate lyase (Asl), which would lead to abundant NO production. Instead, we find that citrulline is exported from macrophages during early stages of NO production with < 2% retained for recycling via the Ass1-Asl pathway. Later, extracellular arginine is depleted, and Ass1 expression allows macrophages to synthesize arginine from imported citrulline to sustain NO output. Ass1-deficient macrophages fail to salvage citrulline in arginine-scarce conditions, leading to their inability to control mycobacteria infection. Thus, extracellular arginine fuels rapid NO production in activated macrophages, and citrulline recycling via Ass1 and Asl is a fail-safe system that sustains optimum NO production. PMID:22980328

Mycobacterium chimaera colonisation of heater-cooler units (HCU) in Western Australia, 2015: investigation of possible iatrogenic infection using whole genome sequencing.

PubMed

Robinson, James Owen; Coombs, Geoffrey Wallace; Speers, David John; Keehner, Terillee; Keil, Anthony David; D'Abrera, Victoria; Boan, Peter; Pang, Stanley

2016-11-17

Following the reported link between heater-cooler unit (HCU) colonisation with Mycobacterium chimaera and endocarditis, mycobacterial sampling of all HCUs in use in Western Australia was initiated from August 2015, revealing M. chimaera colonisation in 10 of 15 HCUs. After M. chimaera was isolated from a pleural biopsy from a cardiothoracic patient who may have been exposed to a colonised HCU, a whole genome sequencing investigation was performed involving 65 specimens from 15 HCUs across five hospitals to assess if this infection was related to the HCU. Genetic relatedness was found between the 10 HCU M. chimaera isolates from four hospitals. However the M. chimaera isolate from the cardiothoracic patient was not genetically related to the HCU M. chimaera isolates from that hospital, nor to the other HCU isolates, indicating that the HCUs were not the source of the infection in this patient. This article is copyright of The Authors, 2016.

Disseminated Aspergillus fumigatus infection with consecutive mitral valve endocarditis in a lung transplant recipient.

PubMed

Scherer, Mirela; Fieguth, Hans-Gerd; Aybek, Tayfun; Ujvari, Zsolt; Moritz, Anton; Wimmer-Greinecker, Gerhard

2005-12-01

Aspergillus infection is a known complication of lung transplantation and remains associated with high mortality rates. The manifestation of the infection varies from simple colonization of the lung to disseminated complicated infections. Early Aspergillus infection has been rarely observed in a small number of lung transplant recipients; most cases occur during the late post-operative period. The pulmonary involvement has often been described as the first clinical localization of the disease. Although other various forms of Aspergillus infection are not uncommonly encountered after lung transplantation, Aspergillus mitral valve endocarditis is rare. We present a case of disseminated Aspergillus fumigatus infection with consecutive mitral valve endocarditis having developed 78 days after double-lung transplantation for cystic fibrosis.

Vaccines for Leprosy and Tuberculosis: Opportunities for Shared Research, Development, and Application

PubMed Central

Coppola, Mariateresa; van den Eeden, Susan J. F.; Robbins, Naoko; Wilson, Louis; Franken, Kees L. M. C.; Adams, Linda B.; Gillis, Tom P.; Ottenhoff, Tom H. M.; Geluk, Annemieke

2018-01-01

Tuberculosis (TB) and leprosy still represent significant public health challenges, especially in low- and lower middle-income countries. Both poverty-related mycobacterial diseases require better tools to improve disease control. For leprosy, there has been an increased emphasis on developing tools for improved detection of infection and early diagnosis of disease. For TB, there has been a similar emphasis on such diagnostic tests, while increased research efforts have also focused on the development of new vaccines. Bacille Calmette–Guérin (BCG), the only available TB vaccine, provides insufficient and inconsistent protection to pulmonary TB in adults. The impact of BCG on leprosy, however, is significant, and the introduction of new TB vaccines that might replace BCG could, therefore, have serious impact also on leprosy. Given the similarities in antigenic makeup between the pathogens Mycobacterium tuberculosis (Mtb) and M. leprae, it is well possible, however, that new TB vaccines could cross-protect against leprosy. New TB subunit vaccines currently evaluated in human phase I and II studies indeed often contain antigens with homologs in M. leprae. In this review, we discuss pre-clinical studies and clinical trials of subunit or whole mycobacterial vaccines for TB and leprosy and reflect on the development of vaccines that could provide protection against both diseases. Furthermore, we provide the first preclinical evidence of such cross-protection by Mtb antigen 85B (Ag85B)-early secretory antigenic target (ESAT6) fusion recombinant proteins in in vivo mouse models of Mtb and M. leprae infection. We propose that preclinical integration and harmonization of TB and leprosy research should be considered and included in global strategies with respect to cross-protective vaccine research and development. PMID:29535713

Effect of Apoptotic Cell Recognition on Macrophage Polarization and Mycobacterial Persistence

PubMed Central

de Oliveira Fulco, Tatiana; Andrade, Priscila Ribeiro; de Mattos Barbosa, Mayara Garcia; Pinto, Thiago Gomes Toledo; Ferreira, Paula Fernandez; Ferreira, Helen; da Costa Nery, José Augusto; Real, Suzana Côrte; Borges, Valéria Matos; Moraes, Milton Ozório; Sarno, Euzenir Nunes; Sampaio, Elizabeth Pereira

2014-01-01

Intracellular Mycobacterium leprae infection modifies host macrophage programming, creating a protective niche for bacterial survival. The milieu regulating cellular apoptosis in the tissue plays an important role in defining susceptible and/or resistant phenotypes. A higher density of apoptotic cells has been demonstrated in paucibacillary leprosy lesions than in multibacillary ones. However, the effect of apoptotic cell removal on M. leprae-stimulated cells has yet to be fully elucidated. In this study, we investigated whether apoptotic cell removal (efferocytosis) induces different phenotypes in proinflammatory (Mϕ1) and anti-inflammatory (Mϕ2) macrophages in the presence of M. leprae. We stimulated Mϕ1 and Mϕ2 cells with M. leprae in the presence or absence of apoptotic cells and subsequently evaluated the M. leprae uptake, cell phenotype, and cytokine pattern in the supernatants. In the presence of M. leprae and apoptotic cells, Mϕ1 macrophages changed their phenotype to resemble the Mϕ2 phenotype, displaying increased CD163 and SRA-I expression as well as higher phagocytic capacity. Efferocytosis increased M. leprae survival in Mϕ1 cells, accompanied by reduced interleukin-15 (IL-15) and IL-6 levels and increased transforming growth factor beta (TGF-β) and IL-10 secretion. Mϕ1 cells primed with M. leprae in the presence of apoptotic cells induced the secretion of Th2 cytokines IL-4 and IL-13 in autologous T cells compared with cultures stimulated with M. leprae or apoptotic cells alone. Efferocytosis did not alter the Mϕ2 cell phenotype or cytokine secretion profile, except for TGF-β. Based on these data, we suggest that, in paucibacillary leprosy patients, efferocytosis contributes to mycobacterial persistence by increasing the Mϕ2 population and sustaining the infection. PMID:25024361

An intradural-extramedullary gas-forming spinal abscess in a patient with diabetes mellitus.

PubMed

Nadkarni, Trimurti; Shah, Abhidha; Kansal, Ritesh; Goel, Atul

2010-02-01

Spinal infections are commonly reported to be located in the extradural or intramedullary spaces. Infection involving the intradural-extramedullary space are uncommon. We report a patient with uncontrolled diabetes mellitus and an infected foot ulcer who presented with a cervical cord abscess and intradural gas. Early diagnosis and aggressive treatment are necessary for a favourable outcome in gas-forming intradural spinal abscesses. To our knowledge, a gas-forming intradural spinal abscess has not been reported previously and we discuss the relevant literature. Copyright 2009 Elsevier Ltd. All rights reserved.

Disseminated Salmonella arizona infection associated with rattlesnake meat ingestion.

PubMed

Bhatt, B D; Zuckerman, M J; Foland, J A; Polly, S M; Marwah, R K

1989-04-01

Salmonella arizona is an uncommon enteric pathogen. We report a case of a woman with systemic lupus erythematosus, receiving prednisone therapy, who developed fatal disseminated S. arizona infection after ingesting raw dried rattlesnake meat as a form of treatment for her illness. S. arizona was isolated from stool, blood, peritoneal fluid, and cerebrospinal fluid. The importance of being aware of the Mexican-American folk remedy involving the ingestion of rattlesnake meat in the forms of dried snake, snake powder, or snake powder capsules, and the risk of acquiring S. arizona enteric infections is discussed.

Treatment of Non-Tuberculous Mycobacterial Lung Disease.

PubMed

Philley, Julie V; DeGroote, Mary Ann; Honda, Jennifer R; Chan, Michael M; Kasperbauer, Shannon; Walter, Nicholas D; Chan, Edward D

2016-12-01

Treatment of non-tuberculous mycobacterial lung disease (NTM-LD) is challenging for several reasons including the relative resistance of NTM to currently available drugs and the difficulty in tolerating prolonged treatment with multiple drugs. Yet-to-be-done, large, multicenter, prospective randomized studies to establish the best regimens will also be arduous because multiple NTM species are known to cause human lung disease, differences in virulence and response to treatment between different species and strains within a species will make randomization more difficult, the need to distinguish relapse from a new infection, and the difficulty in adhering to the prescribed treatment due to intolerance, toxicity, and/or drug-drug interactions, often necessitating modification of therapeutic regimens. Furthermore, the out-of-state resident status of many patients seen at the relatively few centers that care for large number of NTM-LD patients pose logistical issues in monitoring response to treatment. Thus, current treatment regimens for NTM-LD is largely based on small case series, retrospective analyses, and guidelines based on expert opinions. It has been nearly 10 years since the publication of a consensus guideline for the treatment of NTM-LD. This review is a summary of the available evidence on the treatment of the major NTM-LD until more definitive studies and guidelines become available.

Heat killed Saccharomyces cerevisiae as an adjuvant for the induction of vaccine-mediated immunity against infection with Mycobacterium tuberculosis.

PubMed

Grover, Ajay; McLean, Jennifer L; Troudt, JoLynn M; Foster, Chad; Izzo, Linda; Creissen, Elisabeth; MacDonald, Elisabeth; Troy, Amber; Izzo, Angelo A

2016-05-27

The use of novel vaccine delivery systems allows for the manipulation of the adaptive immune systems through the use of molecular adjuvants that target specific innate pathways. Such strategies have been used extensively for vaccines against cancer and multiple pathogens such as Mycobacterium tuberculosis. In the current study we used heat killed non-pathogenic recombinant Saccharomyces cerevisiae expressing M. tuberculosis antigen Rv1886c (fbpB, mpt59, Ag85B) as a delivery system in conjunction with its ability to stimulate innate immunity to determine its ability to induce immunity. We established that the recombinant yeast induced activated antigen specific T cells are capable of reducing the mycobacterial burden. Inoculation of the recombinant yeast after vaccination with BCG resulted in a systemic alteration of the phenotype of the immune response although this was not reflected in an increase in the reduction of the mycobacterial burden. Taken together the data suggest that heat killed yeast can induce multiple cytokines required for induction of protective immunity and can function as a vehicle for delivery of M. tuberculosis antigens in a vaccine formulation. In addition, while it can enhance the effector memory response induced by BCG, it had little effect on central memory responses. Copyright © 2016 Elsevier Ltd. All rights reserved.

Systems-level modeling of mycobacterial metabolism for the identification of new (multi-)drug targets.

PubMed

Rienksma, Rienk A; Suarez-Diez, Maria; Spina, Lucie; Schaap, Peter J; Martins dos Santos, Vitor A P

2014-12-01

Systems-level metabolic network reconstructions and the derived constraint-based (CB) mathematical models are efficient tools to explore bacterial metabolism. Approximately one-fourth of the Mycobacterium tuberculosis (Mtb) genome contains genes that encode proteins directly involved in its metabolism. These represent potential drug targets that can be systematically probed with CB models through the prediction of genes essential (or the combination thereof) for the pathogen to grow. However, gene essentiality depends on the growth conditions and, so far, no in vitro model precisely mimics the host at the different stages of mycobacterial infection, limiting model predictions. These limitations can be circumvented by combining expression data from in vivo samples with a validated CB model, creating an accurate description of pathogen metabolism in the host. To this end, we present here a thoroughly curated and extended genome-scale CB metabolic model of Mtb quantitatively validated using 13C measurements. We describe some of the efforts made in integrating CB models and high-throughput data to generate condition specific models, and we will discuss challenges ahead. This knowledge and the framework herein presented will enable to identify potential new drug targets, and will foster the development of optimal therapeutic strategies. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Do I Need a Tetanus Shot?

MedlinePlus

... nail or a puncture wound could cause a tetanus infection, a bacterial disease that affects the nervous system and is often ... that break the skin. "Your best defense against tetanus is vaccination," said ... has made this disease uncommon in the United States, too many people, ...

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

Anti-mycobacterial peptides: made to order with delivery included.

PubMed

Carroll, James; O' Mahony, Jim

2011-01-01

"TB is too often a death sentence. It does not have to be this way,"- Nelson Mandela. Despite the success of anti-mycobacterial drugs over the past 70 years, mycobacterial disease, particularly tuberculosis is still responsible for millions of annual deaths worldwide. Additionally, the emergence of Multidrug Resistant (MDR-TB) and Extensively Drug Resistant (XDR-TB) Tuberculosis has motivated calls by the World Health Organization (WHO) for novel drugs, vaccines and diagnostic tests. Consequently, the identification and evaluation of a range of anti-mycobacterial compounds against pathogenic mycobacterial species is of paramount importance. My colleagues and I at Cork Institute of Technology (CIT) and University College Cork (UCC) have tackled this issue through the initial optimization of the rapid, robust and inexpensive microtitre alamarBlue assay (MABA) and subsequent employment of this assay to facilitate the rapid assessment of a new wave of potential therapeutic compounds, namely bacteriocins, in particular type 1 bacteriocins known as lantibiotics. The gene encoded nature of these peptides facilitates their genetic manipulation and consequent activities as anti-microbial agents. In this regard, it may be possible to one day develop diverse populations of anti-mycobacterial bacteriocins with species specific activities. This may in turn provide more targeted therapies, resulting in less side effects, shorter treatment times and thus better patient compliance. Although current drug regimes are effective in the interim, previous lessons have taught us not to be complacent. In the words of the Intel founder Andrew Grove, 'Success breeds complacency. Complacency breeds failure. Only the paranoid survive'. Armed with knowledge of previous failures, it is the duty of the scientific community to anticipate future bacterial resistance and have an arsenal of compounds standing by in such an eventuality.

Molecular Analysis of Sarcoidosis Granulomas Reveals Antimicrobial Targets

PubMed Central

Celada, Lindsay J.; Polosukhin, Vasiliy V.; Atkinson, James B.; Drake, Wonder P.

2016-01-01

Sarcoidosis is a granulomatous disease of unknown cause. Prior molecular and immunologic studies have confirmed the presence of mycobacterial virulence factors, such as catalase peroxidase and superoxide dismutase A, within sarcoidosis granulomas. Molecular analysis of granulomas can identify targets of known antibiotics classes. Currently, major antibiotics are directed against DNA synthesis, protein synthesis, and cell wall formation. We conducted molecular analysis of 40 sarcoidosis diagnostic specimens and compared them with 33 disease control specimens for the presence of mycobacterial genes that encode antibiotic targets. We assessed for genes involved in DNA synthesis (DNA gyrase A [gyrA] and DNA gyrase B), protein synthesis (RNA polymerase subunit β), cell wall synthesis (embCAB operon and enoyl reductase), and catalase peroxidase. Immunohistochemical analysis was conducted to investigate the locale of mycobacterial genes such as gyrA within 12 sarcoidosis specimens and 12 disease controls. Mycobacterial DNA was detected in 33 of 39 sarcoidosis specimens by quantitative real-time polymerase chain reaction compared with 2 of 30 disease control specimens (P < 0.001, two-tailed Fisher’s test). Twenty of 39 were positive for three or more mycobacterial genes, compared with 1 of 30 control specimens (P < 0.001, two-tailed Fisher’s test). Immunohistochemistry analysis localized mycobacterial gyrA nucleic acids to sites of granuloma formation in 9 of 12 sarcoidosis specimens compared with 1 of 12 disease controls (P < 0.01). Microbial genes encoding enzymes that can be targeted by currently available antimycobacterial antibiotics are present in sarcoidosis specimens and localize to sites of granulomatous inflammation. Use of antimicrobials directed against target enzymes may be an innovative treatment alternative. PMID:26807608

Enterobius vermicularis presentation during laparoscopic cholecystectomy.

