Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection.

PubMed

Cantone, Martina; Santos, Guido; Wentker, Pia; Lai, Xin; Vera, Julio

2017-01-01

Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung.

M-CSF Mediates Host Defense during Bacterial Pneumonia by Promoting the Survival of Lung and Liver Mononuclear Phagocytes.

PubMed

Bettina, Alexandra; Zhang, Zhimin; Michels, Kathryn; Cagnina, R Elaine; Vincent, Isaah S; Burdick, Marie D; Kadl, Alexandra; Mehrad, Borna

2016-06-15

Gram-negative bacterial pneumonia is a common and dangerous infection with diminishing treatment options due to increasing antibiotic resistance among causal pathogens. The mononuclear phagocyte system is a heterogeneous group of leukocytes composed of tissue-resident macrophages, dendritic cells, and monocyte-derived cells that are critical in defense against pneumonia, but mechanisms that regulate their maintenance and function during infection are poorly defined. M-CSF has myriad effects on mononuclear phagocytes but its role in pneumonia is unknown. We therefore tested the hypothesis that M-CSF is required for mononuclear phagocyte-mediated host defenses during bacterial pneumonia in a murine model of infection. Genetic deletion or immunoneutralization of M-CSF resulted in reduced survival, increased bacterial burden, and greater lung injury. M-CSF was necessary for the expansion of lung mononuclear phagocytes during infection but did not affect the number of bone marrow or blood monocytes, proliferation of precursors, or recruitment of leukocytes to the lungs. In contrast, M-CSF was essential to survival and antimicrobial functions of both lung and liver mononuclear phagocytes during pneumonia, and its absence resulted in bacterial dissemination to the liver and hepatic necrosis. We conclude that M-CSF is critical to host defenses against bacterial pneumonia by mediating survival and antimicrobial functions of mononuclear phagocytes in the lungs and liver. Copyright © 2016 by The American Association of Immunologists, Inc.

M-CSF mediates host defense during bacterial pneumonia by promoting the survival of lung and liver mononuclear phagocytes

PubMed Central

Bettina, Alexandra; Zhang, Zhimin; Michels, Kathryn; Cagnina, R. Elaine; Vincent, Isaah S.; Burdick, Marie D.; Kadl, Alexandra; Mehrad, Borna

2016-01-01

Gram-negative bacterial pneumonia is a common and dangerous infection with diminishing treatment options due to increasing antibiotic resistance among causal pathogens. The mononuclear phagocyte system is a heterogeneous group of leukocytes composed of tissue-resident macrophages, dendritic cells and monocyte-derived cells that are critical in defense against pneumonia, but mechanisms that regulate their maintenance and function during infection are poorly defined. Macrophage-colony stimulating factor (M-CSF) has myriad effects on mononuclear phagocytes but its role in pneumonia is unknown. We therefore tested the hypothesis that M-CSF is required for mononuclear phagocyte-mediated host defenses during bacterial pneumonia in a murine model of infection. Genetic deletion or immunoneutralization of M-CSF resulted in reduced survival, increased bacterial burden and greater lung injury. M-CSF was necessary for the expansion of lung mononuclear phagocytes during infection but did not affect the number of bone marrow or blood monocytes, the proliferation of precursors or the recruitment of leukocytes to the lungs. In contrast, M-CSF was essential to survival and anti-microbial functions of both lung and liver mononuclear phagocytes during pneumonia and its absence resulted in bacterial dissemination to the liver and hepatic necrosis. We conclude that M-CSF is critical to host defenses against bacterial pneumonia by mediating survival and anti-microbial functions of mononuclear phagocytes in the lungs and liver. PMID:27183631

Bacterial infection and acute lung injury in hamsters.

PubMed

Seidenfeld, J J; Mullins, R C; Fowler, S R; Johanson, W G

1986-07-01

Bacterial pneumonia is a common complication of lung injury that can be an important determinant of outcome. We studied experimental lung injury produced in hamsters by injecting 20 mg/kg paraquat (PQ) intraperitoneally; control animals received saline vehicle. Three days later, Pseudomonas aeruginosa (PAO1), 10(8) organisms in 0.25 ml, or saline, 0.25 ml, was inoculated intratracheally. Lung and systemic antibacterial defenses were studied at death 24 h later. Paraquat alone produced focal interstitial pneumonitis and neutrophilic alveolitis, and resulted in a 12% (3 of 26) mortality. PAO1 alone caused focal pneumonias and no deaths. Animals receiving both agents (PAO1/PQ) had extensive diffuse alveolar damage characterized by alveolar hemorrhage, edema, influx of neutrophils, and vasculitis; 50% (16 of 32) died within 96 h of PQ injection. Mean lung counts of PAO1 at death were 7.6 X 10(4) colony forming units/g in PAO1 and 2.8 X 10(7) in PAO1/PQ animals (p less than 0.05). PAO1 colony counts in liver were increased nearly 100-fold in PAO1/PQ animals (p less than 0.05). Half-time of clearance of P. aeruginosa from the blood was prolonged in PAO1 and in PAO1/PQ animals (p less than 0.05) but not in PQ animals. Phagocytosis of Staphylococcus aureus by leukocytes lavaged from the lung was not impaired in any group compared with that in control animals, but intracellular killing was impaired in PAO1 and PAO1/PQ but not in PQ animals. Paraquat injury impairs lung antibacterial defenses by uncertain mechanisms. Superinfection of PQ-injured lungs by PAO1 appears responsible for defects in intrapulmonary and systemic antibacterial defenses.

Bacterial infection imaging with [18F]fluoropropyl-trimethoprim

PubMed Central

Lee, Iljung; Hou, Catherine; Weng, Chi-Chang; Li, Shihong; Lieberman, Brian P.; Zeng, Chenbo; Mankoff, David A.; Mach, Robert H.

2017-01-01

There is often overlap in the diagnostic features of common pathologic processes such as infection, sterile inflammation, and cancer both clinically and using conventional imaging techniques. Here, we report the development of a positron emission tomography probe for live bacterial infection based on the small-molecule antibiotic trimethoprim (TMP). [18F]fluoropropyl-trimethoprim, or [18F]FPTMP, shows a greater than 100-fold increased uptake in vitro in live bacteria (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa) relative to controls. In a rodent myositis model, [18F]FPTMP identified live bacterial infection without demonstrating confounding increased signal in the same animal from other etiologies including chemical inflammation (turpentine) and cancer (breast carcinoma). Additionally, the biodistribution of [18F]FPTMP in a nonhuman primate shows low background in many important tissues that may be sites of infection such as the lungs and soft tissues. These results suggest that [18F]FPTMP could be a broadly useful agent for the sensitive and specific imaging of bacterial infection with strong translational potential. PMID:28716936

PPARγ in Bacterial Infections: A Friend or Foe?

PubMed

Reddy, Aravind T; Lakshmi, Sowmya P; Reddy, Raju C

2016-01-01

Peroxisome proliferator-activated receptor γ (PPAR γ ) is now recognized as an important modulator of leukocyte inflammatory responses and function. Its immunoregulatory function has been studied in a variety of contexts, including bacterial infections of the lungs and central nervous system, sepsis, and conditions such as chronic granulomatous disease. Although it is generally believed that PPAR γ activation is beneficial for the host during bacterial infections via its anti-inflammatory and antibacterial properties, PPAR γ agonists have also been shown to dampen the host immune response and in some cases exacerbate infection by promoting leukocyte apoptosis and interfering with leukocyte migration and infiltration. In this review we discuss the role of PPAR γ and its activation during bacterial infections, with focus on the potential of PPAR γ agonists and perhaps antagonists as novel therapeutic modalities. We conclude that adjustment in the dosage and timing of PPAR γ agonist administration, based on the competence of host antimicrobial defenses and the extent of inflammatory response and tissue injury, is critical for achieving the essential balance between pro- and anti-inflammatory effects on the immune system.

PPARγ in Bacterial Infections: A Friend or Foe?

PubMed Central

2016-01-01

Peroxisome proliferator-activated receptor γ (PPARγ) is now recognized as an important modulator of leukocyte inflammatory responses and function. Its immunoregulatory function has been studied in a variety of contexts, including bacterial infections of the lungs and central nervous system, sepsis, and conditions such as chronic granulomatous disease. Although it is generally believed that PPARγ activation is beneficial for the host during bacterial infections via its anti-inflammatory and antibacterial properties, PPARγ agonists have also been shown to dampen the host immune response and in some cases exacerbate infection by promoting leukocyte apoptosis and interfering with leukocyte migration and infiltration. In this review we discuss the role of PPARγ and its activation during bacterial infections, with focus on the potential of PPARγ agonists and perhaps antagonists as novel therapeutic modalities. We conclude that adjustment in the dosage and timing of PPARγ agonist administration, based on the competence of host antimicrobial defenses and the extent of inflammatory response and tissue injury, is critical for achieving the essential balance between pro- and anti-inflammatory effects on the immune system. PMID:27774097

Bacterial infection profiles in lung cancer patients with febrile neutropenia.

PubMed

Lanoix, Jean-Philippe; Pluquet, Emilie; Lescure, Francois Xavier; Bentayeb, Houcine; Lecuyer, Emmanuelle; Boutemy, Marie; Dumont, Patrick; Jounieaux, Vincent; Schmit, Jean Luc; Dayen, Charles; Douadi, Youcef

2011-06-27

The chemotherapy used to treat lung cancer causes febrile neutropenia in 10 to 40% of patients. Although most episodes are of undetermined origin, an infectious etiology can be suspected in 30% of cases. In view of the scarcity of data on lung cancer patients with febrile neutropenia, we performed a retrospective study of the microbiological characteristics of cases recorded in three medical centers in the Picardy region of northern France. We analyzed the medical records of lung cancer patients with neutropenia (neutrophil count < 500/mm(3)) and fever (temperature > 38.3°C). The study included 87 lung cancer patients with febrile neutropenia (mean age: 64.2). Two thirds of the patients had metastases and half had poor performance status. Thirty-three of the 87 cases were microbiologically documented. Gram-negative bacteria (mainly enterobacteriaceae from the urinary and digestive tracts) were identified in 59% of these cases. Staphylococcus species (mainly S. aureus) accounted for a high proportion of the identified Gram-positive bacteria. Bacteremia accounted for 60% of the microbiologically documented cases of fever. 23% of the blood cultures were positive. 14% of the infections were probably hospital-acquired and 14% were caused by multidrug-resistant strains. The overall mortality rate at day 30 was 33% and the infection-related mortality rate was 16.1%. Treatment with antibiotics was successful in 82.8% of cases. In a multivariate analysis, predictive factors for treatment failure were age >60 and thrombocytopenia < 20000/mm(3). Gram-negative species were the most frequently identified bacteria in lung cancer patients with febrile neutropenia. Despite the success of antibiotic treatment and a low-risk neutropenic patient group, mortality is high in this particular population.