PubMed

Dick, Lachlan; Hannay, Jonathan

2017-01-17

Enterobius vermicularis infection is uncommon in adults, compared to children, and rarely causes significant illness. Adult infection is usually colonic in nature and found incidentally at colonoscopy. Worm migration to other tissues is rare. We here-in describe the case of a 73-year-old woman found to have biliary tree E. vermicularis-an as yet undescribed site of migration. Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author 2017.

Salvage liver transplantation for hepatic gas gangrene.

PubMed

Birnbaum, David Jérémie; Grégoire, Emilie; Hardwigsen, Jean; Le Treut, Yves Patrice

2012-09-01

Hepatic gas gangrene is an uncommon situation mainly due to bacterial infection by Clostridium perfringens. It remains a life-threatening condition associated with a high mortality rate. Quick diagnosis and aggressive therapy including liver transplantation should be proposed to improve the outcome. This report describes a rare case of hepatic gas gangrene on native liver, secondary to iatrogenic hepatic artery thrombosis and instrumental biliary tree infection, which was successfully treated by liver transplantation.

Uncommon Pathways of Immune Escape Attenuate HIV-1 Integrase Replication Capacity

PubMed Central

Chopera, Denis R.; Olvera, Alex; Brumme, Chanson J.; Sela, Jennifer; Markle, Tristan J.; Martin, Eric; Carlson, Jonathan M.; Le, Anh Q.; McGovern, Rachel; Cheung, Peter K.; Kelleher, Anthony D.; Jessen, Heiko; Markowitz, Martin; Rosenberg, Eric; Frahm, Nicole; Sanchez, Jorge; Mallal, Simon; John, Mina; Harrigan, P. Richard; Heckerman, David; Brander, Christian; Walker, Bruce D.; Brumme, Zabrina L.

2012-01-01

An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naïve individuals with early (n = 88) and chronic (n = 304) infections and measured the in vitro RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection (R = −0.2; P = 0.003); however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and -B*52, respectively, correlated with lower RC (all q < 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF114–121) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a ∼35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA-driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies. PMID:22496233

Uncommon pathways of immune escape attenuate HIV-1 integrase replication capacity.

PubMed

Brockman, Mark A; Chopera, Denis R; Olvera, Alex; Brumme, Chanson J; Sela, Jennifer; Markle, Tristan J; Martin, Eric; Carlson, Jonathan M; Le, Anh Q; McGovern, Rachel; Cheung, Peter K; Kelleher, Anthony D; Jessen, Heiko; Markowitz, Martin; Rosenberg, Eric; Frahm, Nicole; Sanchez, Jorge; Mallal, Simon; John, Mina; Harrigan, P Richard; Heckerman, David; Brander, Christian; Walker, Bruce D; Brumme, Zabrina L

2012-06-01

An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naïve individuals with early (n = 88) and chronic (n = 304) infections and measured the in vitro RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection (R = -0.2; P = 0.003); however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and -B*52, respectively, correlated with lower RC (all q < 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF(114-121)) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a ~35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA-driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies.

Smallpox and live-virus vaccination in transplant recipients.

PubMed

Fishman, Jay A

2003-07-01

Recent bioterrorism raises the specter of reemergence of smallpox as a clinical entity. The mortality of variola major infection ('typical smallpox') was approximately 30% in past outbreaks. Programs for smallpox immunization for healthcare workers have been proposed. Atypical forms of smallpox presenting with flat or hemorrhagic skin lesions are most common in individuals with immune deficits with historic mortality approaching 100%. Smallpox vaccination, even after exposure, is highly effective. Smallpox vaccine contains a highly immunogenic live virus, vaccinia. Few data exist for the impact of variola or safety of vaccinia in immunocompromised hosts. Both disseminated infection by vaccinia and person-to-person spread after vaccination are uncommon. When it occurs, secondary vaccinia has usually affected individuals with pre-existing skin conditions (atopic dermatitis or eczema) or with other underlying immune deficits. Historically, disseminated vaccinia infection was uncommon but often fatal even in the absence of the most severe form of disease, "progressive vaccinia". Some responded to vaccinia immune globulin. Smallpox exposure would be likely to cause significant mortality among immunocompromised hosts. In the absence of documented smallpox exposures, immunocompromised hosts should not be vaccinated against smallpox. Planning for bioterrorist events must include consideration of uniquely susceptible hosts.

Synthesis, structure-activity relationship of novel substituted 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylates as potential anti-mycobacterial and anticancer agents.

PubMed

Raju, B China; Rao, R Nageswara; Suman, P; Yogeeswari, P; Sriram, D; Shaik, Thokhir Basha; Kalivendi, Shasi Vardhan

2011-05-15

Series of 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives 7a-7zb, 8a-8d and 9a-9d were synthesized and screened for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H(37)Rv (MTB) and cytotoxicity against three human cancer cell lines including A549, SK-N-SH and HeLa. The results indicate that six compounds are more potent and 7za is most effective anti-mycobacterial derivative compared to the standard drugs Ethambutol and Ciprofloxacin. However, 12 compounds exhibited cytotoxicity against human neuroblastoma cell line; amongst them the compound 7v is most effective compared to the standard drug Doxorubicin. This is the first report assigning in vitro anti-mycobacterial, anticancer and structure-activity relationship for this new class of 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylates. Copyright © 2011 Elsevier Ltd. All rights reserved.

Respiratory infections associated with anti-TNFα agents.

PubMed

Blanchard, E; Truchetet, M-E; Machelart, I; Séneschal, J; Raherison-Semjen, C

2017-10-01

Anti-TNFα agents have proved effective in the treatment of various inflammatory, rheumatologic, dermatologic, and gastrointestinal diseases. Severe respiratory tract infections of bacterial or fungal origin have emerged as important complications in patients receiving such treatments. The risk of infection due to anti-TNFα therapy is difficult to assess in these patients who are immunocompromised because of the underlying disease itself and of previous or concomitant immunosuppressive drugs. This excessive infection risk seems real, particularly in the first six months following treatment initiation, and higher for patients receiving anti-TNFα monoclonal antibodies than for those receiving soluble TNFα receptor. The involved pathogens are pyogenic bacteria but also Mycobacterium tuberculosis, mostly by reactivation of latent tuberculosis infection, warranting a systematic preventive approach to screening and chemoprophylaxis before initiating the anti-TNFα therapy. In countries with low tuberculosis endemicity, an increased prevalence of nontuberculous mycobacterial infections has been reported. The incidence rate of legionellosis is high in this population. In case of pneumonia, empirical antibiotic therapy should cover Legionella pneumophila. Several cases of histoplasmosis have also been reported and this diagnosis should be suspected in patients who have traveled to endemic areas. Other opportunistic infections have been reported including Pneumocystis pneumonia, aspergillosis, and nocardiosis mostly in patients receiving other immunosuppressive treatments. The risk of infection should be evaluated as an individual risk depending on comorbidities and past or concomitant treatments. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

LL-37 immunomodulatory activity during Mycobacterium tuberculosis infection in macrophages.

PubMed

Torres-Juarez, Flor; Cardenas-Vargas, Albertina; Montoya-Rosales, Alejandra; González-Curiel, Irma; Garcia-Hernandez, Mariana H; Enciso-Moreno, Jose A; Hancock, Robert E W; Rivas-Santiago, Bruno

2015-12-01

Tuberculosis is one of the most important infectious diseases worldwide. The susceptibility to this disease depends to a great extent on the innate immune response against mycobacteria. Host defense peptides (HDP) are one of the first barriers to counteract infection. Cathelicidin (LL-37) is an HDP that has many immunomodulatory effects besides its weak antimicrobial activity. Despite advances in the study of the innate immune response in tuberculosis, the immunological role of LL-37 during M. tuberculosis infection has not been clarified. Monocyte-derived macrophages were infected with M. tuberculosis strain H37Rv and then treated with 1, 5, or 15 μg/ml of exogenous LL-37 for 4, 8, and 24 h. Exogenous LL-37 decreased tumor necrosis factor alpha (TNF-α) and interleukin-17 (IL-17) while inducing anti-inflammatory IL-10 and transforming growth factor β (TGF-β) production. Interestingly, the decreased production of anti-inflammatory cytokines did not reduce antimycobacterial activity. These results are consistent with the concept that LL-37 can modulate the expression of cytokines during mycobacterial infection and this activity was independent of the P2X7 receptor. Thus, LL-37 modulates the response of macrophages during infection, controlling the expression of proinflammatory and anti-inflammatory cytokines. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

[Non-tuberculous mycobacterial infections related to esthetic care in France, 2001-2010].

PubMed

Couderc, C; Carbonne, A; Thiolet, J M; Brossier, F; Savey, A; Bernet, C; Ortmans, C; Lecadet-Morin, C; Coudière, I; Aggoune, M; Astagneau, P; Coignard, B; Cambau, E

2011-07-01

Non-tuberculous mycobacteria (NTM) infections usually occur in immunocompromised patients but also in immunocompetent patients following invasive procedures, especially for esthetic purposes. Since 2001, 20 episodes (57 cases) of NTM infections, seven of which (43 cases) were related to esthetic care, have been reported to the regional infection control coordinating centers (RICCC), the local health authorities (LHA), and the national institute for public health surveillance. Four notifications (40 cases) were related to non-surgical procedures performed by general practitioners in private settings: mesotherapy, carboxytherapy, and sclerosis of microvaricosities. The three other notifications (three cases) concerned surgical procedures-lifting and mammary prosthesis. Practice evaluations performed by the RICCC and LHA for five notifications showed deficiency of standard hygiene precautions and tap water misuse for injection equipment cleaning, or skin disinfection. Microbiological investigations (national reference center for mycobacteria) demonstrated the similarity of patient and environmental strains: in one episode (16 cases after mesotherapy), M. chelonae isolated from tap water was similar to those isolated from 11 cases. Healthcare-associated NTM infections are rare but have a potentially severe outcome. These cases stress the need of healthcare-associated infection notifications in outpatient settings. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

The Mycobacterium tuberculosis cell-surface glycoprotein apa as a potential adhesin to colonize target cells via the innate immune system pulmonary C-type lectin surfactant protein A.

PubMed

Ragas, Aude; Roussel, Lucie; Puzo, Germain; Rivière, Michel

2007-02-23

Tuberculosis is still a major health problem, and understanding the mechanism by which Mycobacterium tuberculosis (Mtb) invades and colonizes its host target cells remains an important issue for the control of infection. The innate immune system C-type lectins (C-TLs), including the human pulmonary surfactant protein A (PSP-A), have been recently identified as determinant players in the early recognition of the invading pathogen and in mounting the host defense response. Although the antigenic lipoglycan mannosylated lipoarabinomannan is currently considered to be the major C-TL target on the mycobacterial surface, the recognition by some C-TLs of the only mycobacterial species composing the "Mtb complex" indicates that mannosylated lipoarabinomannan cannot account alone for this specificity. Thus, we searched for the mycobacterial molecules targeted by human PSP-A, focusing our attention on the Mtb surface glycoproteins. We developed an original functional proteomic approach based on a lectin blot assay using crude human bronchoalveolar lavage fluid as a source of physiological PSP-A. Combined with selective cell-surface protein extraction and mass spectrometry peptide mapping, this strategy allowed us to identify the Apa (alanine- and proline-rich antigenic) glycoprotein as new potential target for PSP-A. This result was supported by direct binding of PSP-A to purified Apa. Moreover, EDTA addition or deglycosylation of purified Apa samples completely abolished the interaction, demonstrating that the interaction is calcium- and mannose-dependent, as expected. Finally, we provide convincing evidence that Apa, formerly considered as mainly secreted, is associated with the cell wall for a sufficiently long time to aid in the attachment of PSP-A. Because, to date, Apa seems to be restricted to the Mtb complex strains, we propose that it may account for the selective recognition of those strains by PSP-A and other immune system C-TLs containing homologous functional domains.

Innate immune response to Mycobacterium tuberculosis Beijing and other genotypes.

PubMed

Wang, Chongzhen; Peyron, Pascale; Mestre, Olga; Kaplan, Gilla; van Soolingen, Dick; Gao, Qian; Gicquel, Brigitte; Neyrolles, Olivier

2010-10-25

As a species, Mycobacterium tuberculosis is more diverse than previously thought. In particular, the Beijing family of M. tuberculosis strains is spreading and evaluating throughout the world and this is giving rise to public health concerns. Genetic diversity within this family has recently been delineated further and a specific genotype, called Bmyc10, has been shown to represent over 60% of all Beijing clinical isolates in several parts of the world. How the host immune system senses and responds to various M. tuberculosis strains may profoundly influence clinical outcome and the relative epidemiological success of the different mycobacterial lineages. We hypothesised that the success of the Bmyc10 group may, at least in part, rely upon its ability to alter innate immune responses and the secretion of cytokines and chemokines by host phagocytes. We infected human macrophages and dendritic cells with a collection of genetically well-defined M. tuberculosis clinical isolates belonging to various mycobacterial families, including Beijing. We analyzed cytokine and chemokine secretion on a semi-global level using antibody arrays allowing the detection of sixty-five immunity-related soluble molecules. Our data indicate that Beijing strains induce significantly less interleukin (IL)-6, tumor necrosis factor (TNF), IL-10 and GRO-α than the H37Rv reference strain, a feature that is variously shared by other modern and ancient M. tuberculosis families and which constitutes a signature of the Beijing family as a whole. However, Beijing strains did not differ relative to each other in their ability to modulate cytokine secretion. Our results confirm and expand upon previous reports showing that M. tuberculosis Beijing strains in general are poor in vitro cytokine inducers in human phagocytes. The results suggest that the epidemiological success of the Beijing Bmyc10 is unlikely to rely upon any specific ability of this group of strains to impair anti-mycobacterial innate immunity.

Antimicrobial Resistance in Hospital-Acquired Gram-Negative Bacterial Infections

PubMed Central

Mehrad, Borna; Clark, Nina M.; Zhanel, George G.

2015-01-01

Aerobic gram-negative bacilli, including the family of Enterobacteriaceae and non-lactose fermenting bacteria such as Pseudomonas and Acinetobacter species, are major causes of hospital-acquired infections. The rate of antibiotic resistance among these pathogens has accelerated dramatically in recent years and has reached pandemic scale. It is no longer uncommon to encounter gram-negative infections that are untreatable using conventional antibiotics in hospitalized patients. In this review, we provide a summary of the major classes of gram-negative bacilli and their key mechanisms of antimicrobial resistance, discuss approaches to the treatment of these difficult infections, and outline methods to slow the further spread of resistance mechanisms. PMID:25940252

Neonatal herpes simplex virus infections.

PubMed

Pinninti, Swetha G; Kimberlin, David W

2018-04-01

Neonatal herpes simplex virus (HSV) is an uncommon but devastating infection in the newborn, associated with significant morbidity and mortality. The use of PCR for identification of infected infants and acyclovir for treatment has significantly improved the prognosis for affected infants. The subsequent use of suppressive therapy with oral acyclovir following completion of parenteral treatment of acute disease has further enhanced the long-term prognosis for these infants. This review article will discuss the epidemiology, risk factors and routes of acquisition, clinical presentation, and evaluation of an infant suspected to have the infection, and treatment of proven neonatal HSV disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Emerging infectious diseases with cutaneous manifestations: Viral and bacterial infections.