[Tobacco smoke and risk of bacterial infection].

PubMed

Trosini-Desert, V; Germaud, P; Dautzenberg, B

2004-06-01

Tobacco smoke is a proven risk factor for bacterial infection. In adults without COPD, smoking is associated with a significant increase in the relative risk (RR) of pneumonia (RR=2.97; 95% CI 1.52-5.81), S pneumoniae pneumonia (RR=2.50; 95% IC 1.50-5.10), Legionella infection (RR=3.75; 95% CI 2.17-6.17). Smoking has clearly been shown to be associated with an increased risk of tuberculosis (RR=2.60; 95% CI 2,20-3,20), and also with increased incidence of post-operative infections. In young children whose parents smoke, passive exposure to tobacco smoke is associated with an increased relative risk of seasonal infections (RR=1.7; CI 95% 1.55-1.91) and recurrent otitis media (RR=1.48; 95% CI 1.08-2.04). Passive smoking also increases risk of pneumonia in adults (RR=2.5; CI 95% 1.2-5.1). Plausible explanations of the increased risk of infection in active or passive smokers include increased bacterial adherence, decrease of lung and nasal clearance, and changes in the immune response. Exposure to tobacco smoke approximately doubles the risk of infection. This increased burden of infection has significant healthcare cost implications. Each infectious episode in an individual should prompt an attempt at smoking cessation.

Bacterial infection profiles in lung cancer patients with febrile neutropenia

PubMed Central

2011-01-01

Background The chemotherapy used to treat lung cancer causes febrile neutropenia in 10 to 40% of patients. Although most episodes are of undetermined origin, an infectious etiology can be suspected in 30% of cases. In view of the scarcity of data on lung cancer patients with febrile neutropenia, we performed a retrospective study of the microbiological characteristics of cases recorded in three medical centers in the Picardy region of northern France. Methods We analyzed the medical records of lung cancer patients with neutropenia (neutrophil count < 500/mm3) and fever (temperature > 38.3°C). Results The study included 87 lung cancer patients with febrile neutropenia (mean age: 64.2). Two thirds of the patients had metastases and half had poor performance status. Thirty-three of the 87 cases were microbiologically documented. Gram-negative bacteria (mainly enterobacteriaceae from the urinary and digestive tracts) were identified in 59% of these cases. Staphylococcus species (mainly S. aureus) accounted for a high proportion of the identified Gram-positive bacteria. Bacteremia accounted for 60% of the microbiologically documented cases of fever. 23% of the blood cultures were positive. 14% of the infections were probably hospital-acquired and 14% were caused by multidrug-resistant strains. The overall mortality rate at day 30 was 33% and the infection-related mortality rate was 16.1%. Treatment with antibiotics was successful in 82.8% of cases. In a multivariate analysis, predictive factors for treatment failure were age >60 and thrombocytopenia < 20000/mm3. Conclusion Gram-negative species were the most frequently identified bacteria in lung cancer patients with febrile neutropenia. Despite the success of antibiotic treatment and a low-risk neutropenic patient group, mortality is high in this particular population. PMID:21707992

STAT1-Regulated Lung MDSC-like Cells Produce IL-10 and Efferocytose Apoptotic Neutrophils With Relevance In Resolution of Bacterial Pneumonia

PubMed Central

Poe, Stephanie L.; Arora, Meenakshi; Oriss, Timothy B.; Yarlagadda, Manohar; Isse, Kumiko; Khare, Anupriya; Levy, David E.; Lee, Janet S.; Mallampalli, Rama; Ray, Anuradha; Ray, Prabir

2012-01-01

Bacterial pneumonia remains a significant burden worldwide. Although an inflammatory response in the lung is required to fight the causative agent, persistent tissue-resident neutrophils in non-resolving pneumonia can induce collateral tissue damage and precipitate acute lung injury. However, little is known about mechanisms orchestrated in the lung tissue that remove apoptotic neutrophils to restore tissue homeostasis. In mice infected with Klebsiella pneumoniae, a bacterium commonly associated with hospital-acquired pneumonia, we show that interleukin-10 is essential for resolution of lung inflammation and recovery of mice after infection. Although IL-10−/− mice cleared bacteria, they displayed increased morbidity with progressive weight loss and persistent lung inflammation in the later phase after infection. A source of tissue IL-10 was found to be resident CD11b+Gr1intF4/80+ cells resembling myeloid-derived suppressor cells that appeared with a delayed kinetics after infection. These cells efficiently efferocytosed apoptotic neutrophils, which was aided by IL-10. The lung neutrophil burden was attenuated in infected STAT1−/− mice with concomitant increase in the frequency of the MDSC-like cells and lung IL-10 levels. Thus, inhibiting STAT1 in combination with antibiotics may be a novel therapeutic strategy to address inefficient resolution of bacterial pneumonia. PMID:22785228

Bacterial infections after pediatric heart transplantation: Epidemiology, risk factors and outcomes.

PubMed

Rostad, Christina A; Wehrheim, Karla; Kirklin, James K; Naftel, David; Pruitt, Elizabeth; Hoffman, Timothy M; L'Ecuyer, Thomas; Berkowitz, Katie; Mahle, William T; Scheel, Janet N

2017-09-01

Bacterial infections represent a major cause of morbidity and mortality in heart transplant recipients. However, data describing the epidemiology and outcomes of these infections in children are limited. We analyzed the Pediatric Heart Transplant Study database of patients transplanted between 1993 and 2014 to determine the etiologies, risk factors and outcomes of children with bacterial infections post-heart transplantation. Of 4,458 primary transplants in the database, there were 4,815 infections that required hospitalization or intravenous therapy, 2,047 (42.51%) of which were bacterial. The risk of bacterial infection was highest in the first month post-transplant, and the bloodstream was the most common site (24.82%). In the early post-transplant period (<30 days post-transplant), coagulase-negative staphylococci were the most common pathogens (16.97%), followed by Enterobacter sp (11.99%) and Pseudomonas sp (11.62%). In the late post-transplant period, community-acquired pathogens Streptococcus pneumoniae (6.27%) and Haemophilus influenzae (2.82%) were also commonly identified. Patients' characteristics independently associated with acquisition of bacterial infection included younger age (p < 0.0001) and ventilator (p < 0.0001) or extracorporeal membrane oxygenation (p = 0.03) use at time of transplant. Overall mortality post-bacterial infection was 33.78%, and previous cardiac surgery (p < 0.001) and multiple sites of infection (p = 0.004) were independent predictors of death. Bacteria were the most common causes of severe infections in pediatric heart transplant recipients and were associated with high mortality rates. The risk of acquiring a bacterial infection was highest in the first month post-transplant, and a large proportion of the infections were caused by multidrug-resistant pathogens. Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Superficial herpes simplex virus wound infection following lung transplantation.

PubMed

Karolak, Wojtek; Wojarski, Jacek; Zegleń, Sławomir; Ochman, Marek; Urlik, Maciej; Hudzik, Bartosz; Wozniak-Grygiel, Elzbieta; Maruszewski, Marcin

2017-08-01

Surgical site infections (SSIs) are infections of tissues, organs, or spaces exposed by surgeons during performance of an invasive procedure. SSIs are classified into superficial, which are limited to skin and subcutaneous tissues, and deep. The incidence of deep SSIs in lung transplant (LTx) patients is estimated at 5%. No reports have been published as to the incidence of superficial SSIs specifically in LTx patients. Common sense would dictate that the majority of superficial SSIs would be bacterial. Uncommonly, fungal SSIs may occur, and we believe that no reports exist as to the incidence of viral wound infections in LTx patients, or in any solid organ transplant patients. We report a de novo superficial wound infection with herpes simplex virus following lung transplantation, its possible source, treatment, and resolution. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The innate immune rheostat: influence on lung inflammatory disease and secondary bacterial pneumonia.

PubMed

Hussell, Tracy; Cavanagh, Mary M

2009-08-01

The activity of innate immunity is not simply dictated by the presence of an antigen but also by the balance between negative regulatory and immune potentiator pathways. Even in the absence of antigen, innate immunity can 'inflame' if negative regulators are absent. This resting state is adaptable and dictated by environmental influences, host genetics and past infection history. A return to homoeostasis post inflammation may therefore not leave the tissue in an identical state to that prior to the inflammatory event. This adaptability makes us all unique and also explains the variable outcome experienced by a diverse population to the same inflammatory stimulus. Using murine models we have identified that influenza virus causes a long-term modification of the lung microenvironment by a de-sensitization to bacterial products and an increase in the myeloid negative regulator CD200R (CD200 receptor). These two events prevent subsequent inflammatory damage while the lung is healing, but also they may predispose to bacterial colonization of the lower respiratory tract should regulatory mechanisms overshoot. In the extreme, this leads to bacterial pneumonia, sepsis and death. A deeper understanding of the consequences arising from innate immune cell alteration during influenza infection and the subsequent development of bacterial complications has important implications for future drug development.

Antibiotic management of lung infections in cystic fibrosis. II. Nontuberculous mycobacteria, anaerobic bacteria, and fungi.

PubMed

Chmiel, James F; Aksamit, Timothy R; Chotirmall, Sanjay H; Dasenbrook, Elliott C; Elborn, J Stuart; LiPuma, John J; Ranganathan, Sarath C; Waters, Valerie J; Ratjen, Felix A

2014-10-01

Airway infections are a key component of cystic fibrosis (CF) lung disease. Whereas the approach to common pathogens such as Pseudomonas aeruginosa is guided by a significant body of evidence, other infections often pose a considerable challenge to treating physicians. In Part I of this series on the antibiotic management of difficult lung infections, we discussed bacterial organisms including methicillin-resistant Staphylococcus aureus, gram-negative bacterial infections, and treatment of multiple bacterial pathogens. Here, we summarize the approach to infections with nontuberculous mycobacteria, anaerobic bacteria, and fungi. Nontuberculous mycobacteria can significantly impact the course of lung disease in patients with CF, but differentiation between colonization and infection is difficult clinically as coinfection with other micro-organisms is common. Treatment consists of different classes of antibiotics, varies in intensity, and is best guided by a team of specialized clinicians and microbiologists. The ability of anaerobic bacteria to contribute to CF lung disease is less clear, even though clinical relevance has been reported in individual patients. Anaerobes detected in CF sputum are often resistant to multiple drugs, and treatment has not yet been shown to positively affect patient outcome. Fungi have gained significant interest as potential CF pathogens. Although the role of Candida is largely unclear, there is mounting evidence that Scedosporium species and Aspergillus fumigatus, beyond the classical presentation of allergic bronchopulmonary aspergillosis, can be relevant in patients with CF and treatment should be considered. At present, however there remains limited information on how best to select patients who could benefit from antifungal therapy.

Antibiotic Management of Lung Infections in Cystic Fibrosis. II. Nontuberculous Mycobacteria, Anaerobic Bacteria, and Fungi

PubMed Central

Aksamit, Timothy R.; Chotirmall, Sanjay H.; Dasenbrook, Elliott C.; Elborn, J. Stuart; LiPuma, John J.; Ranganathan, Sarath C.; Waters, Valerie J.; Ratjen, Felix A.

2014-01-01

Airway infections are a key component of cystic fibrosis (CF) lung disease. Whereas the approach to common pathogens such as Pseudomonas aeruginosa is guided by a significant body of evidence, other infections often pose a considerable challenge to treating physicians. In Part I of this series on the antibiotic management of difficult lung infections, we discussed bacterial organisms including methicillin-resistant Staphylococcus aureus, gram-negative bacterial infections, and treatment of multiple bacterial pathogens. Here, we summarize the approach to infections with nontuberculous mycobacteria, anaerobic bacteria, and fungi. Nontuberculous mycobacteria can significantly impact the course of lung disease in patients with CF, but differentiation between colonization and infection is difficult clinically as coinfection with other micro-organisms is common. Treatment consists of different classes of antibiotics, varies in intensity, and is best guided by a team of specialized clinicians and microbiologists. The ability of anaerobic bacteria to contribute to CF lung disease is less clear, even though clinical relevance has been reported in individual patients. Anaerobes detected in CF sputum are often resistant to multiple drugs, and treatment has not yet been shown to positively affect patient outcome. Fungi have gained significant interest as potential CF pathogens. Although the role of Candida is largely unclear, there is mounting evidence that Scedosporium species and Aspergillus fumigatus, beyond the classical presentation of allergic bronchopulmonary aspergillosis, can be relevant in patients with CF and treatment should be considered. At present, however there remains limited information on how best to select patients who could benefit from antifungal therapy. PMID:25167882

Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations

PubMed Central

Lambert, Christophe; Clarke, Stuart C; Kim, Viktoriya L; Magid-Slav, Michal; Miller, Bruce E; Patel, Ruchi; Sathe, Ganesh; Simola, Daniel F; Sung, Ruby; Tal-Singer, Ruth; Tuck, Andrew C; Van Horn, Stephanie; Weynants, Vincent; Williams, Nicholas P; Devaster, Jeanne-Marie; Wilkinson, Tom M A

2018-01-01

Background Alterations in the composition of the lung microbiome associated with adverse clinical outcomes, known as dysbiosis, have been implicated with disease severity and exacerbations in COPD. Objective To characterise longitudinal changes in the lung microbiome in the AERIS study (Acute Exacerbation and Respiratory InfectionS in COPD) and their relationship with associated COPD outcomes. Methods We surveyed 584 sputum samples from 101 patients with COPD to analyse the lung microbiome at both stable and exacerbation time points over 1 year using high-throughput sequencing of the 16S ribosomal RNA gene. We incorporated additional lung microbiology, blood markers and in-depth clinical assessments to classify COPD phenotypes. Results The stability of the lung microbiome over time was more likely to be decreased in exacerbations and within individuals with higher exacerbation frequencies. Analysis of exacerbation phenotypes using a Markov chain model revealed that bacterial and eosinophilic exacerbations were more likely to be repeated in subsequent exacerbations within a subject, whereas viral exacerbations were not more likely to be repeated. We also confirmed the association of bacterial genera, including Haemophilus and Moraxella, with disease severity, exacerbation events and bronchiectasis. Conclusions Subtypes of COPD have distinct bacterial compositions and stabilities over time. Some exacerbation subtypes have non-random probabilities of repeating those subtypes in the future. This study provides insights pertaining to the identification of bacterial targets in the lung and biomarkers to classify COPD subtypes and to determine appropriate treatments for the patient. Trial registration number Results, NCT01360398. PMID:29386298

Sputum colour for diagnosis of a bacterial infection in patients with acute cough.

PubMed

Altiner, Attila; Wilm, Stefan; Däubener, Walter; Bormann, Christiane; Pentzek, Michael; Abholz, Heinz-Harald; Scherer, Martin

2009-01-01

Sputum colour plays an important role in the disease concepts for acute cough, both in the patients' and the doctors' view. However, it is unclear whether the sputum colour can be used for diagnosis of a bacterial infection. Cross-sectional study. A total of 42 GP practices in Dusseldorf, Germany. Sputum samples obtained from 241 patients suffering from an episode of acute cough seeing their doctor within a routine consultation. Relation of sputum colour and microbiological proof of bacterial infection defined as positive culture and at least a moderate number of leucocytes per low magnification field. In 28 samples (12%) a bacterial infection was proven. Yellowish or greenish colour of the sputum sample and bacterial infection showed a significant correlation (p = 0.014, Fisher's exact test). The sensitivity of yellowish or greenish sputum used as a test for a bacterial infection was 0.79 (95% CI 0.63-0.94); the specificity was 0.46 (95% CI 0.038-0.53). The positive likelihood-ratio (+LR) was 1.46 (95% CI 1.17-1.85). The sputum colour of patients with acute cough and no underlying chronic lung disease does not imply therapeutic consequences such as prescription of antibiotics.

Lung Microbiota Changes Associated with Chronic Pseudomonas aeruginosa Lung Infection and the Impact of Intravenous Colistimethate Sodium

PubMed Central

Collie, David; Glendinning, Laura; Govan, John; Wright, Steven; Thornton, Elisabeth; Tennant, Peter; Doherty, Catherine; McLachlan, Gerry

2015-01-01

Background Exacerbations associated with chronic lung infection with Pseudomonas aeruginosa are a major contributor to morbidity, mortality and premature death in cystic fibrosis. Such exacerbations are treated with antibiotics, which generally lead to an improvement in lung function and reduced sputum P. aeruginosa density. This potentially suggests a role for the latter in the pathogenesis of exacerbations. However, other data suggesting that changes in P. aeruginosa sputum culture status may not reliably predict an improvement in clinical status, and data indicating no significant changes in either total bacterial counts or in P. aeruginosa numbers in sputum samples collected prior to pulmonary exacerbation sheds doubt on this assumption. We used our recently developed lung segmental model of chronic Pseudomonas infection in sheep to investigate the lung microbiota changes associated with chronic P. aeruginosa lung infection and the impact of systemic therapy with colistimethate sodium (CMS). Methodology/Principal Findings We collected protected specimen brush (PSB) samples from sheep (n = 8) both prior to and 14 days after establishment of chronic local lung infection with P aeruginosa. Samples were taken from both directly infected lung segments (direct) and segments spatially remote to such sites (remote). Four sheep were treated with daily intravenous injections of CMS between days 7 and 14, and four were treated with a placebo. Necropsy examination at d14 confirmed the presence of chronic local lung infection and lung pathology in every direct lung segment. The predominant orders in lung microbiota communities before infection were Bacillales, Actinomycetales and Clostridiales. While lung microbiota samples were more likely to share similarities with other samples derived from the same lung, considerable within- and between-animal heterogeneity could be appreciated. Pseudomonadales joined the aforementioned list of predominant orders in lung microbiota

A role for Toll-like receptor 4 in the host response to the lung infection of Yersinia pseudotuberculosis in mice.

PubMed

Choi, Jin-A; Jeong, Yu-Jin; Kim, Jae-Eun; Kang, Min-Jung; Kim, Jee-Cheon; Oh, Sang-Muk; Lee, Kyung-Bok; Kim, Dong-Hyun; Kim, Dong-Jae; Park, Jong-Hwan

2016-02-01

Although a Yersinia pseudotuberculosis (Yptb) lung infection model has been developed to study Y. pestis pathogenesis, it is still necessary to establish a new animal model to mimic the pathophysiological features induced by Y. pestis infection. Here, we provide a new lung infection model using the Yptb strain, IP2777, which displayed rapid spread of bacteria to the liver, spleen, and blood. In addition, we examined whether TLR4 is involved in Yptb-induced pathogenesis in the lung infection model of mice we generated. Following lung infection of WT and TLR4-deficient mice with the Yptb strain IP2777, the survival rate, bacterial colonization, histopathology, and level of cytokines and chemokines in the lung, spleen, liver, and blood were analyzed. TLR4-deficient mice had a lower survival rate than WT mice in response to Yptb lung infection. Although the bacterial colonization and pathology of the lung were comparable between WT and TLR4-deficient mice, those of the spleen and liver were more severe in TLR4-deficient mice. In addition, the levels of TNF-α and CXCL2 in the liver and IL-6 and CXCL2 in the blood were higher in TLR4-deficient mice than in WT mice. Our results demonstrate that TLR4 is necessary for optimal host protection against Yptb lung infection and TLR4-deficient mice may serve as a better genetic model of Yptb infection for mimicking Y. pestis infection. Copyright © 2016 Elsevier Ltd. All rights reserved.