PubMed

Nawas, Zeena Y; Tong, Yun; Kollipara, Ramya; Peranteau, Andrew J; Woc-Colburn, Laila; Yan, Albert C; Lupi, Omar; Tyring, Stephen K

2016-07-01

Given increased international travel, immigration, and climate change, bacterial and viral infections that were once unrecognized or uncommon are being seen more frequently in the Western Hemisphere. A delay in diagnosis and treatment of these diseases can lead to significant patient morbidity and mortality. However, the diagnosis and management of these infections is fraught with a lack of consistency because there is a dearth of dermatology literature on the cutaneous manifestations of these infections. We review the epidemiology, cutaneous manifestations, diagnosis, and management of these emerging bacterial and viral diseases. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Nominal dysphasia and euphoria caused by EBV encephalitis

PubMed Central

Carman, Kursat Bora; Yakut, Ayten; Ekici, Arzu; Isikay, Sedat

2013-01-01

Encephalitis is an uncommon neurological complication of Ebstein-Barr virus (EBV) infection and usually presents with confusion, decreased level of consciousness, fever, epileptic seizure, emotional instability and chorea. We present a patient with EBV encephalitis, characterised by nominal dysphasia, euphoria and personality changes. PMID:23307455

A Case of Pulmonary Mycobacterium kansasii Disease Complicated with Tension Pneumothorax.

PubMed

Boo, Ki Yung; Lee, Jong Hoo

2015-10-01

Pneumothorax is an extremely rare complication of non-tuberculous mycobacterial infection. A 52-year-old man presenting with difficulty breathing and chest pain was admitted to our hospital. A right-sided pneumothorax was observed on chest radiography and chest computed tomography showed multiple cavitating and non-cavitating nodules with consolidation in the upper to middle lung zones bilaterally. Serial sputum cultures were positive for Mycobacterium kansasii, and he was diagnosed with pulmonary M. kansasii disease complicated by tension pneumothorax. After initiation of treatment including decortications and pleurodesis, the patient made a full recovery. We herein describe this patient's course in detail and review the current relevant literature.

Gender differences in pulmonary disease.

PubMed

Caracta, Cynthia F

2003-09-01

Epidemiologic evidence points to gender-based differences in incidence, risk, histology, and pathogenesis of certain lung diseases in women as compared with men. Gender influences not only physiological differences, but also the social, economic, and cultural context in which men and women coexist. Central to these differences is the role of sex hormones, which may contribute to the pathogenesis of disease or serve as protective factors. This paper seeks to review the role of gender in major areas of pulmonary disease and explore the mechanisms that may underlie gender differences in asthma, chronic obstructive pulmonary disease and mycobacterial disease (tuberculosis and Mycobacterium avium intracellulare infection), on lung cancer.

Simultaneous influenza and respiratory syncytial virus infection in human respiratory tract

NASA Astrophysics Data System (ADS)

Pinky, Lubna Jahan Rashid; Dobrovolny, Hana

2015-03-01

Studies have shown that simultaneous infection of the respiratory tract with at least two viruses is not uncommon in hospitalized patients, although it is not clear whether these infections are more or less severe than single infections. We use mathematical models to study the dynamics of simultaneous influenza (flu) and respiratory syncytial virus (RSV) infection, two of the more common respiratory viruses, in an effort to understand simultaneous infections. We examine the roles of initial viral inoculum, relative starting time, and cell regeneration on the severity of the infection. We also study the effect of antiviral treatment on the course of the infection. This study shows that, unless treated with antivirals, flu always takes over the infection no matter how small the initial dose and how delayed it starts with respect to RSV.

Direct healthcare costs of selected diseases primarily or partially transmitted by water.

PubMed

Collier, S A; Stockman, L J; Hicks, L A; Garrison, L E; Zhou, F J; Beach, M J

2012-11-01

Despite US sanitation advancements, millions of waterborne disease cases occur annually, although the precise burden of disease is not well quantified. Estimating the direct healthcare cost of specific infections would be useful in prioritizing waterborne disease prevention activities. Hospitalization and outpatient visit costs per case and total US hospitalization costs for ten waterborne diseases were calculated using large healthcare claims and hospital discharge databases. The five primarily waterborne diseases in this analysis (giardiasis, cryptosporidiosis, Legionnaires' disease, otitis externa, and non-tuberculous mycobacterial infection) were responsible for over 40 000 hospitalizations at a cost of $970 million per year, including at least $430 million in hospitalization costs for Medicaid and Medicare patients. An additional 50 000 hospitalizations for campylobacteriosis, salmonellosis, shigellosis, haemolytic uraemic syndrome, and toxoplasmosis cost $860 million annually ($390 million in payments for Medicaid and Medicare patients), a portion of which can be assumed to be due to waterborne transmission.

Atypical mycobacteria infection in an immunocompromised patient.

PubMed

Berger, Emily; Batra, Priya; Ralston, Jonathan; Sanchez, Miguel R; Franks, Andrew G

2010-11-15

A 61-year-old woman with systemic lupus erythematosus and Sjögren syndrome presented with a two-month history of symptomatic nodules on the buttocks and thighs that progressed to involve the dorsal aspects of the hands. On examination, infiltrative papules, nodules, and plaques were present in these regions. Biopsy specimens demonstrated granulomatous inflammation and acid-fast bacilli with the use of a Fite stain, although a culture and polymerase chain reaction analysis were negative. The patient continues to improve on long-term clarithromycin therapy. Atypical mycobacterial infections are becoming more common, especially in immunocompromised patients. Antimicrobial therapy, either with a single agent or multiple agents, often is prolonged. A high index of suspicion is warranted in immunocompromised patients, which includes those with connective-tissue diseases that are active or that require immunosuppression. In these patients, the differential diagnosis includes infectious as well as inflammatory, reactive, or neoplastic processes.

Antibodies Induced by Lipoarabinomannan in Bovines: Characterization and Effects on the Interaction between Mycobacterium Avium Subsp. Paratuberculosis and Macrophages In Vitro

PubMed Central

Jolly, Ana; Colavecchia, Silvia Beatriz; Fernández, Bárbara; Fernández, Eloy; Mundo, Silvia Leonor

2011-01-01

Lipoarabinomannan (LAM) is a major glycolipidic antigen on the mycobacterial envelope. The aim of this study was to characterize the humoral immune response induced by immunization with a LAM extract in bovines and to evaluate the role of the generated antibodies in the in vitro infection of macrophages with Mycobacterium avium subsp. paratuberculosis (MAP). Sera from fourteen calves immunized with LAM extract or PBS emulsified in Freund's Incomplete Adjuvant and from five paratuberculosis-infected bovines were studied. LAM-immunized calves developed specific antibodies with IgG1 as the predominant isotype. Serum immunoglobulins were isolated and their effect was examined in MAP ingestion and viability assays using a bovine macrophage cell line. Our results show that the antibodies generated by LAM immunization significantly increase MAP ingestion and reduce its intracellular viability, suggesting an active role in this model. PMID:21772964

Antibodies Induced by Lipoarabinomannan in Bovines: Characterization and Effects on the Interaction between Mycobacterium Avium Subsp. Paratuberculosis and Macrophages In Vitro.

PubMed

Jolly, Ana; Colavecchia, Silvia Beatriz; Fernández, Bárbara; Fernández, Eloy; Mundo, Silvia Leonor

2011-01-01

Lipoarabinomannan (LAM) is a major glycolipidic antigen on the mycobacterial envelope. The aim of this study was to characterize the humoral immune response induced by immunization with a LAM extract in bovines and to evaluate the role of the generated antibodies in the in vitro infection of macrophages with Mycobacterium avium subsp. paratuberculosis (MAP). Sera from fourteen calves immunized with LAM extract or PBS emulsified in Freund's Incomplete Adjuvant and from five paratuberculosis-infected bovines were studied. LAM-immunized calves developed specific antibodies with IgG1 as the predominant isotype. Serum immunoglobulins were isolated and their effect was examined in MAP ingestion and viability assays using a bovine macrophage cell line. Our results show that the antibodies generated by LAM immunization significantly increase MAP ingestion and reduce its intracellular viability, suggesting an active role in this model.

Mycobacterium haemophilum infection in a juvenile leatherback sea turtle (Dermochelys coriacea).

PubMed

Donnelly, Kyle; Waltzek, Thomas B; Wellehan, James F X; Stacy, Nicole I; Chadam, Maria; Stacy, Brian A

2016-11-01

Mycobacteriosis is infrequently reported in free-ranging sea turtles. Nontuberculous Mycobacterium haemophilum was identified as the causative agent of disseminated mycobacteriosis in a juvenile leatherback turtle (Dermochelys coriacea) that was found stranded on the Atlantic coast of Florida. Disseminated granulomatous inflammation was identified histologically, most notably affecting the nervous system. Identification of mycobacterial infection was based on cytologic, molecular, histologic, and microbiologic methods. Among stranded sea turtles received for diagnostic evaluation from the Atlantic and Gulf of Mexico coasts of the United States between 2004 and 2015, the diagnosis of mycobacteriosis was overrepresented in stranded oceanic-phase juveniles compared with larger size classes, which suggests potential differences in susceptibility or exposure among different life phases in this region. We describe M. haemophilum in a sea turtle, which contributes to the knowledge of diseases of small juvenile sea turtles, an especially cryptic life phase of the leatherback turtle. © 2016 The Author(s).

Direct healthcare costs of selected diseases primarily or partially transmitted by water

PubMed Central

COLLIER, S. A.; STOCKMAN, L. J.; HICKS, L. A.; GARRISON, L. E.; ZHOU, F. J.; BEACH, M. J.

2015-01-01

SUMMARY Despite US sanitation advancements, millions of waterborne disease cases occur annually, although the precise burden of disease is not well quantified. Estimating the direct healthcare cost of specific infections would be useful in prioritizing waterborne disease prevention activities. Hospitalization and outpatient visit costs per case and total US hospitalization costs for ten waterborne diseases were calculated using large healthcare claims and hospital discharge databases. The five primarily waterborne diseases in this analysis (giardiasis, cryptosporidiosis, Legionnaires’ disease, otitis externa, and non-tuberculous mycobacterial infection) were responsible for over 40 000 hospitalizations at a cost of $970 million per year, including at least $430 million in hospitalization costs for Medicaid and Medicare patients. An additional 50 000 hospitalizations for campylobacteriosis, salmonellosis, shigellosis, haemolytic uraemic syndrome, and toxoplasmosis cost $860 million annually ($390 million in payments for Medicaid and Medicare patients), a portion of which can be assumed to be due to waterborne transmission. PMID:22233584

Protein Kinase G Induces an Immune Response in Cows Exposed to Mycobacterium avium Subsp. paratuberculosis

PubMed Central

Bach, Eviatar; Chaffer, Marcelo; Lai, Wanika; Keefe, Greg; Begg, Douglas J.

2018-01-01

To establish infection, pathogens secrete virulence factors, such as protein kinases and phosphatases, to modulate the signal transduction pathways used by host cells to initiate immune response. The protein MAP3893c is annotated in the genome sequence of Mycobacterium avium subspecies paratuberculosis (MAP), the causative agent of Johne's disease, as the serine/threonine protein kinase G (PknG). In this work, we report that PknG is a functional kinase that is secreted within macrophages at early stages of infection. The antigen is able to induce an immune response from cattle exposed to MAP in the form of interferon gamma production after stimulation of whole blood with PknG. These findings suggest that PknG may contribute to the pathogenesis of MAP by phosphorylating macrophage signalling and/or adaptor molecules as observed with other pathogenic mycobacterial species. PMID:29581962

Protein Kinase G Induces an Immune Response in Cows Exposed to Mycobacterium avium Subsp. paratuberculosis.

PubMed

Bach, Horacio; Richard-Greenblatt, Melissa; Bach, Eviatar; Chaffer, Marcelo; Lai, Wanika; Keefe, Greg; Begg, Douglas J

2018-01-01

To establish infection, pathogens secrete virulence factors, such as protein kinases and phosphatases, to modulate the signal transduction pathways used by host cells to initiate immune response. The protein MAP3893c is annotated in the genome sequence of Mycobacterium avium subspecies paratuberculosis (MAP), the causative agent of Johne's disease, as the serine/threonine protein kinase G (PknG). In this work, we report that PknG is a functional kinase that is secreted within macrophages at early stages of infection. The antigen is able to induce an immune response from cattle exposed to MAP in the form of interferon gamma production after stimulation of whole blood with PknG. These findings suggest that PknG may contribute to the pathogenesis of MAP by phosphorylating macrophage signalling and/or adaptor molecules as observed with other pathogenic mycobacterial species.

[Localized purpura revealing vascular prosthetic graft infection].

PubMed

Boureau, A S; Lescalie, F; Cassagnau, E; Clairand, R; Connault, J

2013-07-01

Prosthetic graft infection after vascular reconstruction is a rare but serious complication. We report a case of infection occurring late after implantation of an iliofemoral prosthetic vascular graft. The Staphylococcus aureus infection was revealed by vascular purpura localized on the right leg 7 years after implantation of a vascular prosthesis. This case illustrates an uncommonly late clinical manifestation presenting as an acute infection 7 years after the primary operation. In this situation, the presentation differs from early infection, which generally occurs within the first four postoperative months. Diagnosis and treatment remain a difficult challenge because prosthetic graft infection is a potentially life-threatening complication. Morbidity and mortality rates are high. Here we detail specific aspects of the clinical and radiological presentation. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition.

PubMed

Cocaign, Angélique; Kubiak, Xavier; Xu, Ximing; Garnier, Guillaume; Li de la Sierra-Gallay, Inès; Chi-Bui, Linh; Dairou, Julien; Busi, Florent; Abuhammad, Areej; Haouz, Ahmed; Dupret, Jean Marie; Herrmann, Jean Louis; Rodrigues-Lima, Fernando

2014-11-01

Mycobacterium abscessus is the most pathogenic rapid-growing mycobacterium and is one of the most resistant organisms to chemotherapeutic agents. However, structural and functional studies of M. abscessus proteins that could modify/inactivate antibiotics remain nonexistent. Here, the structural and functional characterization of an arylamine N-acetyltransferase (NAT) from M. abscessus [(MYCAB)NAT1] are reported. This novel prokaryotic NAT displays significant N-acetyltransferase activity towards aromatic substrates, including antibiotics such as isoniazid and p-aminosalicylate. The enzyme is endogenously expressed and functional in both the rough and smooth M. abscessus morphotypes. The crystal structure of (MYCAB)NAT1 at 1.8 Å resolution reveals that it is more closely related to Nocardia farcinica NAT than to mycobacterial isoforms. In particular, structural and physicochemical differences from other mycobacterial NATs were found in the active site. Peculiarities of (MYCAB)NAT1 were further supported by kinetic and docking studies showing that the enzyme was poorly inhibited by the piperidinol inhibitor of mycobacterial NATs. This study describes the first structure of an antibiotic-modifying enzyme from M. abscessus and provides bases to better understand the substrate/inhibitor-binding specificities among mycobacterial NATs and to identify/optimize specific inhibitors. These data should also contribute to the understanding of the mechanisms that are responsible for the pathogenicity and extensive chemotherapeutic resistance of M. abscessus.

Rapid identification of clinical mycobacterial isolates by protein profiling using matrix assisted laser desorption ionization-time of flight mass spectrometry.