Monitoring of early humoral immunity to identify lung recipients at risk for development of serious infections: A multicenter prospective study.

PubMed

Sarmiento, Elizabeth; Cifrian, Jose; Calahorra, Leticia; Bravo, Carles; Lopez, Sonia; Laporta, Rosalia; Ussetti, Piedad; Sole, Amparo; Morales, Carmen; de Pablos, Alicia; Jaramillo, Maria; Ezzahouri, Ikram; García, Sandra; Navarro, Joaquin; Lopez-Hoyos, Marcos; Carbone, Javier

2018-04-06

Infection is still a leading cause of death during the first year after lung transplantation. We performed a multicenter study among teaching hospitals to assess monitoring of early humoral immunity as a means of identifying lung recipients at risk of serious infections. We prospectively analyzed 82 adult lung recipients at 5 centers in Spain. Data were collected before transplantation and at 7 and 30 days after transplantation. Biomarkers included IgG, IgM, IgA, complement factors C3 and C4, titers of antibodies to pneumococcal polysaccharide antigens (IgG, IgA, IgM) and antibodies to cytomegalovirus (IgG), and serum B-cell activating factor (BAFF) levels. The clinical follow-up period lasted 6 months. Clinical outcomes were bacterial infections requiring intravenous anti-microbial agents, cytomegalovirus (CMV) disease, and fungal infections requiring therapy. We found that 33 patients (40.2%) developed at least 1 serious bacterial infection, 8 patients (9.8%) had CMV disease, and 10 patients (12.2%) had fungal infections. Lower IgM antibody levels against pneumococcal polysaccharide antigens at Day 7 (defined as <5 mg/dl) were a risk factor for serious bacterial infection (adjusted odds ratio [OR] 3.96; 95% confidence interval [CI] 1.39 to 11.26; p = 0.0099). At Day 7 after transplantation, IgG hypogammaglobulinemia (defined as IgG <600 mg/dl) was associated with a higher risk of CMV disease (after adjustment for CMV mismatch: OR 8.15; 95% CI 1.27 to 52.55; p = 0.028) and fungal infection (adjusted OR 8.03, 95% CI 1.51 to 42.72; p = 0.015). Higher BAFF levels before transplantation were associated with a higher rate of development of serious bacterial infection and acute cellular rejection. Early monitoring of specific humoral immunity parameters proved useful for the identification of lung recipients who are at risk of serious infections. Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights

Sputum colour for diagnosis of a bacterial infection in patients with acute cough

PubMed Central

Altiner, Attila; Wilm, Stefan; Däubener, Walter; Bormann, Christiane; Pentzek, Michael; Abholz, Heinz-Harald; Scherer, Martin

2009-01-01

Objective Sputum colour plays an important role in the disease concepts for acute cough, both in the patients’ and the doctors’ view. However, it is unclear whether the sputum colour can be used for diagnosis of a bacterial infection. Design Cross-sectional study. Setting A total of 42 GP practices in Düsseldorf, Germany. Subjects Sputum samples obtained from 241 patients suffering from an episode of acute cough seeing their doctor within a routine consultation. Main outcome measures Relation of sputum colour and microbiological proof of bacterial infection defined as positive culture and at least a moderate number of leucocytes per low magnification field. Results In 28 samples (12%) a bacterial infection was proven. Yellowish or greenish colour of the sputum sample and bacterial infection showed a significant correlation (p = 0.014, Fisher's exact test). The sensitivity of yellowish or greenish sputum used as a test for a bacterial infection was 0.79 (95% CI 0.63–0.94); the specificity was 0.46 (95% CI 0.038–0.53). The positive likelihood-ratio (+LR) was 1.46 (95% CI 1.17-1.85). Conclusions The sputum colour of patients with acute cough and no underlying chronic lung disease does not imply therapeutic consequences such as prescription of antibiotics. PMID:19242860

Role of Mutant CFTR in Hypersusceptibility of Cystic Fibrosis Patients to Lung Infections

NASA Astrophysics Data System (ADS)

Pier, Gerald B.; Grout, Martha; Zaidi, Tanweer S.; Olsen, John C.; Johnson, Larry G.; Yankaskas, James R.; Goldberg, Joanna B.

1996-01-01

Cystic fibrosis (CF) patients are hypersusceptible to chronic Pseudomonas aeruginosa lung infections. Cultured human airway epithelial cells expressing the ΔF508 allele of the cystic fibrosis transmembrane conductance regulator (CFTR) were defective in uptake of P. aeruginosa compared with cells expressing the wild-type allele. Pseudomonas aeruginosa lipopolysaccharide (LPS)-core oligosaccharide was identified as the bacterial ligand for epithelial cell ingestion; exogenous oligosaccharide inhibited bacterial ingestion in a neonatal mouse model, resulting in increased amounts of bacteria in the lungs. CFTR may contribute to a host-defense mechanism that is important for clearance of P. aeruginosa from the respiratory tract.

Protective mechanical ventilation does not exacerbate lung function impairment or lung inflammation following influenza A infection.

PubMed

Zosky, Graeme R; Cannizzaro, Vincenzo; Hantos, Zoltan; Sly, Peter D

2009-11-01

The degree to which mechanical ventilation induces ventilator-associated lung injury is dependent on the initial acute lung injury (ALI). Viral-induced ALI is poorly studied, and this study aimed to determine whether ALI induced by a clinically relevant infection is exacerbated by protective mechanical ventilation. Adult female BALB/c mice were inoculated with 10(4.5) plaque-forming units of influenza A/Mem/1/71 in 50 microl of medium or medium alone. This study used a protective ventilation strategy, whereby mice were anesthetized, tracheostomized, and mechanically ventilated for 2 h. Lung mechanics were measured periodically throughout the ventilation period using a modification of the forced oscillation technique to obtain measures of airway resistance and coefficients of tissue damping and tissue elastance. Thoracic gas volume was measured and used to obtain specific airway resistance, tissue damping, and tissue elastance. At the end of the ventilation period, a bronchoalveolar lavage sample was collected to measure inflammatory cells, macrophage inflammatory protein-2, IL-6, TNF-alpha, and protein leak. Influenza infection caused significant increases in inflammatory cells, protein leak, and deterioration in lung mechanics that were not exacerbated by mechanical ventilation, in contrast to previous studies using bacterial and mouse-specific viral infection. This study highlighted the importance of type and severity of lung injury in determining outcome following mechanical ventilation.

Curcumin alone and in combination with augmentin protects against pulmonary inflammation and acute lung injury generated during Klebsiella pneumoniae B5055-induced lung infection in BALB/c mice.

PubMed

Bansal, Shruti; Chhibber, Sanjay

2010-04-01

Acute lung injuries due to acute lung infections remain a major cause of mortality. Thus a combination of an antibiotic and a compound with immunomodulatory and anti-inflammatory activities can help to overcome acute lung infection-induced injuries. Curcumin derived from the rhizome of turmeric has been used for decades and it exhibits anti-inflammatory, anti-carcinogenic, immunomodulatory properties by downregulation of various inflammatory mediators. Keeping these properties in mind, we investigated the anti-inflammatory properties of curcumin in a mouse model of acute inflammation by introducing Klebsiella pneumoniae B5055 into BALB/c mice via the intranasal route. Intranasal instillation of bacteria in this mouse model of acute pneumonia-induced inflammation resulted in a significant increase in neutrophil infiltration in the lungs along with increased production of various inflammatory mediators [i.e. malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), tumour necrosis factor (TNF)-alpha] in the lung tissue. The animals that received curcumin alone orally or in combination with augmentin, 15 days prior to bacterial instillation into the lungs via the intranasal route, showed a significant (P <0.05) decrease in neutrophil influx into the lungs and a significant (P <0.05) decrease in the production of MDA, NO, MPO activity and TNF-alpha levels. Augmentin treatment alone did not decrease the MDA, MPO, NO and TNF-alpha levels significantly (P >0.05) as compared to the control group. We therefore conclude that curcumin ameliorates lung inflammation induced by K. pneumoniae B5055 without significantly (P <0.05) decreasing the bacterial load in the lung tissue whereas augmentin takes care of bacterial proliferation. Hence, curcumin can be used as an adjunct therapy along with antibiotics as an anti-inflammatory or an immunomodulatory agent in the case of acute lung infection.

Lung needle biopsy

MedlinePlus

... may be due to any of the following: Bacterial, viral, or fungal lung infection Cancerous cells ( lung cancer , mesothelioma) Pneumonia Risks Sometimes, a collapsed lung ( pneumothorax ) occurs after ...

Facial bacterial infections: folliculitis.

PubMed

Laureano, Ana Cristina; Schwartz, Robert A; Cohen, Philip J

2014-01-01

Facial bacterial infections are most commonly caused by infections of the hair follicles. Wherever pilosebaceous units are found folliculitis can occur, with the most frequent bacterial culprit being Staphylococcus aureus. We review different origins of facial folliculitis, distinguishing bacterial forms from other infectious and non-infectious mimickers. We distinguish folliculitis from pseudofolliculitis and perifolliculitis. Clinical features, etiology, pathology, and management options are also discussed. Copyright © 2014. Published by Elsevier Inc.

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

PubMed Central

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

2016-01-01

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

Bacterial lung sepsis in patients with febrile neutropenia.

PubMed

Lanoix, Jean-Philippe; Schmit, Jean-Luc; Douadi, Youcef

2012-05-01

This review provides an update on microbiological and therapeutic data in febrile neutropenic patients in general and those with bacterial lung sepsis in particular. Although the Infectious Diseases Society of America updated its guidelines on febrile neutropenia in 2010, changing epidemiological factors and the spread of new drug resistance constitutes challenges for initial treatment of this condition. Lung sepsis stands out because of the frequent absence of microbiological identification. We review the use of newly available, novel, broad-spectrum antibiotics (linezolid, tigecycline, daptomycin, etc.) in this indication. Although the incidence of Gram-negative infections in neutropenic fever is leveling off, there is a worrying increase in resistance. New drugs are available but not well studied in febrile neutropenia; daptomycin and tigecycline should not be used in suspected lung sepsis in these patients. New diagnostic tools (such as the procalcitonin assay and the LightCycler SeptiFast assay, Roche Molecular Systems) appear to be unhelpful in febrile neutropenia, although more data on fungal sepsis are required. There are no specific features of the treatment of pneumonia or septic shock in neutropenic fever, but both conditions increase the mortality rate.

Sinus surgery can improve quality of life, lung infections, and lung function in patients with primary ciliary dyskinesia.

PubMed

Alanin, Mikkel Christian; Aanaes, Kasper; Høiby, Niels; Pressler, Tania; Skov, Marianne; Nielsen, Kim Gjerum; Johansen, Helle Krogh; von Buchwald, Christian

2017-03-01

Chronic rhinosinusitis (CRS) and bacterial sinusitis are ubiquitous in patients with primary ciliary dyskinesia (PCD). From the sinuses, Pseudomonas aeruginosa can infect the lungs. We studied the effect of endoscopic sinus surgery (ESS) on symptoms of CRS and lower airway infections in PCD patients in a prospective single-arm intervention study of ESS with adjuvant therapy using nasal irrigation with saline, topical nasal steroids, and 2 weeks of systemic antibiotics. Additional treatment with local colistin for 6 months was instigated when P. aeruginosa was cultured at ESS. Twenty-four PCD patients underwent ESS to search for an infectious focus (n = 10), due to severe symptoms of CRS (n = 8), or both (n = 6). Bacteria were cultured from sinus samples in 21 patients (88%), and simultaneous sinus and lung colonization with identical pathogens were observed in 13 patients (62%). Four patients with preoperative P. aeruginosa lung colonization (25%) had no regrowth during follow-up; 2 of these had P. aeruginosa sinusitis. Sinonasal symptoms were improved 12 months after ESS and we observed a trend toward better lung function after ESS. We demonstrated an improvement in CRS-related symptoms after ESS and adjuvant therapy. In selected PCD patients, the suggested regimen may postpone chronic lung infection with P. aeruginosa and stabilize lung function. © 2016 ARS-AAOA, LLC.

Soluble metals in residual oil fly ash alter innate and adaptive pulmonary immune responses to bacterial infection in rats

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

Roberts, Jenny R.; Young, Shih-Houng; Castranova, Vincent

2007-06-15

The soluble metals of the pollutant, residual oil fly ash (ROFA), have been shown to alter pulmonary bacterial clearance in rats. The goal of this study was to determine the potential effects on both the innate and adaptive lung immune responses after bacterial infection in rats pre-exposed to the soluble metals in ROFA. Sprague-Dawley rats were intratracheally dosed (i.t.) at day 0 with ROFA (R-Total) (1.0 mg/100 g body weight), the soluble fraction of ROFA (R-Soluble), the soluble sample subject to a chelator (R-Chelex), or phosphate-buffered saline (Saline). On day 3, rats were administered an i.t. dose of 5 xmore » 10{sup 4} Listeria monocytogenes. On days 6, 8, and 10, bacterial pulmonary clearance was monitored and bronchoalveolar lavage (BAL) was performed on days 3 (pre-infection), 6, 8, and 10. A concentrated first fraction of lavage fluid was retained for analysis of lactate dehydrogenase and albumin to assess lung injury. BAL cell number, phenotype, and production of reactive oxygen (ROS) and nitrogen species (RNS) were assessed, and a variety of cytokines were measured in the BAL fluid. Rats pre-treated with R-Soluble showed elevated lung injury/cytotoxicity and increased cellular influx into the lungs. R-Soluble-treatment also altered ROS, RNS, and cytokine levels, and caused a degree of macrophage and T cell inhibition. These effects of R-Soluble result in increased pulmonary bacterial burden after infection. The results suggest that soluble metals in ROFA increase lung injury and inflammation, and alter both innate and adaptive pulmonary immune responses.« less

Correlation of the lung microbiota with metabolic profiles in bronchoalveolar lavage fluid in HIV infection.

PubMed

Cribbs, Sushma K; Uppal, Karan; Li, Shuzhao; Jones, Dean P; Huang, Laurence; Tipton, Laura; Fitch, Adam; Greenblatt, Ruth M; Kingsley, Lawrence; Guidot, David M; Ghedin, Elodie; Morris, Alison

2016-01-20

While 16S ribosomal RNA (rRNA) sequencing has been used to characterize the lung's bacterial microbiota in human immunodeficiency virus (HIV)-infected individuals, taxonomic studies provide limited information on bacterial function and impact on the host. Metabolic profiles can provide functional information on host-microbe interactions in the lungs. We investigated the relationship between the respiratory microbiota and metabolic profiles in the bronchoalveolar lavage fluid of HIV-infected and HIV-uninfected outpatients. Targeted sequencing of the 16S rRNA gene was used to analyze the bacterial community structure and liquid chromatography-high-resolution mass spectrometry was used to detect features in bronchoalveolar lavage fluid. Global integration of all metabolic features with microbial species was done using sparse partial least squares regression. Thirty-nine HIV-infected subjects and 20 HIV-uninfected controls without acute respiratory symptoms were enrolled. Twelve mass-to-charge ratio (m/z) features from C18 analysis were significantly different between HIV-infected individuals and controls (false discovery rate (FDR) = 0.2); another 79 features were identified by network analysis. Further metabolite analysis demonstrated that four features were significantly overrepresented in the bronchoalveolar lavage (BAL) fluid of HIV-infected individuals compared to HIV-uninfected, including cystine, two complex carbohydrates, and 3,5-dibromo-L-tyrosine. There were 231 m/z features significantly associated with peripheral blood CD4 cell counts identified using sparse partial least squares regression (sPLS) at a variable importance on projection (VIP) threshold of 2. Twenty-five percent of these 91 m/z features were associated with various microbial species. Bacteria from families Caulobacteraceae, Staphylococcaceae, Nocardioidaceae, and genus Streptococcus were associated with the greatest number of features. Glycerophospholipid and lineolate pathways correlated

Nanoparticle Approaches against Bacterial Infections

PubMed Central

Gao, Weiwei; Thamphiwatana, Soracha; Angsantikul, Pavimol; Zhang, Liangfang

2014-01-01

Despite the wide success of antibiotics, the treatment of bacterial infection still faces significant challenges, particularly the emergence of antibiotic resistance. As a result, nanoparticle drug delivery platforms including liposomes, polymeric nanoparticles, dendrimers, and various inorganic nanoparticles have been increasingly exploited to enhance the therapeutic effectiveness of existing antibiotics. This review focuses on areas where nanoparticle approaches hold significant potential to advance the treatment of bacterial infection. These areas include targeted antibiotic delivery, environmentally responsive antibiotic delivery, combinatorial antibiotic delivery, nanoparticle-enabled antibacterial vaccination, and nanoparticle-based bacterial detection. In each area we highlight the innovative antimicrobial nanoparticle platforms and review their progress made against bacterial infections. PMID:25044325

The Metabolic Sensor GPR43 Receptor Plays a Role in the Control of Klebsiella pneumoniae Infection in the Lung

PubMed Central

Galvão, Izabela; Tavares, Luciana P.; Corrêa, Renan O.; Fachi, José Luís; Rocha, Vitor Melo; Rungue, Marcela; Garcia, Cristiana C.; Cassali, Geovanni; Ferreira, Caroline M.; Martins, Flaviano S.; Oliveira, Sergio C.; Mackay, Charles R.; Teixeira, Mauro M.; Vinolo, Marco Aurélio R.; Vieira, Angélica T.

2018-01-01

Pneumonia is one of the leading causes of death and mortality worldwide. The inflammatory responses that follow respiratory infections are protective leading to pathogen clearance but can also be deleterious if unregulated. The microbiota is known to be an important protective barrier against infections, mediating both direct inhibitory effects against the potential pathogen and also regulating the immune responses contributing to a proper clearance of the pathogen and return to homeostasis. GPR43 is one receptor for acetate, a microbiota metabolite shown to induce and to regulate important immune functions. Here, we addressed the role of GPR43 signaling during pulmonary bacterial infections. We have shown for the first time that the absence of GPR43 leads to increased susceptibility to Klebsiella pneumoniae infection, which was associated to both uncontrolled proliferation of bacteria and to increased inflammatory response. Mechanistically, we showed that GPR43 expression especially in neutrophils and alveolar macrophages is important for bacterial phagocytosis and killing. In addition, treatment with the GPR43 ligand, acetate, is protective during bacterial lung infection. This was associated to reduction in the number of bacteria in the airways and to the control of the inflammatory responses. Altogether, GPR43 plays an important role in the “gut–lung axis” as a sensor of the host gut microbiota activity through acetate binding promoting a proper immune response in the lungs. PMID:29515566

Longitudinal analysis of the lung microbiota of cynomolgous macaques during long-term SHIV infection.