PubMed

Panda, A; Kurapati, S; Samantaray, J C; Myneedu, V P; Verma, A; Srinivasan, A; Ahmad, H; Behera, D; Singh, U B

2013-01-01

The purpose of this study was to evaluate the identification of Mycobacterium tuberculosis which is often plagued with ambiguity. It is a time consuming process requiring 4-8 weeks after culture positivity, thereby delaying therapeutic intervention. For a successful treatment and disease management, timely diagnosis is imperative. We evaluated a rapid, proteomic based technique for identification of clinical mycobacterial isolates by protein profiling using matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Freshly grown mycobacterial isolates were used. Acetonitrile/trifluoroacetic acid extraction procedure was carried out, following which cinnamic acid charged plates were subjected to identification by MALDI-TOF MS. A comparative analysis of 42 clinical mycobacterial isolates using the MALDI-TOF MS and conventional techniques was carried out. Among these, 97.61% were found to corroborate with the standard methods at genus level and 85.36% were accurate till the species level. One out of 42 was not in accord with the conventional assays because MALDI-TOF MS established it as Mycobacterium tuberculosis (log (score)>2.0) and conventional methods established it to be non-tuberculous Mycobacterium. MALDI-TOF MS was found to be an accurate, rapid, cost effective and robust system for identification of mycobacterial species. This innovative approach holds promise for early therapeutic intervention leading to better patient care.

Editorial: Current status and perspective on drug targets in tubercle bacilli and drug design of antituberculous agents based on structure-activity relationship.

PubMed

Tomioka, Haruaki

2014-01-01

Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. However, the development of new drugs for the treatment and prophylaxis of TB, particularly those truly active against dormant and persistent types of tubercle bacilli, has been slow, although some promising drugs, such as diarylquinoline TMC207, nitroimidazopyran PA-824, nitroimidazo-oxazole Delamanid (OPC-67683), oxazolidinone PNU-100480, ethylene diamine SQ-109, and pyrrole derivative LL3858, are currently under phase 1 to 3 clinical trials. Therefore, novel types of antituberculous drug, which act on unique drug targets in Mycobacterium tuberculosis (MTB) pathogens, particularly drug targets related to the establishment of mycobacterial dormancy in the host's macrophages, are urgently needed. In this context, it should be noted that current anti-TB drugs mostly target the metabolic reactions and proteins which are essential for the growth of MTB in extracellular milieus. It may also be promising to develop another type of drug that exerts an inhibitory action against bacterial virulence factors which cross-talk and interfere with signaling pathways of MTB-infected immunocompetent host cells, such as lymphocytes, macrophages, and NK cells, thereby changing the intracellular milieus that are favorable to intramacrophage survival and the growth of infected bacilli. This special issue contains ten review articles, dealing with recent approaches to identify and establish novel drug targets in MTB for the development of new and unique antitubercular drugs, including those related to mycobacterial dormancy and crosstalk with cellular signaling pathways. In addition, this special issue contains some review papers with special reference to the drug design based on quantitative structure-activity relationship (QSAR) analysis, especially three-dimensional (3D)-QSAR. New, critical information on the entire genome of MTB and mycobacterial virulence genes is promoting the elucidation of the molecular structures of drug targets in MTB, and are consequently markedly useful for the design of new, promising antituberculous drugs using QSAR techniques. In this issue, we review the following areas. Firstly, Dr. Li M. Fu reviews the perspective that combines machine learning and genomics for drug discovery in tuberculosis, in relation to the problem that the exhaustive search for useful drug targets over the entire MTB genome would not be as productive as expected in practice [1]. Secondly, the review article by Drs. R. S. Chauhan. S. K. Chanumolu, C. Rout, and R. Shrivastava focuses on analysis of the current state of MTB genomic resources, host-pathogen interaction studies in the context of mycobacterial persistence, and drug target discovery based on the utilization of computational tools and metabolic network analyses [2]. Thirdly, Drs. Daria Bottai, Agnese Serafini, Alessandro Cascioferro, Roland Brosch, and Riccardo Manganelli review the current knowledge on MTB T7SS/ESX secretion systems and their impact on MTB physiology and virulence, and the possible approaches to develop T7SS/ESX inhibitors [3]. Fourthly, Drs. E. Jeffrey North, Mary Jackson, and Richard E. Lee review and analyze new and emerging inhibitors of the mycolic acid biosynthetic pathway, including mycobacterial enzymes for fatty acid synthesis, mycolic acid-modifying enzymes, fatty acid-activating and -condensing enzymes, transporters, and transferases, that have been discovered in the post-genomic era of tuberculosis drug discovery [4]. Fifthly, Drs. Katarina Mikusova, Vadim Makarov, and Joao Neres review the mycobacterial enzyme DprE1, which catalyzes a unique epimerization reaction in the biosynthesis of decaprenylphosphoryl arabinose, a single donor of the arabinosyl residue for the build-up of arabinans, one of the mycobacterial cell wall components, as an important drug target especially for the development of benzothiazinones [5]. Sixthly, I review the present status of global research on novel drug targets related to the Toll-like receptor in the MTB pathogen, with special reference to mycobacterial virulence factors that cross-talk and interfere with signaling pathways of host macrophages [6]. The following four review articles deal with drug design of novel anti-TB agents employing QSAR techniques. Firstly, Drs. Nidhi and Mohammad Imran Siddiqi review 2D and 3D QSAR approaches and the recent trends of these methods integrated with virtual screening using the 3D pharmacophore and molecular docking approaches for the identification and design of novel antituberculous agents, by presenting a comprehensive overview of QSAR studies reported for newer antituberculous agents [7]. Secondly, Drs. Filomena Martins, Cristina Ventura, Susana Santos, and Miguel Viveiros review the current status of different QSAR-based strategies for the design of novel anti-TB drugs based upon the most active anti-TB agent, isoniazid, from the viewpoint of the development of promising derivatives that are active against isoniazid- resistant strains with katG mutations [8]. Thirdly, Drs. Sanchaita Rajkhowa and Ramesh C. Deka review current studies concerning 2D and 3D QSAR models that contain density-functional theory (DFT)-based descriptors as their parameters [9]. Notably, DFT-based descriptors such as atomic charges, molecular orbital energies, frontier orbital densities, and atom-atom polarizabilities are very useful in predicting the reactivity of atoms in molecules. Fourthly, Drs. Renata V. Bueno, Rodolpho C. Braga, Natanael D. Segretti, Elizabeth I. Ferreira, Gustavo H. G. Trossini, and Carolina H. Andrade review the current progress and applications of QSAR analysis for the discovery of innovative tuberculostatic agents as inhibitors of ribonucleotide reductase, DNA gyrase, ATP synthase, and thymidylate kinase enzymes, highlighting present challenges and new opportunities in TB drug design [10]. The aim of this issue is to address the future prospects for the development of new antituberculous drugs. There are a number of difficulties in computational drug-design for the development of new drug formulations with potential antimycobacterial effects, especially therapeutic and prophylactic efficacy against infection due to dormant-type MTB pathogens. In addition, it should be emphasized that the most urgent goal of TB chemotherapy is develop highly active, low-cost drugs which can be used not only in industrialized but also in developing countries, because most global TB incidence occurs in the latter. I am sincerely grateful to the individuals who contributed to this work. All authors are experts in their fields and they made earnest efforts to perform these in-depth reviews. I thank them all.

Adult gonococcal keratoconjunctivitis with AIDS.

PubMed Central

Lau, R K; Goh, B T; Estreich, S; Cox, S N; Levy, I

1990-01-01

Gonococcal eye infection in adults is an uncommon cause of blindness, where prompt diagnosis and effective treatment are essential in the prevention of ophthalmic morbidity. We present a case report detailing the management and complications encountered in this condition in a patient coinfected with human immunodeficiency virus (HIV). PMID:2306446

Mycobacterium bovis infections in domesticated non-bovine mammalian species. Part 1: Review of epidemiology and laboratory submissions in Great Britain 2004-2010.

PubMed

Broughan, J M; Downs, S H; Crawshaw, T R; Upton, P A; Brewer, J; Clifton-Hadley, R S

2013-11-01

Mycobacterium bovis, the causative agent of bovine tuberculosis (bTB), can infect a broad range of mammalian species in addition to domestic and feral cattle and badgers. Since legislation introduced in 2006 in Great Britain requires animal keepers, meat inspectors and veterinarians to notify the authorities of suspect bTB lesions or the isolation of M. bovis in any mammal excluding humans, the organism has been increasingly identified in domestic species other than cattle. Although in most cases 'spill-over' hosts, these remain a potential source of infection for cattle, wildlife, and possibly humans. In this first part of a two-part review of M. bovis infections in non-bovine domestic species, current knowledge of the epidemiology of such infections is presented along with novel data relating to diagnostic submissions for mycobacterial culture between 2004 and 2010. Over this period M. bovis infection was identified in 116 cats, 7 dogs, 34 llamas, 133 alpacas, 35 goats, 24 sheep and 85 pigs and wild boar. The risk that such infections pose to the control of bTB, and as zoonoses, is discussed. In part two, the options available to diagnose bTB in these species, as well as the challenges posed to disease detection and control will be discussed in depth. Copyright © 2013. Published by Elsevier Ltd.

Multisite Infection with Mycobacterium abscessus after Replacement of Breast Implants and Gluteal Lipofilling

PubMed Central

Rüegg, Eva; Cheretakis, Alexandre; Modarressi, Ali; Harbarth, Stephan; Pittet-Cuénod, Brigitte

2015-01-01

Introduction. Medical tourism for aesthetic surgery is popular. Nontuberculous mycobacteria (NTM) occasionally cause surgical-site infections. As NTM grow in biofilms, implantations of foreign bodies are at risk. Due to late manifestation, infections occur when patients are back home, where they must be managed properly. Case Report. A 39-year-old healthy female was referred for acute infection of the right gluteal area. Five months before, she had breast implants replacement, abdominal liposuction, and gluteal lipofilling in Mexico. Three months postoperatively, implants were removed for NTM-infection in Switzerland. Adequate antibiotic treatment was stopped after seven days for drug-related hepatitis. At entrance, gluteal puncture for bacterial analysis was performed. MRI showed large subcutaneous collection. Debridement under general anaesthesia was followed by open wound management. Total antibiotic treatment was 20 weeks. Methods. Bacterial analysis of periprosthetic and gluteal liquids included Gram-stain plus acid-fast stain, and aerobic, anaerobic and mycobacterial cultures.  Results. In periprosthetic fluid, Mycobacterium abscessus, Propionibacterium, and Staphylococcus epidermidis were identified. The same M. abscessus strain was found gluteally. The gluteal wound healed within six weeks. At ten months' follow-up, gluteal asymmetry persists for deep scarring. Conclusion. This case presents major complications of multisite aesthetic surgery. Surgical-site infections in context of medical tourism need appropriate bacteriological investigations, considering potential NTM-infections. PMID:25893122

S-layer proteins from Lactobacillus sp. inhibit bacterial infection by blockage of DC-SIGN cell receptor.

PubMed

Prado Acosta, Mariano; Ruzal, Sandra M; Cordo, Sandra M

2016-11-01

Many species of Lactobacillus sp. possess Surface(s) layer proteins in their envelope. Among other important characteristics S-layer from Lactobacillus acidophilus binds to the cellular receptor DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin; CD209), which is involved in adhesion and infection of several families of bacteria. In this report we investigate the activity of new S-layer proteins from the Lactobacillus family (Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus helveticus and Lactobacillus kefiri) over the infection of representative microorganisms important to human health. After the treatment of DC-SIGN expressing cells with these proteins, we were able to diminish bacterial infection by up to 79% in both gram negative and mycobacterial models. We discovered that pre-treatment of the bacteria with S-layers from Lactobacillus acidophilus and Lactobacillus brevis reduced bacteria viability but also prevent infection by the pathogenic bacteria. We also proved the importance of the glycosylation of the S-layer from Lactobacillus kefiri in the binding to the receptor and thus inhibition of infection. This novel characteristic of the S-layers proteins may contribute to the already reported pathogen exclusion activity for these Lactobacillus probiotic strains; and might be also considered as a novel enzymatic antimicrobial agents to inhibit bacterial infection and entry to host cells. Copyright © 2016 Elsevier B.V. All rights reserved.

Non-tuberculous mycobacterial infections.

PubMed

Petrini, Björn

2006-01-01

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms in contrast to those belonging to the M. tuberculosi complex (MTB). NTM infects and causes disease only in hosts with local or general predisposing factors. Lung infection following inhalation of NTM is the most common NTM disease but soft tissue infections may occur in connection with contaminated trauma or surgery. Microbiological diagnosis is obtained by microscopy for acid-fast bacteria (AFB) on secretions or biopsies, and by culture on special media. With the high specificity of MTB- polymerase chain reaction (PCR), a positive AFB smear combined with negative MTB-PCR denotes infection with NTM. Sophisticated species diagnosis of cultured NTM is attained by various molecular methods, where 16S rDNA-sequencing remains the gold standard. The panorama of infection with different rapidly growing (RGM) or slowly growing mycobacteria (SGM) in Sweden is described. Sensitivity testing in vitro to antimycobacterial drugs against NTM does not always preclude the in vivo efficacy. Standard antimycobacterial treatment regimens have been defined for infection with several NTM species. Sensitivity testing should be performed in selected cases only, as in case of relapse or suspected development of resistance of the NTM strain. The spectrum of disease caused by NTM species that display a very low pathogenic potential is likely to widen over time as severe immunosuppression will continue to be prevalent in several patient categories.

Cerebral Candidal Abscess and Bovine Viral Diarrhoea Virus Infection in an Aborted Bovine Fetus.

PubMed

Vilander, A C; Niles, G A; Frank, C B

2016-01-01

Candida species are opportunistic fungi associated with immunosuppression and are the most commonly isolated fungal pathogens from the human central nervous system. Invasive candidiasis is reported uncommonly in animals and there have only been two reports of candidal infection of the brain. This report presents a case of a cerebral candidal abscess in an aborted late-term calf co-infected with bovine viral diarrhoea virus. Candida etchellsii, a species not previously identified as pathogenic, was identified as the causative agent by polymerase chain reaction. Copyright © 2016 Elsevier Ltd. All rights reserved.

Endovascular Repair of a Secondary Aorto-Appendiceal Fistula

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

Tse, Donald M. L., E-mail: donald.tse@gmail.com; Thompson, Andrew R. A.; Perkins, Jeremy

2011-10-15

Aortoenteric fistula (AEF) is an uncommon but serious complication occurring after aortic surgery and may occur at any site in the gastrointestinal tract, with the duodenum being the most common. Conventional surgical repair of secondary AEF has high mortality, whereas endovascular repair has emerged as an alternative treatment despite concerns about persistent or recurrent infection. We report the case of a 91-year old man who was admitted with rectal bleeding from an aorto-appendiceal fistula 9 years after open abdominal aortic aneurysm repair. This rare site for AEF was diagnosed on computed tomography, and we present the first case of endovascularmore » treatment of this uncommon complication.« less

The 100 most-cited articles on non-tuberculous mycobacterial infection from 1995 to 2015.

PubMed

Jhun, B W; Kim, S-Y; Kong, J H; Park, J R; Park, S Y; Shim, M A; Jeon, K; Park, H Y; Shin, S J; Koh, W-J

2017-01-01

Citation analyses aid in assessing quality, trends and future directions of research fields. To identify the most influential articles on infections caused by non-tuberculous mycobacteria (NTM) in the last 20 years. We performed a cited reference search of the Web of Science database from 1995 to 2015. The 100 most cited articles on NTM infections were analysed. The top 100 articles were cited 114-1471 times, and were published from 1995 to 2013. Sixty-five were laboratory-based, basic science articles, with the major topics being pathophysiology (n = 20) and molecular methods for NTM identification (n = 15). Among the 35 non-laboratory studies, major topics were clinical management (n = 15) and epidemiology (n = 14). The top article was a clinical treatise on the management of NTM disease, published in 2007. Although there was a correlation between article rank and journal impact factor (P = 0.043, ρ = -0.202), the five articles from the journals with highest impact factors did not rank among the top 10 articles. A large proportion of influential articles on NTM infection are basic scientific studies, and the most influential articles are not always published in high-impact journals.