PubMed

Morris, Alison; Paulson, Joseph N; Talukder, Hisham; Tipton, Laura; Kling, Heather; Cui, Lijia; Fitch, Adam; Pop, Mihai; Norris, Karen A; Ghedin, Elodie

2016-07-08

Longitudinal studies of the lung microbiome are challenging due to the invasive nature of sample collection. In addition, studies of the lung microbiome in human disease are usually performed after disease onset, limiting the ability to determine early events in the lung. We used a non-human primate model to assess lung microbiome alterations over time in response to an HIV-like immunosuppression and determined impact of the lung microbiome on development of obstructive lung disease. Cynomolgous macaques were infected with the SIV-HIV chimeric virus SHIV89.6P. Bronchoalveolar lavage fluid samples were collected pre-infection and every 4 weeks for 53 weeks post-infection. The microbiota was characterized at each time point by 16S ribosomal RNA (rRNA) sequencing. We observed individual variation in the composition of the lung microbiota with a proportion of the macaques having Tropheryma whipplei as the dominant organism in their lungs. Bacterial communities varied over time both within and between animals, but there did not appear to be a systematic alteration due to SHIV infection. Development of obstructive lung disease in the SHIV-infected animals was characterized by a relative increase in abundance of oral anaerobes. Network analysis further identified a difference in community composition that accompanied the development of obstructive disease with negative correlations between members of the obstructed and non-obstructed groups. This emphasizes how species shifts can impact multiple other species, potentially resulting in disease. This study is the first to investigate the dynamics of the lung microbiota over time and in response to immunosuppression in a non-human primate model. The persistence of oral bacteria in the lung and their association with obstruction suggest a potential role in pathogenesis. The lung microbiome in the non-human primate is a valuable tool for examining the impact of the lung microbiome in human health and disease.

PilY1 Promotes Legionella pneumophila Infection of Human Lung Tissue Explants and Contributes to Bacterial Adhesion, Host Cell Invasion, and Twitching Motility.

PubMed

Hoppe, Julia; Ünal, Can M; Thiem, Stefanie; Grimpe, Louisa; Goldmann, Torsten; Gaßler, Nikolaus; Richter, Matthias; Shevchuk, Olga; Steinert, Michael

2017-01-01

Legionnaires' disease is an acute fibrinopurulent pneumonia. During infection Legionella pneumophila adheres to the alveolar lining and replicates intracellularly within recruited macrophages. Here we provide a sequence and domain composition analysis of the L. pneumophila PilY1 protein, which has a high homology to PilY1 of Pseudomonas aeruginosa . PilY1 proteins of both pathogens contain a von Willebrand factor A (vWFa) and a C-terminal PilY domain. Using cellular fractionation, we assigned the L. pneumophila PilY1 as an outer membrane protein that is only expressed during the transmissive stationary growth phase. PilY1 contributes to infection of human lung tissue explants (HLTEs). A detailed analysis using THP-1 macrophages and A549 lung epithelial cells revealed that this contribution is due to multiple effects depending on host cell type. Deletion of PilY1 resulted in a lower replication rate in THP-1 macrophages but not in A549 cells. Further on, adhesion to THP-1 macrophages and A549 epithelial cells was decreased. Additionally, the invasion into non-phagocytic A549 epithelial cells was drastically reduced when PilY1 was absent. Complementation variants of a PilY1-negative mutant revealed that the C-terminal PilY domain is essential for restoring the wild type phenotype in adhesion, while the putatively mechanosensitive vWFa domain facilitates invasion into non-phagocytic cells. Since PilY1 also promotes twitching motility of L. pneumophila , we discuss the putative contribution of this newly described virulence factor for bacterial dissemination within infected lung tissue.

THE MODIFYING EFFECTS OF CERTAIN SUBSTANCES OF BACTERIAL ORIGIN ON THE COURSE OF INFECTION WITH PNEUMONIA VIRUS OF MICE (PVM)

PubMed Central

Horsfall, Frank L.; McCarty, Maclyn

1947-01-01

Evidence is presented which indicates that certain polysaccharide preparations derived from various bacterial species, as well as similar materials not of bacterial origin, are capable of lessening the severity of infection with pneumonia virus of mice (PVM) and inhibiting multiplication of the virus in mouse lungs infected with this agent. It seems probable that modification with respect to the virus is mediated by a substance which may be polysaccharide in nature. PMID:19871640

Chronic Mycobacterium abscessus infection and lung function decline in cystic fibrosis.

PubMed

Esther, Charles R; Esserman, Denise A; Gilligan, Peter; Kerr, Alan; Noone, Peadar G

2010-03-01

Although nontuberculous mycobacteria (NTM) are recognized pathogens in cystic fibrosis (CF), associations with clinical outcomes remain unclear. Microbiological data was obtained from 1216 CF patients over 8years (481+/-55patients/year). Relationships to clinical outcomes were examined in the subset (n=271, 203+/-23 patients/year) with longitudinal data. Five hundred thirty-six of 4862 (11%) acid-fast bacilli (AFB) cultures grew NTM, with Mycobacterium abscessus (n=298, 55.6%) and Mycobacterium avium complex (n=190, 35.4%) most common. Associated bacterial cultures grew Stenotrophomonas or Aspergillus species more often when NTM were isolated (18.2% vs. 8.4% and 13.9% vs. 7.2%, respectively, p<0.01). After controlling for confounders, patients with chronic M. abscessus infection had greater rates of lung function decline than those with no NTM infection (-2.52 vs. -1.64% predicted FEV(1)/year, p<0.05). NTM infection is common in CF and associated with particular pathogens. Chronic M. abscessus infection is associated with increased lung function decline. Copyright (c) 2009 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Increased β-glucuronidase activity in bronchoalveolar lavage fluid of children with bacterial lung infection: A case-control study.

PubMed

Panagiotopoulou, Evgenia C; Fouzas, Sotirios; Douros, Konstantinos; Triantaphyllidou, Irene-Eva; Malavaki, Christina; Priftis, Kostas N; Karamanos, Nikos K; Anthracopoulos, Michael B

2015-11-01

β-Glucuronidase is a lysosomal enzyme released into the extracellular fluid during inflammation. Increased β-glucuronidase activity in the cerebrospinal and peritoneal fluid has been shown to be a useful marker of bacterial inflammation. We explored the role of β-glucuronidase in the detection of bacterial infection in bronchoalveolar lavage fluid (BALF) of paediatric patients. In this case-control study, % polymorphonuclear cell count (PMN%), β-glucuronidase activity, interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α) and elastase were measured in culture-positive (≥10(4) cfu/mL, C+) and -negative (C-) BALF samples obtained from children. A total of 92 BALF samples were analysed. The median β-glucuronidase activity (measured in nanomoles of 4-methylumbelliferone (4-MU)/mL BALF/h) was 246.4 in C+ (interquartile range: 71.2-751) and 21.9 in C- (4.0-40.8) (P < 0.001). The levels of TNF-α and IL-8 were increased in C+ as compared with C- (5.4 (1.7-12.6) vs 0.7 (0.2-6.2) pg/mL, P < 0.001 and 288 (76-4300) vs 287 (89-1566) pg/mL, P = 0.042, respectively). Elastase level and PMN% did not differ significantly (50 (21-149) vs 26 (15-59) ng/mL, P = 0.051 and 20 (9-40) vs 18 (9-34) %, P = 0.674, respectively). The area under the curve of β-glucuronidase activity (0.856, 95% confidence interval (CI): 0.767-0.920) was higher than that of TNF-α (0.718; 95% CI: 0.614-0.806; P = 0.040), IL-8 (0.623; 95% CI: 0.516-0.722; P = 0.001), elastase (0.645; 95% CI: 0.514-0.761; P = 0.008) and PMN% (0.526; 95 % CI: 0.418-0.632; P < 0.001). This study demonstrates a significant increase of β-glucuronidase activity in BALF of children with culture-positive bacterial inflammation. In our population β-glucuronidase activity showed superior predictive ability for bacterial lung infection than other markers of inflammation. © 2015 Asian Pacific Society of Respirology.

Lung Cancer in HIV Infection

PubMed Central

Mani, Deepthi; Haigentz, Missak; Aboulafia, David M

2011-01-01

Lung cancer is the most prevalent non-AIDS-defining malignancy in the HAART era. Smoking plays a significant role in the development of HIV-associated lung cancer, but the cancer risk is 2–4 times greater in HIV-infected persons than in the general population, even after adjusting for smoking intensity and duration. Lung cancer is typically diagnosed a decade or more earlier among HIV-infected persons (mean age, 46 years) compared to those without HIV infection. Adenocarcinoma is the commonest histological subtype, and the majority of patients are diagnosed with locally advanced or metastatic carcinoma. Since pulmonary infections are common among HIV-infected individuals, clinicians may not suspect lung cancer in this younger patient population. Surgery with curative intent remains the treatment of choice for early stage disease. Although there is increasing experience in using radiation and chemotherapy for HIV-infected patients who do not have surgical options, there is a need for prospective studies for this population frequently excluded from participating in cancer trials. Evidence-based treatments for smoking-cessation with demonstrated efficacy in the general population must be routinely incorporated into the care of HIV-positive smokers. PMID:21802373

Modeling Intraocular Bacterial Infections

PubMed Central

Astley, Roger A.; Coburn, Phillip S.; Parkunan, Salai Madhumathi; Callegan, Michelle C.

2016-01-01

Bacterial endophthalmitis is an infection and inflammation of the posterior segment of the eye which can result in significant loss of visual acuity. Even with prompt antibiotic, anti-inflammatory and surgical intervention, vision and even the eye itself may be lost. For the past century, experimental animal models have been used to examine various aspects of the pathogenesis and pathophysiology of bacterial endophthalmitis, to further the development of anti-inflammatory treatment strategies, and to evaluate the pharmacokinetics and efficacies of antibiotics. Experimental models allow independent control of many parameters of infection and facilitate systematic examination of infection outcomes. While no single animal model perfectly reproduces the human pathology of bacterial endophthalmitis, investigators have successfully used these models to understand the infectious process and the host response, and have provided new information regarding therapeutic options for the treatment of bacterial endophthalmitis. This review highlights experimental animal models of endophthalmitis and correlates this information with the clinical setting. The goal is to identify knowledge gaps that may be addressed in future experimental and clinical studies focused on improvements in the therapeutic preservation of vision during and after this disease. PMID:27154427

Lung cancer in HIV Infection.