Mycobacteriosis in striped bass

USGS Publications Warehouse

Panek, Frank

2008-01-01

Mycobacteriosis is a bacterial disease in which striped bass (rockfish) may be disfigured as a result of skin ulcers and internal lesions. The bass may also be skinny or in extremely poor condition due to the chronic nature of this wasting disease. Stripers are a highly prized target species for both recreational anglers and commercial fishermen. As such, the economic impact of diseased and devalued fish could be significant. In addition, some of the mycobacteria that commonly infect fishes can cause infections in people and therefore are a human health concern. The total extent to which the disease is occurring along the Eastern seaboard is unknown but the disease has been reported from stripers taken from North Carolina to New York. During 1998-99, skin ulcers attributed to mycobacterial infection were observed in up to 28% of the striped bass from some Virginia tributaries of the Chesapeake Bay. Data obtained during 2002—2003 from fish harvested in Virginia and Maryland waters indicated that, at least in some areas, over 80% of striped bass may be infected with the mycobacteria that are associated with the disease. Given the persistence over the last 8 years of this mycobacteriosis outbreak, this does not appear to be a short-term problem.

Lactobacillus as a rare cause of an infected total knee replacement: a case report

PubMed Central

2009-01-01

Introduction We report a rare case of an infected revision total knee replacement as a result of a Lactobacillus species infection. Lactobacillus infections have been associated with prolonged broad-spectrum antibiotic use. This can have implications in revision surgery, especially when patients have been on previous long-term suppressive antibiotic therapy. Case presentation An 81-year-old British man with a previous history of complex revision knee arthroplasty for infection presented with a hot, swollen knee joint. He had previously been on long-term suppressive antibiotic therapy. Aspiration of the knee joint yielded a culture of Lactobacillus species. Conclusion In patients undergoing revision joint arthroplasty, especially for previous infection, the presence of common and uncommon bacterial species must be excluded and eradicated before further surgical intervention. PMID:19830207

Reactivation West Nile virus infection-related chorioretinitis.

PubMed

Beardsley, Robert; McCannel, Colin

2012-01-01

West Nile Virus is a relatively uncommon infection that can involve retinal and choroidal inflammation leading to photopsias, photophobia, and orbital pain. The diagnosis is made by clinical history, serology, and characteristic funduscopic exam and fluorescein angiography findings. Treatment involves primarily supportive care as there are no known effective anti-viral agents. Visual recovery is usually full. Here we present a case of West Nile Virus Infection Related chorioretinitis that demonstrated active linear chorioretinal lesions approximately one year after the initial infection was diagnosed and treated. The patient noted new onset blurry vision and floaters for two weeks prior to presentation. Antibody titers to West Nile Virus increased from baseline levels indicating active infection. This represents the first case of reactivation West Nile Virus Infection Related chorioretinitis that has been documented.

Group A Streptococcus vulvovaginitis in breastfeeding women.

PubMed

Rahangdale, Lisa; Lacy, Judith; Hillard, Paula A

2008-08-01

Group A beta-hemolytic streptococcus-associated vulvovaginitis is uncommon in adult women. Clinicians should include group A beta-hemolytic streptococcus as a possible cause of vulvovaginal symptoms in breastfeeding women. Along with appropriate antibiotic therapy, vaginal estrogen therapy may be considered to diminish susceptibility to recurrent infection in women with vaginal atrophy.

An unusual case of acute parotitis in a young adult.

PubMed

Sehic, Azra; Haenig, Caitlin; Spear, Francis

2017-08-01

Acute bacterial parotitis is uncommon in young adults. Infection with Serratia marcescens is even rarer and usually found in hospitalized patients. This case report focuses on a young woman with acute bacterial parotitis caused by S. marcescens that required a longer-than-normal course of antibiotics.

A case of acute infectious mononucleosis presenting with very high ferritin

PubMed Central

Thoufeeq, Muhammed Hameed; Ali Khan, Shahul Leyakath; Jain, Sanjiv Kumar; Al-Shakerchi, Hasanain; Hussain, Munem

2007-01-01

Hepatitis is an important but uncommon manifestation of acute Epstein Barr infection. Infectious mononucleosis is usually a disease of young adults. We report a case of infectious mononucleosis in a 72-year old jaundiced gentleman with ferritin level of 2438 that normalised on clinical improvement. PMID:17278235

Structure and function of the mycobacterial transcription initiation complex with the essential regulator RbpA

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

Hubin, Elizabeth A.; Fay, Allison; Xu, Catherine

RbpA and CarD are essential transcription regulators in mycobacteria. Mechanistic analyses of promoter open complex (RPo) formation establish that RbpA and CarD cooperatively stimulate formation of an intermediate (RP2) leading to RPo; formation of RP2 is likely a bottleneck step at the majority of mycobacterial promoters. Once RPo forms, CarD also disfavors its isomerization back to RP2. We determined a 2.76 Å-resolution crystal structure of a mycobacterial transcription initiation complex (TIC) with RbpA as well as a CarD/RbpA/TIC model. Both CarD and RbpA bind near the upstream edge of the -10 element where they likely facilitate DNA bending and impedemore » transcription bubble collapse. In vivo studies demonstrate the essential role of RbpA, show the effects of RbpA truncations on transcription and cell physiology, and indicate additional functions for RbpA not evident in vitro. This work provides a framework to understand the control of mycobacterial transcription by RbpA and CarD.« less

An inducible expression system for high-level expression of recombinant proteins in slow growing mycobacteria.

PubMed

Leotta, Lisa; Spratt, Joanne M; Kong, Carlyn U; Triccas, James A

2015-09-01

A novel protein expression vector utilising the inducible hspX promoter of Mycobacterium tuberculosis was constructed and evaluated in this study. High-level induction of three mycobacterial antigens, comprising up to 9% of bacterial sonicate, was demonstrated in recombinant Mycobacterium bovis BCG when grown under low-oxygen tension, which serves to enhance hspX promoter activity. Recombinant proteins were efficiently purified from bacterial lysates in a soluble form by virtue of a C-terminal 6-histidine tag. Purification of the immunodominant M. tuberculosis Ag85B antigen using this system resulted in a recombinant protein that stimulated significant IFN-γ release from Ag85B-reactive T cells generated after vaccination of mice with an Ag85B-expressing vaccine. Further, the M. tuberculosis L-alanine dehydrogenase (Ald) protein purified from recombinant BCG displayed strong enzymatic activity in recombinant form. This study demonstrated that high levels of native-like recombinant mycobacterial proteins can be produced in mycobacterial hosts, and this may aid the analysis of mycobacterial protein function and the development of new treatments. Copyright © 2015 Elsevier B.V. All rights reserved.

[Tuberculous prosthetic knee joint infection: a case report and literature review].

PubMed

Lara-Oya, A; Liébana-Martos, M C; Rodríguez-Granger, J; Sampedro-Martínez, A; Aliaga-Martínez, L; Gutierrez-Fernández, J; Navarro-Marí, J M

2016-08-01

Prosthetic late infection occurs in the second month after surgery in the context of haematogenous spread from another source. Prosthetic mycobacterial infection is a rare complication whose clinical management is not standardized. Patient of 77 years with no personal history except for diabetes and a prosthetic replacement of right knee with osteoarthritis three years ago. Patient goes to hospital emergency box for 6 months pain in the right knee with mechanical inflammatory signs but no fever associated. After their return within 5 days and clinical worsening is reporting growth of Mycobacterium tuberculosis in knee aspirate and antitubercular treatment is established for 9 months. Nuclear magnetic resonance imaging studies also confirmed the diagnosis of tuberculosis spondylitis in the clinical context of the patients. After surgery, M. tuberculosis was again isolated from intraoperative samples and therefore the patient received another batch of treatment for 9 months. After a year of monitoring, the development was acceptable but few months later, the patient died for cardiovascular causes. In the literature review, 15 publications with a total of 17 clinical cases of prosthetic infection by M. tuberculosis were found from 1980 to 2014. Prosthetic tuberculous arthritis, although it is a rare presentation, it should be noted, especially in patients with predisposing conditions with a history of tuberculosis infection.

The Mycobacterium tuberculosis MmpL11 Cell Wall Lipid Transporter Is Important for Biofilm Formation, Intracellular Growth, and Nonreplicating Persistence

PubMed Central

Wright, Catherine C.; Hsu, Fong Fu; Arnett, Eusondia; Dunaj, Jennifer L.; Davidson, Patrick M.; Pacheco, Sophia A.; Harriff, Melanie J.; Lewinsohn, David M.; Schlesinger, Larry S.

2017-01-01

ABSTRACT The mycobacterial cell wall is crucial to the host-pathogen interface, because it provides a barrier against antibiotics and the host immune response. In addition, cell wall lipids are mycobacterial virulence factors. The mycobacterial membrane protein large (MmpL) proteins are cell wall lipid transporters that are important for basic mycobacterial physiology and Mycobacterium tuberculosis pathogenesis. MmpL3 and MmpL11 are conserved across pathogenic and nonpathogenic mycobacteria, a feature consistent with an important role in the basic physiology of the bacterium. MmpL3 is essential and transports trehalose monomycolate to the mycobacterial surface. In this report, we characterize the role of MmpL11 in M. tuberculosis. M. tuberculosis mmpL11 mutants have altered biofilms associated with lower levels of mycolic acid wax ester and long-chain triacylglycerols than those for wild-type bacteria. While the growth rate of the mmpL11 mutant is similar to that of wild-type M. tuberculosis in macrophages, the mutant exhibits impaired survival in an in vitro granuloma model. Finally, we show that the survival or recovery of the mmpL11 mutant is impaired when it is incubated under conditions of nutrient and oxygen starvation. Our results suggest that MmpL11 and its cell wall lipid substrates are important for survival in the context of adaptive immune pressure and for nonreplicating persistence, both of which are critically important aspects of M. tuberculosis pathogenicity. PMID:28507063

Dengue Haemorrhagic Encephalitis: Rare Case Report with Review of Literature.

PubMed

Kutiyal, Aditya Singh; Malik, Chetanya; Hyanki, Gitika

2017-07-01

Dengue is an endemic arboviral infection prevalent especially in tropical countries including Southern and Southeast Asia. Central Nervous System (CNS) involvement in dengue infection is uncommon. Haemorrhagic encephalitis is a rare presentation in dengue. This is a case of a 58-year-old male who presented with fever, petechial rash and altered sensorium. Dengue serology IgM was reactive and MRI brain was suggestive of haemorrhagic encephalitis. Patient was managed in Intensive Care Unit (ICU) but eventually succumbed to his illness. We report this fatal outcome of a common viral infection with unusual neurological presentation to propose an association between dengue and neurotropism and the need to look at dengue infection beyond its classical features.

Actinomyces meyeri infection: case report and review of the literature.

PubMed

Fazili, Tasaduq; Blair, Donald; Riddell, Scott; Kiska, Deanna; Nagra, Shehzadi

2012-10-01

Actinomyces meyeri is an uncommon cause of actinomycosis. We present a patient with pneumonia and empyema due to A. meyeri. The patient underwent open thoracotomy with decortication and was discharged home on a twelve-month course of oral penicillin. Review of the English literature revealed thirty-two cases of infection due to A. meyeri. The majority of patients were male, and a significant number had poor dental hygiene and a history of alcoholism. More than other Actinomyces species, A. meyeri causes pulmonary infection and has a predilection for dissemination. Prognosis is favorable with prolonged penicillin therapy combined with surgical debridement, if needed. Copyright © 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Achromobacter species endocarditis: A case report and literature review

PubMed Central

Derber, Catherine; Elam, Kara; Forbes, Betty A; Bearman, Gonzalo

2011-01-01

Endocarditis due to Achromobacter species is a rare, yet serious, endovascular infection. Achromobacter species infective endocarditis is associated with underlying immunodeficiencies or prosthetic heart valves and devices. A case of prosthetic pulmonary valve endocarditis secondary to Achromobacter xylosoxidans subspecies denitrificans is described in the present report. This life-threatening infection was successfully treated with combined valve replacement and prolonged antibiotic therapy. A Medline/PubMed literature review of Achromobacter endocarditis was also performed. Achromobacter species are an uncommon, yet important, cause of nosocomial endocarditis. Given the significant associated morbidity and mortality, along with a high degree of intrinsic antibiotic resistance, Achromobacter species infective endocarditis remains a clinical treatment challenge. PMID:22942890

Serratia marcescens Bullous Cellulitis in a Splenectomized Patient: A Case Report and Review of the Literature.

PubMed

Fournier, John B; Dabiri, Ganary; Thomas, Vinod; Skowron, Gail; Carson, Polly; Falanga, Vincent

2016-06-01

Serratia marcescens is a Gram-negative bacillus belonging to the Enterobacteriaceae family. Cutaneous infection with Serratia is rare, and usually occurs in immunocompromised individuals. Primary cutaneous infections are uncommon, but they are typically severe and are associated with significant morbidity and mortality. The pathogenetic factors leading to S. marcescens infection are not fully understood, but contributing virulence factors include proteases, secreted exotoxins, and the formation of biofilm. We report a case of cellulitis occurring in a splenectomized patient, which led to multiple wound debridements and a transmetatarsal amputation. This dramatic case led us to review the published literature on soft tissue infections caused by S. marcescens. © The Author(s) 2016.

AIDS phobia: report of 4 cases.

PubMed

Ross, M W

1988-01-01

Psychological reactions to sexually transmissible disease (STD) infection are common, occurring in up to 85% of some patients with STDs: Hart has suggested that they are among the most common conditions encountered in venereology. Previous psychiatric disturbances in STD patients, however, are relatively uncommon and differ in both etiology and management from such psychological sequelae of STD infection, although both Catalan et al. and Fitzpatrick et al. report that in the United Kingdom, some 40% of STD clinic attenders had General Health Questionnaire scores indicating they were psychiatric cases.

[Septic thrombosis of the cavernous sinus due to folliculitis].

PubMed

Tuettenberg, A; Tuettenberg, J; Knop, J; Enk, A

2003-04-01

Sinus thrombosis is an acute life-threatening disease. While cavernous sinus thrombosis secondary to facial infections is described in the literature, it is uncommon. The key clinical characteristics are a facial infection, headache, chemosis and edema of the eyelid. The main differential diagnostic consideration is meningoencephalitis. Early diagnosis by angiography, magnetic resonance imaging and examination of CSF is important as treatment should be initiated as soon as possible in order to decrease morbidity and mortality. The mainstays of therapy are heparinization and appropriate intravenous antibiotic therapy.

Lymphogranuloma venereum in men who have sex with men: evidence of local transmission in New Zealand.

PubMed

Basu, Indira; Bromhead, Collette; Balm, Michelle; Upton, Arlo; Reid, Murray; Franklin, Rick; Morgan, Jane; Bower, James; Henderson, Gillian; Roberts, Sally A

2015-03-13

Lymphogranuloma venereum (LGV) is a sexually transmitted infection caused by Chlamydia trachomatis. Five laboratory confirmed cases of LGV were detected in MSM (men who have sex with men) in the upper North Island; four in Auckland between September and December 2013 and a fifth case was detected in Waikato in June 2014. The absence of a recent travel history for four cases supports the likelihood of local transmission of this uncommon infection.

Prototheca wickerhamii algaemia presenting as cholestatic hepatitis in a patient with systemic lupus erythematosus: A case report and literature review

PubMed Central

Min, Zaw; Moser, Stephen A.; Pappas, Peter G.

2012-01-01

Human protothecal infection is uncommon and could be localized or systemic disease. Disseminated Prototheca algaemia tends to occur in immunocompromised patients (solid organ transplants, hematological malignancies) with high mortality. Diagnosis could be missed or delayed due to unusual clinical presentation and/or under-recognition of characteristic microscopic features of Prototheca species. Combined approach that includes removal of source of infection and intravenous amphotericin B provides the best chance of cure. PMID:24432207

Myroides odoratus and Chryseobacterium indologenes: two rare isolates in the immunocompromised.

PubMed

Deepa, R; Venkatesh, K G; Parveen, J Durdana; Banu, S Thasneem; Jayalakshmi, G

2014-01-01

Myroides spp and Chryseobacterium spp are uncommon clinical isolates, though more frequently reported to cause infections than other pigmented non-fermentors. Two cases of Myroides odoratus and Chryseobacterium indologenes infection in a diabetic with pulmonary tuberculosis and a patient with de-compensated alcoholic liver disease, respectively, are reported here. Anti-microbial susceptibility testing of the isolates was performed by determining the minimum inhibitory concentration. The clinical picture, characteristic features of the isolates and the antibiotic susceptibility pattern are discussed briefly.

Herpes zoster-associated acute urinary retention in immunocompetent patient*

PubMed Central

Marques, Silvio Alencar; Hortense, Juliana

2014-01-01

Herpes zoster-associated urinary retention is an uncommon event related to virus infection of the S2-S4 dermatome. The possible major reasons are ipsilateral hemicystitis, neuritis-induced or myelitis-associated virus infection. We report a case of a 65-year-old immunocompetent female patient who presented an acute urinary retention after four days under treatment with valacyclovir for gluteal herpes zoster. The patient had to use a vesical catheter, was treated with antibiotics and corticosteroids and fully recovered after eight weeks. PMID:25387508

Detection of Coxiella Burnetii (Q fever) and Borrelia Burgdorferi (Lyme Disease) in Field-Collected Ticks from the Cayo District of Belize, Central America

DTIC Science & Technology

2016-03-25

humans is uncommon, a documented case of crushing an infected tick between the fingers resulted in a Q fever infection [14]. Most human 2...fluid [1,43,49,57]. In humans, presentation of Q fever ranges from asymptomatic, to acute disease, to chronic illness. In the majority of cases ...acute disease presents as a self-limiting febrile illness with half of cases suffering severe headaches. In severe cases of acute disease, atypical

Prophage-mediated defense against viral attack and viral counter-defense

PubMed Central

Dedrick, Rebekah M.; Jacobs-Sera, Deborah; Guerrero Bustamante, Carlos A.; Garlena, Rebecca A.; Mavrich, Travis N.; Pope, Welkin H.; Reyes, Juan C Cervantes; Russell, Daniel A.; Adair, Tamarah; Alvey, Richard; Bonilla, J. Alfred; Bricker, Jerald S.; Brown, Bryony R.; Byrnes, Deanna; Cresawn, Steven G.; Davis, William B.; Dickson, Leon A.; Edgington, Nicholas P.; Findley, Ann M.; Golebiewska, Urszula; Grose, Julianne H.; Hayes, Cory F.; Hughes, Lee E.; Hutchison, Keith W.; Isern, Sharon; Johnson, Allison A.; Kenna, Margaret A.; Klyczek, Karen K.; Mageeney, Catherine M.; Michael, Scott F.; Molloy, Sally D.; Montgomery, Matthew T.; Neitzel, James; Page, Shallee T.; Pizzorno, Marie C.; Poxleitner, Marianne K.; Rinehart, Claire A.; Robinson, Courtney J.; Rubin, Michael R.; Teyim, Joseph N.; Vazquez, Edwin; Ware, Vassie C.; Washington, Jacqueline; Hatfull, Graham F.

2017-01-01

Temperate phages are common and prophages are abundant residents of sequenced bacterial genomes. Mycobacteriophages are viruses infecting mycobacterial hosts including Mycobacterium tuberculosis and Mycobacterium smegmatis, encompass substantial genetic diversity, and are commonly temperate. Characterization of ten Cluster N temperate mycobacteriophages reveals at least five distinct prophage-expressed viral defense systems that interfere with infection of lytic and temperate phages that are either closely-related (homotypic defense) or unrelated (heterotypic defense). Target specificity is unpredictable, ranging from a single target phage to one-third of those tested. The defense systems include a single-subunit restriction system, a heterotypic exclusion system, and a predicted (p)ppGpp synthetase, which blocks lytic phage growth, promotes bacterial survival, and enables efficient lysogeny. The predicted (p)ppGpp synthetase coded by the Phrann prophage defends against phage Tweety infection, but Tweety codes for a tetrapeptide repeat protein, gp54, that acts as a highly effective counter-defense system. Prophage-mediated viral defense offers an efficient mechanism for bacterial success in host-virus dynamics, and counter-defense promotes phage co-evolution. PMID:28067906

Recent mouse models and vaccine candidates for preventing chronic/latent tuberculosis infection and its reactivation.

PubMed

Pedroza-Roldán, César; Flores-Valdez, Mario Alberto

2017-08-31

Tuberculosis (TB) remains a major challenge in public health worldwide. Until today, the only widely used and approved vaccine is the Mycobacterium bovis bacille Calmette-Guerin (BCG). This vaccine provides a highly variable level of protection against the active, pulmonary form of tuberculosis, and practically none against the latent form of TB infection. This disparity in protection has been extensively studied, and for this reason, several groups have focused their research on the quest for attenuated vaccines based on M. tuberculosis or on the identification of latency-associated antigens that can be incorporated into modified BCG, or that can be used as adjuvanted subunit vaccines. In order to seek new potential antigens relevant for infection, some researchers have performed experiments with highly sensitive techniques such as transcriptomic and proteomic analyses using sputum samples from humans or by using mouse models resembling several aspects of TB. In this review, we focus on reports of new mouse models or mycobacterial antigens recently tested for developing vaccine candidates against chronic/latent tuberculosis and its reactivation.

Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis

PubMed Central

Behar, SM; Martin, CJ; Booty, MG; Nishimura, T; Zhao, X; Gan, H; Divangahi, M; Remold, HG

2011-01-01

Two different forms of death are commonly observed when Mycobacterium tuberculosis (Mtb)-infected macrophages die: (i) necrosis, a death modality defined by cell lysis and (ii) apoptosis, a form of death that maintains an intact plasma membrane. Necrosis is a mechanism used by bacteria to exit the macrophage, evade host defenses, and spread. In contrast, apoptosis of infected macrophages is associated with diminished pathogen viability. Apoptosis occurs when tumor necrosis factor activates the extrinsic death domain pathway, leading to caspase-8 activation. In addition, mitochondrial outer membrane permeabilization leading to activation of the intrinsic apoptotic pathway is required. Both pathways lead to caspase-3 activation, which results in apoptosis. We have recently demonstrated that during mycobacterial infection, cell death is regulated by the eicosanoids, prostaglandin E2 (proapoptotic) and lipoxin (LX)A4 (pronecrotic). Although PGE2 protects against necrosis, virulent Mtb induces LXA4 and inhibits PGE2 production. Under such conditions, mitochondrial inner membrane damage leads to macrophage necrosis. Thus, virulent Mtb subverts eicosanoid regulation of cell death to foil innate defense mechanisms of the macrophage. PMID:21307848

Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis.

PubMed

Behar, S M; Martin, C J; Booty, M G; Nishimura, T; Zhao, X; Gan, H-X; Divangahi, M; Remold, H G

2011-05-01

Two different forms of death are commonly observed when Mycobacterium tuberculosis (Mtb)-infected macrophages die: (i) necrosis, a death modality defined by cell lysis and (ii) apoptosis, a form of death that maintains an intact plasma membrane. Necrosis is a mechanism used by bacteria to exit the macrophage, evade host defenses, and spread. In contrast, apoptosis of infected macrophages is associated with diminished pathogen viability. Apoptosis occurs when tumor necrosis factor activates the extrinsic death domain pathway, leading to caspase-8 activation. In addition, mitochondrial outer membrane permeabilization leading to activation of the intrinsic apoptotic pathway is required. Both pathways lead to caspase-3 activation, which results in apoptosis. We have recently demonstrated that during mycobacterial infection, cell death is regulated by the eicosanoids, prostaglandin E(2) (proapoptotic) and lipoxin (LX)A(4) (pronecrotic). Although PGE(2) protects against necrosis, virulent Mtb induces LXA(4) and inhibits PGE(2) production. Under such conditions, mitochondrial inner membrane damage leads to macrophage necrosis. Thus, virulent Mtb subverts eicosanoid regulation of cell death to foil innate defense mechanisms of the macrophage.

Haematuria in Postrenal Transplant Patients

PubMed Central

Wang, Ziting; Vathsala, Anantharaman; Tiong, Ho Yee

2015-01-01

Haematuria has a prevalence of 12% in the postrenal transplant patient population. It heralds potentially dangerous causes which could threaten graft loss. It is important to consider causes in light of the unique, urological, and immunological standpoints of these patients. We review the literature on common causes of haematuria in postrenal transplant patients and suggest the salient approach to the evaluation of this condition. A major cause of haematuria is urinary tract infections. There should be a higher index of suspicion for mycobacterial, fungal, and viral infection in this group of immunosuppressed patients. Measures recommended in the prevention of urinary tract infections include early removal of foreign bodies as well as prophylactic antibiotics during the early transplant phase. Another common cause of haematuria is that of malignancies, in particular, renal cell carcinomas. When surgically managing cancer in the setting of a renal transplant, one has to be mindful of the limited retropubic space and the need to protect the anastomoses. Other causes include graft rejections, recurrences of primary disease, and calculus formation. It is important to perform a comprehensive evaluation with the aid of an experienced multidisciplinary transplant team. PMID:25918706

Engineering Mycobacteria for the Production of Self-Assembling Biopolyesters Displaying Mycobacterial Antigens for Use as a Tuberculosis Vaccine.

PubMed

Lee, Jason W; Parlane, Natalie A; Rehm, Bernd H A; Buddle, Bryce M; Heiser, Axel

2017-03-01

Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis or Mycobacterium bovis and still remains one of the world's biggest global health burdens. Recently, engineered polyhydroxyalkanoate (PHA) biobeads that were produced in both Escherichia coli and Lactococcus lactis and displayed mycobacterial antigens were found to induce significant cell-mediated immune responses in mice. We observed that such PHA beads contained host cell proteins as impurities, which we hypothesized to have the potential to induce immunity. In this study, we aimed to develop PHA beads produced in mycobacteria (mycobacterial PHA biobeads [MBB]) and test their potential as a TB vaccine in a mouse model. As a model organism, nonpathogenic Mycobacterium smegmatis was engineered to produce MBB or MBB with immobilized mycobacterial antigens Ag85A and ESAT-6 on their surface (A:E-MBB). Three key enzymes involved in the poly(3-hydroxybutyric acid) pathway, namely, β-ketothiolase (PhaA), acetoacetyl-coenzyme A reductase (PhaB), and PHA synthase (PhaC), were engineered into E. coli - Mycobacterium shuttle plasmids and expressed in trans Immobilization of specific antigens to the surface of the MBB was achieved by creating a fusion with the PHA synthase which remains covalently attached to the polyester core, resulting in PHA biobeads displaying covalently immobilized antigens. E-MBB, and an M. smegmatis vector control (MVC) were used in a mouse immunology trial, with comparison to phosphate-buffered saline (PBS)-vaccinated and Mycobacterium bovis BCG-vaccinated groups. We successfully produced MBB and A:E-MBB and used them as vaccines to induce a cellular immune response to mycobacterial antigens. IMPORTANCE Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis or Mycobacterium bovis and still remains one of the world's biggest global health burdens. In this study, we produced polyhydroxyalkanoate (PHA) biobeads in mycobacteria and used them as vaccines to induce a cellular immune response to mycobacterial antigens. Copyright © 2017 Lee et al.

Engineering Mycobacteria for the Production of Self-Assembling Biopolyesters Displaying Mycobacterial Antigens for Use as a Tuberculosis Vaccine

PubMed Central

Lee, Jason W.; Parlane, Natalie A.; Rehm, Bernd H. A.; Buddle, Bryce M.

2017-01-01

ABSTRACT Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis or Mycobacterium bovis and still remains one of the world's biggest global health burdens. Recently, engineered polyhydroxyalkanoate (PHA) biobeads that were produced in both Escherichia coli and Lactococcus lactis and displayed mycobacterial antigens were found to induce significant cell-mediated immune responses in mice. We observed that such PHA beads contained host cell proteins as impurities, which we hypothesized to have the potential to induce immunity. In this study, we aimed to develop PHA beads produced in mycobacteria (mycobacterial PHA biobeads [MBB]) and test their potential as a TB vaccine in a mouse model. As a model organism, nonpathogenic Mycobacterium smegmatis was engineered to produce MBB or MBB with immobilized mycobacterial antigens Ag85A and ESAT-6 on their surface (A:E-MBB). Three key enzymes involved in the poly(3-hydroxybutyric acid) pathway, namely, β-ketothiolase (PhaA), acetoacetyl-coenzyme A reductase (PhaB), and PHA synthase (PhaC), were engineered into E. coli-Mycobacterium shuttle plasmids and expressed in trans. Immobilization of specific antigens to the surface of the MBB was achieved by creating a fusion with the PHA synthase which remains covalently attached to the polyester core, resulting in PHA biobeads displaying covalently immobilized antigens. MBB, A:E-MBB, and an M. smegmatis vector control (MVC) were used in a mouse immunology trial, with comparison to phosphate-buffered saline (PBS)-vaccinated and Mycobacterium bovis BCG-vaccinated groups. We successfully produced MBB and A:E-MBB and used them as vaccines to induce a cellular immune response to mycobacterial antigens. IMPORTANCE Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis or Mycobacterium bovis and still remains one of the world's biggest global health burdens. In this study, we produced polyhydroxyalkanoate (PHA) biobeads in mycobacteria and used them as vaccines to induce a cellular immune response to mycobacterial antigens. PMID:28087528

Primed Mycobacterial Uveitis (PMU): Histologic and Cytokine Characterization of a Model of Uveitis in Rats

PubMed Central

Pepple, Kathryn L.; Rotkis, Lauren; Van Grol, Jennifer; Wilson, Leslie; Sandt, Angela; Lam, Deborah L.; Carlson, Eric; Van Gelder, Russell N.

2015-01-01

Purpose The purpose of this study was to compare the histologic features and cytokine profiles of experimental autoimmune uveitis (EAU) and a primed mycobacterial uveitis (PMU) model in rats. Methods In Lewis rats, EAU was induced by immunization with interphotoreceptor binding protein peptide, and PMU was induced by immunization with a killed mycobacterial extract followed by intravitreal injection of the same extract. Clinical course, histology, and the cytokine profiles of the aqueous and vitreous were compared using multiplex bead fluorescence immunoassays. Results Primed mycobacterial uveitis generates inflammation 2 days after intravitreal injection and resolves spontaneously 14 days later. CD68+ lymphocytes are the predominant infiltrating cells and are found in the anterior chamber, surrounding the ciliary body and in the vitreous. In contrast to EAU, no choroidal infiltration or retinal destruction is noted. At the day of peak inflammation, C-X-C motif ligand 10 (CXCL10), IL-1β, IL-18, and leptin were induced in the aqueous of both models. Interleukin-6 was induced 2-fold in the aqueous of PMU but not EAU. Cytokines elevated in the aqueous of EAU exclusively include regulated on activation, normal T cell expressed and secreted (RANTES), lipopolysaccharide-induced CXC chemokine (LIX), growth-related oncogene/keratinocyte chemokine (GRO/KC), VEGF, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), and IL-17A. In the vitreous, CXCL10, GRO/KC, RANTES, and MIP-1α were elevated in both models. Interleukin-17A and IL-18 were elevated exclusively in EAU. Conclusions Primed mycobacterial uveitis generates an acute anterior and intermediate uveitis without retinal involvement. Primed mycobacterial uveitis has a distinct proinflammatory cytokine profile compared with EAU, suggesting PMU is a good complementary model for study of immune-mediated uveitis. CXCL10, a proinflammatory cytokine, was increased in the aqueous and vitreous of both models and may be a viable therapeutic target. PMID:26747775

Primed Mycobacterial Uveitis (PMU): Histologic and Cytokine Characterization of a Model of Uveitis in Rats.