PubMed

Mani, Deepthi; Haigentz, Missak; Aboulafia, David M

2012-01-01

Lung cancer is the most prevalent non-AIDS-defining malignancy in the highly active antiretroviral therapy era. Smoking plays a significant role in the development of HIV-associated lung cancer, but the cancer risk is two to four times greater in HIV-infected persons than in the general population, even after adjusting for smoking intensity and duration. Lung cancer is typically diagnosed a decade or more earlier among HIV-infected persons (mean age, 46 years) compared to those without HIV infection. Adenocarcinoma is the most common histological subtype, and the majority of patients are diagnosed with locally advanced or metastatic carcinoma. Because pulmonary infections are common among HIV-infected individuals, clinicians may not suspect lung cancer in this younger patient population. Surgery with curative intent remains the treatment of choice for early-stage disease. Although there is increasing experience in using radiation and chemotherapy for HIV-infected patients who do not have surgical options, there is a need for prospective studies because this population is frequently excluded from participating in cancer trials. Evidence-based treatments for smoking-cessation with demonstrated efficacy in the general population must be routinely incorporated into the care of HIV-positive smokers. Copyright © 2012 Elsevier Inc. All rights reserved.

Aspirin-triggered resolvin D1 is produced during self-resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation.

PubMed

Abdulnour, R E; Sham, H P; Douda, D N; Colas, R A; Dalli, J; Bai, Y; Ai, X; Serhan, C N; Levy, B D

2016-09-01

Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Host responses to contain infection and mitigate pathogen-mediated lung inflammation are critical for pneumonia resolution. Aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) is a lipid mediator (LM) that displays organ-protective actions in sterile lung inflammation, and regulates pathogen-initiated cellular responses. Here, in a self-resolving murine model of Escherichia coli pneumonia, LM metabololipidomics performed on lungs obtained at baseline, 24, and 72 h after infection uncovered temporal regulation of endogenous AT-RvD1 production. Early treatment with exogenous AT-RvD1 (1 h post infection) enhanced clearance of E. coli and Pseudomonas aeruginosa in vivo, and lung macrophage phagocytosis of fluorescent bacterial particles ex vivo. Characterization of macrophage subsets in the alveolar compartment during pneumonia identified efferocytosis by infiltrating macrophages (CD11b(Hi) CD11c(Low)) and exudative macrophages (CD11b(Hi) CD11c(Hi)). AT-RvD1 increased efferocytosis by these cells ex vivo, and accelerated neutrophil clearance during pneumonia in vivo. These anti-bacterial and pro-resolving actions of AT-RvD1 were additive to antibiotic therapy. Taken together, these findings suggest that the pro-resolving actions of AT-RvD1 during pneumonia represent a novel host-directed therapeutic strategy to complement the current antibiotic-centered approach for combatting infections.

HIV Infection in the Etiology of Lung Cancer

PubMed Central

Kirk, Gregory D.; Merlo, Christian A.

2011-01-01

Persons infected with HIV have an elevated risk of lung cancer, but whether the increase simply reflects a higher smoking prevalence continues to be debated. This review summarizes existing data on the association of HIV infection and lung cancer, with particular attention to study design and adjustment for cigarette smoking. Potential mechanisms by which HIV infection may lead to lung cancer are discussed. Finally, irrespective of causality and mechanisms, lung cancer represents an important and growing problem confronting HIV-infected patients and their providers. Substantial efforts are needed to promote smoking cessation and to control lung cancer among HIV-infected populations. PMID:21653536

Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections.

PubMed

Hisert, Katherine B; Heltshe, Sonya L; Pope, Christopher; Jorth, Peter; Wu, Xia; Edwards, Rachael M; Radey, Matthew; Accurso, Frank J; Wolter, Daniel J; Cooke, Gordon; Adam, Ryan J; Carter, Suzanne; Grogan, Brenda; Launspach, Janice L; Donnelly, Seamas C; Gallagher, Charles G; Bruce, James E; Stoltz, David A; Welsh, Michael J; Hoffman, Lucas R; McKone, Edward F; Singh, Pradeep K

2017-06-15

Previous work indicates that ivacaftor improves cystic fibrosis transmembrane conductance regulator (CFTR) activity and lung function in people with cystic fibrosis and G551D-CFTR mutations but does not reduce density of bacteria or markers of inflammation in the airway. These findings raise the possibility that infection and inflammation may progress independently of CFTR activity once cystic fibrosis lung disease is established. To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with cystic fibrosis and chronic airway infections. We studied 12 subjects with G551D-CFTR mutations and chronic airway infections before and after ivacaftor. We measured lung function, sputum bacterial content, and inflammation, and obtained chest computed tomography scans. Ivacaftor produced rapid decreases in sputum Pseudomonas aeruginosa density that began within 48 hours and continued in the first year of treatment. However, no subject eradicated their infecting P. aeruginosa strain, and after the first year P. aeruginosa densities rebounded. Sputum total bacterial concentrations also decreased, but less than P. aeruginosa. Sputum inflammatory measures decreased significantly in the first week of treatment and continued to decline over 2 years. Computed tomography scans obtained before and 1 year after ivacaftor treatment revealed that ivacaftor decreased airway mucous plugging. Ivacaftor caused marked reductions in sputum P. aeruginosa density and airway inflammation and produced modest improvements in radiographic lung disease in subjects with G551D-CFTR mutations. However, P. aeruginosa airway infection persisted. Thus, measures that control infection may be required to realize the full benefits of CFTR-targeting treatments.

Polymicrobial airway bacterial communities in adult bronchiectasis patients

PubMed Central

2014-01-01

Background Chronic airway infection contributes to the underlying pathogenesis of non-cystic fibrosis bronchiectasis (NCFBr). In contrast to other chronic airway infections, associated with COPD and CF bronchiectasis, where polymicrobial communities have been implicated in lung damage due to the vicious circle of recurrent bacterial infections and inflammation, there is sparse information on the composition of bacterial communities in NCFBr. Seventy consecutive patients were recruited from an outpatient adult NCFBr clinic. Bacterial communities in sputum samples were analysed by culture and pyrosequencing approaches. Bacterial sequences were analysed using partial least square discrimination analyses to investigate trends in community composition and identify those taxa that contribute most to community variation. Results The lower airway in NCFBr is dominated by three bacterial taxa Pasteurellaceae, Streptococcaceae and Pseudomonadaceae. Moreover, the bacterial community is much more diverse than indicated by culture and contains significant numbers of other genera including anaerobic Prevotellaceae, Veillonellaceae and Actinomycetaceae. We found particular taxa are correlated with different clinical states, 27 taxa were associated with acute exacerbations, whereas 11 taxa correlated with stable clinical states. We were unable to demonstrate a significant effect of antibiotic therapy, gender, or lung function on the diversity of the bacterial community. However, presence of clinically significant culturable taxa; particularly Pseudomonas aeruginosa and Haemophilus influenzae correlated with a significant change in the diversity of the bacterial community in the lung. Conclusions We have demonstrated that acute exacerbations, the frequency of exacerbation and episodes of clinical stability are correlated, in some patients, with a significantly different bacterial community structure, that are associated with a presence of particular taxa in the NCFBr lung. Moreover

Intranasal IFNγ extends passive IgA antibody protection of mice against Mycobacterium tuberculosis lung infection

PubMed Central

Reljic, R; Clark, S O; Williams, A; Falero-Diaz, G; Singh, M; Challacombe, S; Marsh, P D; Ivanyi, J

2006-01-01

Intranasal inoculation of mice with monoclonal IgA against the α-crystallin (acr1) antigen can diminish the tuberculous infection in the lungs. As this effect has been observed only over a short-term, we investigated if it could be extended by inoculation of IFNγ 3 days before infection, and further coinoculations with IgA, at 2 h before and 2 and 7 days after aerosol infection with Mycobacterium tuberculosis H37Rv. This treatment reduced the lung infection at 4 weeks more than either IgA or IFNγ alone (i.e. 17-fold, from 4·2 × 107 to 2·5 × 106 CFU, P = 0·006), accompanied also by lower granulomatous infiltration of the lungs. IFNγ added prior to infection of mouse peritoneal macrophages with IgA-opsonized bacilli resulted in a synergistic increase of nitric oxide and TNFα production and a 2–3 fold decrease in bacterial counts. Our improved results suggest, that combined treatment with IFNγ and IgA could be developed towards prophylactic treatment of AIDS patients, or as an adjunct to chemotherapy. PMID:16487246

Role of quorum sensing in bacterial infections

PubMed Central

Castillo-Juárez, Israel; Maeda, Toshinari; Mandujano-Tinoco, Edna Ayerim; Tomás, María; Pérez-Eretza, Berenice; García-Contreras, Silvia Julieta; Wood, Thomas K; García-Contreras, Rodolfo

2015-01-01

Quorum sensing (QS) is cell communication that is widely used by bacterial pathogens to coordinate the expression of several collective traits, including the production of multiple virulence factors, biofilm formation, and swarming motility once a population threshold is reached. Several lines of evidence indicate that QS enhances virulence of bacterial pathogens in animal models as well as in human infections; however, its relative importance for bacterial pathogenesis is still incomplete. In this review, we discuss the present evidence from in vitro and in vivo experiments in animal models, as well as from clinical studies, that link QS systems with human infections. We focus on two major QS bacterial models, the opportunistic Gram negative bacteria Pseudomonas aeruginosa and the Gram positive Staphylococcus aureus, which are also two of the main agents responsible of nosocomial and wound infections. In addition, QS communication systems in other bacterial, eukaryotic pathogens, and even immune and cancer cells are also reviewed, and finally, the new approaches proposed to combat bacterial infections by the attenuation of their QS communication systems and virulence are also discussed. PMID:26244150

Looking Beyond Respiratory Cultures: Microbiome-Cytokine Signatures of Bacterial Pneumonia and Tracheobronchitis in Lung Transplant Recipients.