PubMed

Pepple, Kathryn L; Rotkis, Lauren; Van Grol, Jennifer; Wilson, Leslie; Sandt, Angela; Lam, Deborah L; Carlson, Eric; Van Gelder, Russell N

2015-12-01

The purpose of this study was to compare the histologic features and cytokine profiles of experimental autoimmune uveitis (EAU) and a primed mycobacterial uveitis (PMU) model in rats. In Lewis rats, EAU was induced by immunization with interphotoreceptor binding protein peptide, and PMU was induced by immunization with a killed mycobacterial extract followed by intravitreal injection of the same extract. Clinical course, histology, and the cytokine profiles of the aqueous and vitreous were compared using multiplex bead fluorescence immunoassays. Primed mycobacterial uveitis generates inflammation 2 days after intravitreal injection and resolves spontaneously 14 days later. CD68+ lymphocytes are the predominant infiltrating cells and are found in the anterior chamber, surrounding the ciliary body and in the vitreous. In contrast to EAU, no choroidal infiltration or retinal destruction is noted. At the day of peak inflammation, C-X-C motif ligand 10 (CXCL10), IL-1β, IL-18, and leptin were induced in the aqueous of both models. Interleukin-6 was induced 2-fold in the aqueous of PMU but not EAU. Cytokines elevated in the aqueous of EAU exclusively include regulated on activation, normal T cell expressed and secreted (RANTES), lipopolysaccharide-induced CXC chemokine (LIX), growth-related oncogene/keratinocyte chemokine (GRO/KC), VEGF, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), and IL-17A. In the vitreous, CXCL10, GRO/KC, RANTES, and MIP-1α were elevated in both models. Interleukin-17A and IL-18 were elevated exclusively in EAU. Primed mycobacterial uveitis generates an acute anterior and intermediate uveitis without retinal involvement. Primed mycobacterial uveitis has a distinct proinflammatory cytokine profile compared with EAU, suggesting PMU is a good complementary model for study of immune-mediated uveitis. CXCL10, a proinflammatory cytokine, was increased in the aqueous and vitreous of both models and may be a viable therapeutic target.

Non-tuberculous mycobacterial bloodstream infections in patients with indwelling vascular catheters - the role of sickle cell anaemia.

PubMed

Edun, Babatunde; Shah, Ansal; Durkin, Martin; Whitmire, Melanie; Williams, Shanetta Patterson; Albrecht, Helmut; Al-Hasan, Majdi; Weissman, Sharon

2017-05-01

Few studies have examined risk factors for nontuberculous mycobacteria (NTM) bloodstream infections (BSI) involving indwelling vascular catheters (IDVC). Sickle cell anaemia (HbSS/SC) is known to affect several aspects of the immune system leading to relative immune deficiency. The purpose of this retrospective nested case-control study was to determine if HbSS/SC is a risk factor for NTM BSI among individuals with IDVCs. All NTM IDVC infections (cases) at two tertiary hospitals from 2008 to 2014 were reviewed. Cases were matched 2:1 with controls who had IDVC infections due to organisms other than NTM. Matching criteria included age within 10 years and IDVC infection within three months of index case. Logistic regression was used to identify risk factors for IDVC infection due to NTM. Nineteen NTM BSIs were identified. Three cases were excluded because they did not have IDVCs at the time their BSI was identified. Sixteen cases of NTM IDVC infection were matched to 32 controls with IDVC infections due to other organisms. The mean age of patients with IDVC infections was 48.5 years and 28 (58%) were male. Compared to the control group those with NTM BSI were more likely to have HbSS/SC 38% (6/16) versus 6% (2/32) (p = .006). IDVCs are a risk factor for NTM BSI. Sickle cell anaemia appears to be a risk factor for IDVC infections due to NTM. This study is limited by the small sample size. A larger study is needed to further investigate the association between HbSS/SC and NTM IDVC infections.

Cell wall lipids from Mycobacterium bovis BCG are inflammatory when inoculated within a gel matrix: characterization of a new model of the granulomatous response to mycobacterial components.

PubMed

Rhoades, Elizabeth R; Geisel, Rachel E; Butcher, Barbara A; McDonough, Sean; Russell, David G

2005-05-01

The chronic inflammatory response to Mycobacterium generates complex granulomatous lesions that balance containment with destruction of infected tissues. To study the contributing factors from host and pathogen, we developed a model wherein defined mycobacterial components and leukocytes are delivered in a gel, eliciting a localized response that can be retrieved and analysed. We validated the model by comparing responses to the cell wall lipids from Mycobacterium bovis bacillus Calmette-Guerin (BCG) to reported activities in other models. BCG lipid-coated beads and bone marrow-derived macrophages (input macrophages) were injected intraperitoneally into BALB/c mice. Input macrophages and recruited peritoneal exudate cells took up fluorescently tagged BCG lipids, and matrix-associated macrophages and neutrophils produced tumor necrosis factor, interleukin-1alpha, and interleukin-6. Leukocyte numbers and cytokine levels were greater in BCG lipid-bearing matrices than matrices containing non-coated or phosphatidylglycerol-coated beads. Leukocytes arrived in successive waves of neutrophils, macrophages and eosinophils, followed by NK and T cells (CD4(+), CD8(+), or gammadelta) at 7 days and B cells within 12 days. BCG lipids also predisposed matrices for adherence and vascularization, enhancing cellular recruitment. We submit that the matrix model presents pertinent features of the murine granulomatous response that will prove to be an adaptable method for study of this complex response.

Sustained elevated levels of C-reactive protein and ferritin in pulmonary tuberculosis patients remaining culture positive upon treatment initiation

PubMed Central

Oliveira, Marina G.; Mesquita, Eliene D. D.; Silva, Elisangela; Rauwerdink, Anneloek; Cobelens, Frank; Oliveira, Martha M.; Kritski, Afrânio

2017-01-01

Background Clinical trials that evaluate new anti-tubercular drugs and treatment regimens take years to complete due to the slow clearance of Mycobacterium tuberculosis infection and the lack of early biomarkers that predict treatment outcomes. Host Inflammation markers have been associated with tuberculosis (TB) pathogenesis. In the present study, we tested if circulating levels of C-reactive protein (CRP) and ferritin reflect mycobacterial loads and inflammation in pulmonary TB (PTB) patients undergoing anti-tuberculous therapy (ATT). Methods Prospective measurements of CRP and ferritin, used as readouts of systemic inflammation, were performed in cryopreserved serum samples from 165 Brazilian patients with active PTB initiating ATT. Associations between levels of these laboratory parameters with mycobacterial loads in sputum as well as with sputum conversion at day 60 of ATT were tested. Results Circulating levels of both ferritin and CRP gradually decreased over time on ATT. At pre-treatment, concentrations of these parameters were unable to distinguish patients with positive from those with negative acid-fast bacilli (AFB) in sputum cultures. However, patients who remained with positive cultures at day 60 of ATT exhibited heightened levels of these inflammatory markers compared to those with negative cultures at that time point. Conclusions CRP and Ferritin levels in serum may be useful to identify patients with positive cultures at day 60 of ATT. PMID:28384354

Targeting Mycobacterium tuberculosis Antigens to Dendritic Cells via the DC-Specific-ICAM3-Grabbing-Nonintegrin Receptor Induces Strong T-Helper 1 Immune Responses

PubMed Central

Velasquez, Lis Noelia; Stüve, Philipp; Gentilini, Maria Virginia; Swallow, Maxine; Bartel, Judith; Lycke, Nils Yngve; Barkan, Daniel; Martina, Mariana; Lujan, Hugo D.; Kalay, Hakan; van Kooyk, Yvette; Sparwasser, Tim D.; Berod, Luciana

2018-01-01

Tuberculosis remains a major global health problem and efforts to develop a more effective vaccine have been unsuccessful so far. Targeting antigens (Ags) to dendritic cells (DCs) in vivo has emerged as a new promising vaccine strategy. In this approach, Ags are delivered directly to DCs via antibodies that bind to endocytic cell-surface receptors. Here, we explored DC-specific-ICAM3-grabbing-nonintegrin (DC-SIGN) targeting as a potential vaccine against tuberculosis. For this, we made use of the hSIGN mouse model that expresses human DC-SIGN under the control of the murine CD11c promoter. We show that in vitro and in vivo delivery of anti-DC-SIGN antibodies conjugated to Ag85B and peptide 25 of Ag85B in combination with anti-CD40, the fungal cell wall component zymosan, and the cholera toxin-derived fusion protein CTA1-DD induces strong Ag-specific CD4+ T-cell responses. Improved anti-mycobacterial immunity was accompanied by increased frequencies of Ag-specific IFN-γ+ IL-2+ TNF-α+ polyfunctional CD4+ T cells in vaccinated mice compared with controls. Taken together, in this study we provide the proof of concept that the human DC-SIGN receptor can be efficiently exploited for vaccine purposes to promote immunity against mycobacterial infections. PMID:29662482

In situ analysis of lung antigen-presenting cells during murine pulmonary infection with virulent Mycobacterium tuberculosis

PubMed Central

Pedroza-González, Alexander; García-Romo, Gina S; Aguilar-León, Diana; Calderon-Amador, Juana; Hurtado-Ortiz, Raquel; Orozco-Estevez, Hector; Lambrecht, Bart N; Estrada-García, Iris; Hernández-Pando, Rogelio; Flores-Romo, Leopoldo

2004-01-01

Scarce information exists about the role of lung antigen-presenting cells (APCs) in vivo during pulmonary tuberculosis. As APCs activate cellular immunity, following intratracheal inoculation with virulent Mycobacterium tuberculosis, we assessed in situ lung APC recruitment, distribution, granuloma involvement, morphology and mycobacterial burden by using MHC-CII, CD14, scavenger receptor class A (SRA), the murine dendritic cell (DC)-restricted marker CD11c and Ziehl–Neelsen staining. CD11c+ DC and CD14+ cell recruitment into lungs appeared by day 14, continuing until day 60. MHC-CII+ cells increased since day 7, persisting until day 60. Thus, virulent mycobacteria delays (14–21 days) lung APC recruitment compared to model antigens and nonvirulent bacilli (24–48 h). Regarding granuloma constitution, highly bacillary CD14+ and SRA+ cells were centrally located. MHC-CII+ cells were more peripheral, with less mycobacteria. CD11c+ cells were heterogeneously distributed within granulomas, with scarce bacilli. When labelling lung suspensions for MHC-CII and classifying cells as macrophages or DC, then staining for Ziehl–Neelsen, a remarkable segregation was found regarding bacillary burden. Most macrophage-like cells contained numerous bacilli, while DC had no or scarce mycobacteria. This implies differential APC contributions in situ during pulmonary tuberculosis regarding mycobacterial uptake, granuloma involvement and perhaps bacillary growth. PMID:15255967

Molecular study on human tuberculosis in three geographically distinct and time delineated populations from ancient Egypt.

PubMed Central

Zink, A. R.; Grabner, W.; Reischl, U.; Wolf, H.; Nerlich, A. G.

2003-01-01

We describe the molecular identification of human tuberculosis (TB) from vertebral bone tissue samples from three different populations of ancient Egypt. The specimens were obtained from the predynastic to early dynastic necropolis of Abydos (7 individuals, c. 3500-2650 B.C.), from a Middle Kingdom to Second Intermediate Period tomb of the necropolis of Thebes-West (37. c. 2100-1550 B.C.) and from five further Theban tombs used in the New Kingdom and the Late Period (39, c. 1450-500 B.C.). A total of 18 cases tested positive for the presence of ancient DNA (aDNA) of the M. tuberculosis complex. Out of the 9 cases with typical macromorphological signs of tuberculous spondylitis, 6 were positive for mycobacterial aDNA (66.7%). Of 24 cases with non-specific pathological alterations, 5 provided a positive result (20.8%). In 50 cases of normally appearing vertebral bones 7 tested positive (14.0%). There were only minor differences in the frequencies between the three populations. These data strongly support the notion that tuberculosis was present and prevalent in ancient Egypt since very early periods of this civilization. The unexpectedly high rate of mycobacterial aDNA in normal bone samples is presumably due to a pre- to perimortal systemic spread of the bacteria and indicates a generalized infection by M. tuberculosis. PMID:12729192

Immunopathological evaluation of recombinant mycobacterial antigen Hsp65 expressed in Lactococcus lactis as a novel vaccine candidate

PubMed Central

Herrera Ramírez, J. C.; De la Mora, A. Ch.; De la Mora Valle, A.; Lopez-Valencia, G.; Hurtado, R. M. B.; Rentería Evangelista, T. B.; Rodríguez Castillo, J. L.; Rodríguez Gardea, A.; Gómez Gómez, S. D.; Medina-Basulto, G. E.

2017-01-01

Bovine tuberculosis (TBB) is a zoonotic disease distributed worldwide and is of great importance for public health and the livestock industry. Several experimental vaccines against this disease have been evaluated in recent years, yielding varying results. An example is the Bacillus Calmette-Guérin (BCG) vaccine, which has been used extensively in humans and tested in cattle showing mixed results related to protection (0-80%) against Mycobacterium bovis. In this study, we used the food-grade bacterium Lactococcus lactis as an expression system for production of mycobacterial protein Hsp65. For this purpose, the construction of a replicable plasmid in strain NZ9000 L. lactis (pVElepr) was conducted, which expressed the Mycobacterium leprae Hsp65 antigen, and was recognized by traded anti-Hsp65 antibodies. The strain NZ9000-pVElepr was applied to calves that were negative to tuberculin test and the immune response was monitored. The results showed that immune response was not significantly increased in calves with NZ9000-pVElepr with respect to control groups, and no injury was observed in any lung or lymph of the calves. Finally, this study suggest that the recombinant NZ9000 strain of L. lactis may protect against the development of M. bovis infection, although studies with longer exposure to this pathogen are necessary to conclude the matter. PMID:29163649

Normalised quantitative polymerase chain reaction for diagnosis of tuberculosis-associated uveitis.

PubMed

Barik, Manas Ranjan; Rath, Soveeta; Modi, Rohit; Rana, Rajkishori; Reddy, Mamatha M; Basu, Soumyava

2018-05-01

Polymerase chain reaction (PCR)-based diagnosis of tuberculosis-associated uveitis (TBU) in TB-endemic countries is challenging due to likelihood of latent mycobacterial infection in both immune and non-immune cells. In this study, we investigated normalised quantitative PCR (nqPCR) in ocular fluids (aqueous/vitreous) for diagnosis of TBU in a TB-endemic population. Mycobacterial copy numbers (mpb64 gene) were normalised to host genome copy numbers (RNAse P RNA component H1 [RPPH1] gene) in TBU (n = 16) and control (n = 13) samples (discovery cohort). The mpb64:RPPH1 ratios (normalised value) from each TBU and control sample were tested against the current reference standard i.e. clinically-diagnosed TBU, to generate Receiver Operating Characteristic (ROC) curves. The optimum cut-off value of mpb64:RPPH1 ratio (0.011) for diagnosing TBU was identified from the highest Youden index. This cut-off value was then tested in a different cohort of TBU and controls (validation cohort, 20 cases and 18 controls), where it yielded specificity, sensitivity and diagnostic accuracy of 94.4%, 85.0%, and 89.4% respectively. The above values for conventional quantitative PCR (≥1 copy of mpb64 per reaction) were 61.1%, 90.0%, and 74.3% respectively. Normalisation markedly improved the specificity and diagnostic accuracy of quantitative PCR for diagnosis of TBU. Copyright © 2018 Elsevier Ltd. All rights reserved.

Inorganic Phosphate Limitation Modulates Capsular Polysaccharide Composition in Mycobacteria.

PubMed

van de Weerd, Robert; Boot, Maikel; Maaskant, Janneke; Sparrius, Marion; Verboom, Theo; van Leeuwen, Lisanne M; Burggraaf, Maroeska J; Paauw, Nanne J; Dainese, Elisa; Manganelli, Riccardo; Bitter, Wilbert; Appelmelk, Ben J; Geurtsen, Jeroen

2016-05-27

Mycobacterium tuberculosis is protected by an unusual and highly impermeable cell envelope that is critically important for the successful colonization of the host. The outermost surface of this cell envelope is formed by capsular polysaccharides that play an important role in modulating the initial interactions once the bacillus enters the body. Although the bioenzymatic steps involved in the production of the capsular polysaccharides are emerging, information regarding the ability of the bacterium to modulate the composition of the capsule is still unknown. Here, we study the mechanisms involved in regulation of mycobacterial capsule biosynthesis using a high throughput screen for gene products involved in capsular α-glucan production. Utilizing this approach we identified a group of mutants that all carried mutations in the ATP-binding cassette phosphate transport locus pst These mutants collectively exhibited a strong overproduction of capsular polysaccharides, including α-glucan and arabinomannan, suggestive of a role for inorganic phosphate (Pi) metabolism in modulating capsular polysaccharide production. These findings were corroborated by the observation that growth under low Pi conditions as well as chemical activation of the stringent response induces capsule production in a number of mycobacterial species. This induction is, in part, dependent on σ factor E. Finally, we show that Mycobacterium marinum, a model organism for M. tuberculosis, encounters Pi stress during infection, which shows the relevance of our findings in vivo. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Prevalence of Nontuberculous Mycobacterial Pulmonary Disease, Germany, 2009–2014

PubMed Central

Wagner, Dirk; de Roux, Andrés; Diel, Roland; Hohmann, David; Hickstein, Lennart; Welte, Tobias; Rademacher, Jessica

2016-01-01

We analyzed routine statutory health insurance claim data to determine prevalence of nontuberculous mycobacterial pulmonary disease in Germany. Documented prevalence rates of this nonnotifiable disease increased from 2.3 to 3.3 cases/100,000 population from 2009 to 2014. Prevalence showed a strong association with advanced age and chronic obstructive pulmonary disease. PMID:27191473

Outbreak of a cutaneous Mycobacterium marinum infection in Jiangsu Haian, China.

PubMed

Feng, Yumiao; Xu, Huaisheng; Wang, Hongsheng; Zhang, Caiping; Zong, Wenkai; Wu, Qinxue

2011-11-01

Mycobacterium marinum is a slow-growing mycobacterium. In November 2008, we diagnosed a patient with M. marinum infection who worked at a fish farm in Jiangsu Haian, China. We conducted an investigation and found 18 patients with the same infection. In suspected cases, complete data were collected including medical history, clinical manifestations, laboratory features, and responses to treatment. Therapeutic regimens, including clarithromycin monotherapy or combined treatment with clarithromycin, rifampicin, and ethambutol, were prescribed. A total of 18 patients with M. marinum infection were found. All patients showed only skin lesions. Biopsies were performed and 16 patients showed infective granulomas. Acid-fast bacilli stain (Ziehl-Neelson stain) for cutaneous samples were positive in 7 patients. Ten patients were positive in purified protein derivative tests (tubercles were ≥10 mm in diameter). In 16 patients, colonies grew after tissue samples were incubated on Löwenstein-Jensen medium at 32 °C. All the isolates were identified as M. marinum by polymerase chain reaction-restriction fragment length polymorphism analysis, by direct gene sequencing, and by genotyping using mycobacterial interspersed repetitive units. Fifteen of the 18 patients were cured using clarithromycin-containing antibiotic regimens. The history of contact with fish and aquaria plays an important role in diagnosis. Clarithromycin-containing regimens were successful in most patients with M. marinum infections limited to the skin. Copyright © 2011 Elsevier Inc. All rights reserved.

Evidence of a pro-apoptotic effect of specific antibodies in a bovine macrophage model of infection with Mycobacterium avium subsp. paratuberculosis.

PubMed

Jolly, Ana; Lompardía, Silvina; Hajos, Silvia E; Mundo, Silvia L

2016-01-01

Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent of Johne's disease (JD), a chronic granulomatous enteritis in ruminants. Understanding the protective immune response following infection is crucial to improve the diagnosis and the development of vaccines against this disease. The goal of this work was to assess whether specific antibodies were able to modulate the macrophage response to MAP infection by evaluating apoptosis and TNF-α secretion in an in vitro model. Sera from healthy (n=2), MAP-infected (n=3) and lipoarabinomannan (LAM)-immunized (n=3) bovines were evaluated. LAM was chosen as immunogen due to its relevant role in mycobacterial pathogenesis. We demonstrated by two different techniques (Acridine Orange/Ethidium Bromide microscopy and Annexin V/7-Amino-Actinomycin D flow cytometry) that the immune sera from both, MAP-infected and LAM-immunized bovines, significantly increased macrophage apoptosis in infected cultures. Comparable levels of apoptosis were detected when MAP was pre-incubated with purified specific antibodies instead of whole serum. Furthermore, this effect was accompanied by a significantly higher secretion of TNF-α. These results strongly suggest that specific antibodies could limit the impact of MAP on the apoptosis of bovine cells. This work would contribute to elucidate the role of the specific antibody response in bovine JD and its prevention. Copyright © 2015 Elsevier B.V. All rights reserved.

Pseudo-outbreak of septicemia due to rapidly growing mycobacteria associated with extrinsic contamination of culture supplement.

PubMed Central

Ashford, D A; Kellerman, S; Yakrus, M; Brim, S; Good, R C; Finelli, L; Jarvis, W R; McNeil, M M

1997-01-01

Between April and December 1994, 23 blood cultures from human immunodeficiency virus-infected patients grew rapidly growing mycobacteria suspected to be Mycobacterium chelonae at a hospital in New Jersey. The isolates were later identified as M. abscessus. Several bacterial species, including M. abscessus, were cultured from an opened multidose supplement vial (BBL Septi-Chek AFB Supplement) that had been used for mycobacterial blood cultures. The M. abscessus isolates from case patients and the supplement vial had identical multilocus enzyme electrophoresis and antimicrobial susceptibility patterns. Finding a contaminated vial of supplement, together with the lack of a distinct syndrome in case patients, was consistent with a pseudo-outbreak. PMID:9230377

Intradermal tuberculin testing of wild African lions (Panthera leo) naturally exposed to infection with Mycobacterium bovis.

PubMed

Keet, D F; Michel, A L; Bengis, R G; Becker, P; van Dyk, D S; van Vuuren, M; Rutten, V P M G; Penzhorn, B L

2010-08-26

African lions in the southern half of Kruger National Park (KNP) are infected with Mycobacterium bovis. Historically, reliable detection of mycobacteriosis in lions was limited to necropsy and microbiological analysis of lesion material collected from emaciated and ailing or repeat-offender lions. We report on a method of cervical intradermal tuberculin testing of lions and its interpretation capable of identifying natural exposure to M. bovis. Infected lions (n=52/95) were identified by detailed necropsy and mycobacterial culture. A large proportion of these confirmed infected lions (45/52) showed distinct responses to bovine tuberculin purified protein derivative (PPD) while responses to avian tuberculin PPD were variable and smaller. Confirmed uninfected lions from non-infected areas (n=11) responded variably to avian tuberculin PPD only. Various non-tuberculous mycobacteria (NTM) were cultured from 45/95 lions examined, of which 21/45 were co-infected with M. bovis. Co-infection with M. bovis and NTM did not influence skin reactions to bovine tuberculin PPD. Avian tuberculin PPD skin reactions were larger in M. bovis-infected lions compared to uninfected ones. Since NTM co-infections are likely to influence the outcome of skin testing, stricter test interpretation criteria were applied. When test data of bovine tuberculin PPD tests were considered on their own, as for a single skin test, sensitivity increased (80.8-86.5%) but false positive rate for true negatives (18.75%) remained unchanged. Finally, the adapted skin test procedure was shown not to be impeded by persistent Feline Immunodeficiency Virus(Ple) co-infection. Copyright 2010 Elsevier B.V. All rights reserved.

An investigation on the population structure of mixed infections of Mycobacterium tuberculosis in Inner Mongolia, China.

PubMed

Wang, Xiaoying; Liu, Haican; Wei, Jianhao; Wu, Xiaocui; Yu, Qin; Zhao, Xiuqin; Lyu, Jianxin; Lou, Yongliang; Wan, Kanglin

2015-12-01

Mixed infections of Mycobacterium tuberculosis strains have attracted more attention due to their increasing frequencies worldwide, especially in the areas of high tuberculosis (TB) prevalence. In this study, we accessed the rates of mixed infections in a setting with high TB prevalence in Inner Mongolia Autonomous Region of China. A total of 384 M. tuberculosis isolates from the local TB hospital were subjected to mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing method. The single clones of the strains with mixed infections were separated by subculturing them on the Löwenstein-Jensen medium. Of these 384 isolates, twelve strains (3.13%) were identified as mixed infections by MIRU-VNTR. Statistical analysis indicated that demographic characteristics and drug susceptibility profiles showed no statistically significant association with the mixed infections. We further subcultured the mixed infection strains and selected 30 clones from the subculture for each mixed infection. Genotyping data revealed that eight (8/12, 66.7%) strains with mixed infections had converted into single infection through subculture. The higher growth rate was associated with the increasing proportion of variant subpopulation through subculture. In conclusion, by using the MIRU-VNTR method, we demonstrate that the prevalence of mixed infections in Inner Mongolia is low. Additionally, our findings reveal that the subculture changes the population structures of mixed infections, and the subpopulation with higher growth rate show better fitness, which is associated with high proportion among the population structure after subculture. This study highlights that the use of clinical specimens, rather than subcultured isolates, is preferred to estimate the prevalence of mixed infections in the specific regions. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cervical ankylosis following Grisel's syndrome in a 14-year-old boy with infectious mononucleosis.

PubMed

Haidar, Salwa; Drake, James; Armstrong, Derek

2005-03-01

Non-traumatic atlanto-axial subluxation (Grisel's syndrome) is an uncommon complication of neck space infection or otolaryngologic procedures. It most frequently affects children, although it may occur in adults. We present a 14-year-old boy with Grisel's syndrome as a complication of infectious mononucleosis proceeding to cervical ankylosis.

First isolation of the Stephanoascus ciferrii in feline otitis in Brazil.

PubMed

Gomes, Angelita dos Reis; Cabana, Ângela Leitzke; Osório, Luiza da Gama; Santin, Rosema; Schuch, Isabel Duarte; Serra, Emanoele Figueiredo; Nascente, Patrícia Silva; Meireles, Mário Carlos Araújo

2014-01-01

Ear infections in cats are uncommon, especially involving yeasts. This report describes the first isolation of the Stephanoascus ciferrii, teleomorph of the Candida genus, in a case of feline otitis in Brazil. The identification and characterization of Stephanoascus ciferrii were confirmed by the Vitek2 System (BioMerieux ®).

Acute urinary retention attributable to sacral herpes zoster.

PubMed

Acheson, J; Mudd, D

2004-11-01

Acute urinary retention in women is uncommon. A 63 year old woman presented with suprapubic pain, a palpable bladder, and multiple grouped vesicles on the right buttock. Catheterisation showed a residual of 2000 ml. A case is reported of acute urinary retention secondary to herpes zoster infection of the sacral nerves (S2-4).

Anterior urethral valves: an uncommon cause of obstructive uropathy in children.

PubMed

Kibar, Yusuf; Coban, Hidayet; Irkilata, H Cem; Erdemir, Fikret; Seckin, Bedrettin; Dayanc, Murat

2007-10-01

Anterior urethral valves (AUV) are rare entities generally described in case reports. They are an uncommon cause of lower urinary tract obstruction in children and can be difficult to diagnose. In the present study, we present our experience in four children with AUV along with a literature review. We retrospectively identified four children with AUV presented between 1998 and 2005 at age 4-9 years. Hematuria, urinary tract infection and weak voiding stream were the most common symptoms. Voiding cystourethrography (VCUG) confirmed the diagnosis of AUV. On cystourethroscopy, cusp-like valves in the anterior urethra were seen in all children. Transurethral endoscopic resection of the valves was carried out in three children using a pediatric resectoscope. In one child with a massive anterior urethral diverticulum, open resection of the valve, diverticulectomy and urethroplasty were performed. All patients were cured, none had complications as a result of surgery, and all reported a normal urinary stream at follow-up. Children with poor stream and recurrent infections should be evaluated carefully and anterior urethral valves should be considered in differential diagnosis of obstructive lesions.

Sinus of Valsalva Pseudoaneurysm as a Sequela to Infective Endocarditis.

PubMed

Lee, Chin C; Siegel, Robert J

2016-02-01

Pseudoaneurysm is an uncommon sequela of infective endocarditis. We treated a 44-year-old man who had an active case of group B streptococcal infective endocarditis of the aortic valve despite no evidence of valvular dysfunction or vegetation on his initial transesophageal echocardiogram. After completing 6 weeks of intravenous antibiotic therapy, the patient developed a sinus of Valsalva pseudoaneurysm and severe aortic regurgitation caused by partial detachment of the left coronary cusp. We used a pericardial patch to close the pseudoaneurysm and repair the coronary cusp. This case shows the importance of routine clinical follow-up evaluation in infective endocarditis, even after completion of antibiotic therapy. Late sequelae associated with infective endocarditis or its therapy include recurrent infection, heart failure caused by valvular dysfunction (albeit delayed), and antibiotic toxicity such as aminoglycoside-induced nephropathy and vestibular toxicity.

Disseminated Herpes Zoster Ophthalmicus in an Immunocompetent 8-Year Old Boy

PubMed Central

Oladokun, Regina Eziuka; Olomukoro, Chikodili N; Owa, Adewale B.

2013-01-01

Varicella results from a primary infection with the varicella virus while herpes zoster is caused by a reactivation of a latent infection. Dissemination of herpes zoster is uncommon in immunocompetent individuals. Reports of disseminated herpes zoster in children are even less common than in adults. An unusual case of disseminated herpes zoster ophthalmicus in an 8-year old immunocompetent black boy is presented. He had a previous primary Varicella zoster virus infection at three years of age. In the current report, he presented during an on-going chicken pox outbreak and survived with no significant complications. A breakthrough varicella virus re-infection or a reactivation is possible, both of which could present as zoster. This case emphasizes the need for prevention of varicella virus infection through universal childhood immunization and effective infection control strategies in health care settings. PMID:24765504

Disseminated herpes zoster ophthalmicus in an immunocompetent 8-year old boy.

PubMed

Oladokun, Regina Eziuka; Olomukoro, Chikodili N; Owa, Adewale B

2013-08-02

Varicella results from a primary infection with the varicella virus while herpes zoster is caused by a reactivation of a latent infection. Dissemination of herpes zoster is uncommon in immunocompetent individuals. Reports of disseminated herpes zoster in children are even less common than in adults. An unusual case of disseminated herpes zoster ophthalmicus in an 8-year old immunocompetent black boy is presented. He had a previous primary Varicella zoster virus infection at three years of age. In the current report, he presented during an on-going chicken pox outbreak and survived with no significant complications. A breakthrough varicella virus re-infection or a reactivation is possible, both of which could present as zoster. This case emphasizes the need for prevention of varicella virus infection through universal childhood immunization and effective infection control strategies in health care settings.

Vancomycin-resistant Enterococcus in pediatric oncology patients: balancing infection prevention and family-centered care.

PubMed

Singh, Jasjit; Esparza, Samuel; Patterson, Melanie; Vogel, Kate; Patel, Bijal; Gornick, Wendi

2013-04-01

In February 2007, we experienced an abrupt 8-fold increase in vancomycin-resistant Enterococcus (VRE)-positive pediatric hematology/oncology patients in isolation per day, peaking at 12 patients in isolation per day in June 2007. We enforced and expanded infection prevention practices and initiated a rigorous 6-month clearance process. After noting an eventual decrease, we modified clearance to a 3-month process, maintaining <1 patient/day in isolation by June 2009, subjectively improving family and staff satisfaction after this 2-year process. VRE infection was relatively uncommon (7.8%), although continued VRE colonization portended an overall poorer prognosis.