PubMed

Shankar, J; Nguyen, M H; Crespo, M M; Kwak, E J; Lucas, S K; McHugh, K J; Mounaud, S; Alcorn, J F; Pilewski, J M; Shigemura, N; Kolls, J K; Nierman, W C; Clancy, C J

2016-06-01

Bacterial pneumonia and tracheobronchitis are diagnosed frequently following lung transplantation. The diseases share clinical signs of inflammation and are often difficult to differentiate based on culture results. Microbiome and host immune-response signatures that distinguish between pneumonia and tracheobronchitis are undefined. Using a retrospective study design, we selected 49 bronchoalveolar lavage fluid samples from 16 lung transplant recipients associated with pneumonia (n = 8), tracheobronchitis (n = 12) or colonization without respiratory infection (n = 29). We ensured an even distribution of Pseudomonas aeruginosa or Staphylococcus aureus culture-positive samples across the groups. Bayesian regression analysis identified non-culture-based signatures comprising 16S ribosomal RNA microbiome profiles, cytokine levels and clinical variables that characterized the three diagnoses. Relative to samples associated with colonization, those from pneumonia had significantly lower microbial diversity, decreased levels of several bacterial genera and prominent multifunctional cytokine responses. In contrast, tracheobronchitis was characterized by high microbial diversity and multifunctional cytokine responses that differed from those of pneumonia-colonization comparisons. The dissimilar microbiomes and cytokine responses underlying bacterial pneumonia and tracheobronchitis following lung transplantation suggest that the diseases result from different pathogenic processes. Microbiomes and cytokine responses had complementary features, suggesting that they are closely interconnected in the pathogenesis of both diseases. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Degradable polyphosphoester-based silver-loaded nanoparticles as therapeutics for bacterial lung infections

NASA Astrophysics Data System (ADS)

Zhang, Fuwu; Smolen, Justin A.; Zhang, Shiyi; Li, Richen; Shah, Parth N.; Cho, Sangho; Wang, Hai; Raymond, Jeffery E.; Cannon, Carolyn L.; Wooley, Karen L.

2015-01-01

In this study, a new type of degradable polyphosphoester-based polymeric nanoparticle, capable of carrying silver cations via interactions with alkyne groups, has been developed as a potentially effective and safe treatment for lung infections. It was found that up to 15% (w/w) silver loading into the nanoparticles could be achieved, consuming most of the pendant alkyne groups along the backbone, as revealed by Raman spectroscopy. The well-defined Ag-loaded nanoparticles released silver in a controlled and sustained manner over 5 days, and displayed enhanced in vitro antibacterial activities against cystic fibrosis-associated pathogens and decreased cytotoxicity to human bronchial epithelial cells, in comparison to silver acetate.In this study, a new type of degradable polyphosphoester-based polymeric nanoparticle, capable of carrying silver cations via interactions with alkyne groups, has been developed as a potentially effective and safe treatment for lung infections. It was found that up to 15% (w/w) silver loading into the nanoparticles could be achieved, consuming most of the pendant alkyne groups along the backbone, as revealed by Raman spectroscopy. The well-defined Ag-loaded nanoparticles released silver in a controlled and sustained manner over 5 days, and displayed enhanced in vitro antibacterial activities against cystic fibrosis-associated pathogens and decreased cytotoxicity to human bronchial epithelial cells, in comparison to silver acetate. Electronic supplementary information (ESI) available: Materials, experimental details, and characterization. See DOI: 10.1039/c4nr07103d

Clinical significance of the infection-free interval in the management of acute bacterial exacerbations of chronic bronchitis.

PubMed

Chodosh, Sanford

2005-06-01

Rational and appropriate antibiotic use for patients with acute exacerbation of chronic bronchitis (AECB) is a major concern, as approximately half of these patients do not have a bacterial infection. Typically, the result of antimicrobial therapy for patients with acute bacterial exacerbation of chronic bronchitis (ABECB) is not eradication of the pathogen but resolution of the acute symptoms. However, the length of time before the next bacterial exacerbation can be another important variable, as the frequency of exacerbations will affect the overall health of the patient and the rate of lung deterioration over time. Clinical trials comparing antimicrobial therapies commonly measure resolution of symptoms in AECB patients as the primary end point, regardless of whether the exacerbation is documented as bacterial in nature. Ideally, the scientific approach to assessing the efficacy of antibiotic therapy for ABECB should include a measurement of acute bacterial eradication rates in patients with documented bronchial bacterial infection followed by measurement of the infection-free interval (IFI), ie, the time to the next ABECB. The use of these variables can provide a standard for comparing various antimicrobial therapies. As we learn more about how antibiotics can affect the IFI, treatment decisions should be adapted to ensure optimal management of ABECB for the long-term.

The Lung Microbiome After Lung Transplantation

PubMed Central

Becker, Julia B.; Poroyko, Valeriy

2014-01-01

Summary Lung transplantation survival remains significantly impacted by infections and the development of chronic rejection manifesting as bronchiolitis obliterans syndrome (BOS). Traditional microbiologic data has provided insight into the role of infections in BOS. Now, new non-culture-based techniques have been developed to characterize the entire population of microbes resident on the surfaces of the body, also known as the human microbiome. Early studies have identified that lung transplant patients have a different lung microbiome and have demonstrated the important finding that the transplant lung microbiome changes over time. Furthermore, both unique bacterial populations and longitudinal changes in the lung microbiome have now been suggested to play a role in the development of BOS. In the future, this technology will need to be combined with functional assays and assessment of the immune responses in the lung to help further explain the microbiome’s role in the failing lung allograft. PMID:24601662

Lung phenotype of juvenile and adult cystic fibrosis transmembrane conductance regulator-knockout ferrets.

PubMed

Sun, Xingshen; Olivier, Alicia K; Liang, Bo; Yi, Yaling; Sui, Hongshu; Evans, Turan I A; Zhang, Yulong; Zhou, Weihong; Tyler, Scott R; Fisher, John T; Keiser, Nicholas W; Liu, Xiaoming; Yan, Ziying; Song, Yi; Goeken, J Adam; Kinyon, Joann M; Fligg, Danielle; Wang, Xiaoyan; Xie, Weiliang; Lynch, Thomas J; Kaminsky, Paul M; Stewart, Zoe A; Pope, R Marshall; Frana, Timothy; Meyerholz, David K; Parekh, Kalpaj; Engelhardt, John F

2014-03-01

Chronic bacterial lung infections in cystic fibrosis (CF) are caused by defects in the CF transmembrane conductance regulator chloride channel. Previously, we described that newborn CF transmembrane conductance regulator-knockout ferrets rapidly develop lung infections within the first week of life. Here, we report a more slowly progressing lung bacterial colonization phenotype observed in juvenile to adult CF ferrets reared on a layered antibiotic regimen. Even on antibiotics, CF ferrets were still very susceptible to bacterial lung infection. The severity of lung histopathology ranged from mild to severe, and variably included mucus obstruction of the airways and submucosal glands, air trapping, atelectasis, bronchopneumonia, and interstitial pneumonia. In all CF lungs, significant numbers of bacteria were detected and impaired tracheal mucociliary clearance was observed. Although Streptococcus, Staphylococcus, and Enterococcus were observed most frequently in the lungs of CF animals, each animal displayed a predominant bacterial species that accounted for over 50% of the culturable bacteria, with no one bacterial taxon predominating in all animals. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry fingerprinting was used to quantify lung bacteria in 10 CF animals and demonstrated Streptococcus, Staphylococcus, Enterococcus, or Escherichia as the most abundant genera. Interestingly, there was significant overlap in the types of bacteria observed in the lung and intestine of a given CF animal, including bacterial taxa unique to the lung and gut of each CF animal analyzed. These findings demonstrate that CF ferrets develop lung disease during the juvenile and adult stages that is similar to patients with CF, and suggest that enteric bacterial flora may seed the lung of CF ferrets.

Lung Phenotype of Juvenile and Adult Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferrets

PubMed Central

Sun, Xingshen; Olivier, Alicia K.; Liang, Bo; Yi, Yaling; Sui, Hongshu; Evans, Turan I. A.; Zhang, Yulong; Zhou, Weihong; Tyler, Scott R.; Fisher, John T.; Keiser, Nicholas W.; Liu, Xiaoming; Yan, Ziying; Song, Yi; Goeken, J. Adam; Kinyon, Joann M.; Fligg, Danielle; Wang, Xiaoyan; Xie, Weiliang; Lynch, Thomas J.; Kaminsky, Paul M.; Stewart, Zoe A.; Pope, R. Marshall; Frana, Timothy; Meyerholz, David K.; Parekh, Kalpaj

2014-01-01

Chronic bacterial lung infections in cystic fibrosis (CF) are caused by defects in the CF transmembrane conductance regulator chloride channel. Previously, we described that newborn CF transmembrane conductance regulator–knockout ferrets rapidly develop lung infections within the first week of life. Here, we report a more slowly progressing lung bacterial colonization phenotype observed in juvenile to adult CF ferrets reared on a layered antibiotic regimen. Even on antibiotics, CF ferrets were still very susceptible to bacterial lung infection. The severity of lung histopathology ranged from mild to severe, and variably included mucus obstruction of the airways and submucosal glands, air trapping, atelectasis, bronchopneumonia, and interstitial pneumonia. In all CF lungs, significant numbers of bacteria were detected and impaired tracheal mucociliary clearance was observed. Although Streptococcus, Staphylococcus, and Enterococcus were observed most frequently in the lungs of CF animals, each animal displayed a predominant bacterial species that accounted for over 50% of the culturable bacteria, with no one bacterial taxon predominating in all animals. Matrix-assisted laser desorption–ionization time-of-flight mass spectrometry fingerprinting was used to quantify lung bacteria in 10 CF animals and demonstrated Streptococcus, Staphylococcus, Enterococcus, or Escherichia as the most abundant genera. Interestingly, there was significant overlap in the types of bacteria observed in the lung and intestine of a given CF animal, including bacterial taxa unique to the lung and gut of each CF animal analyzed. These findings demonstrate that CF ferrets develop lung disease during the juvenile and adult stages that is similar to patients with CF, and suggest that enteric bacterial flora may seed the lung of CF ferrets. PMID:24074402

Primary mouse lung fibroblasts help macrophages to tackle Mycobacterium tuberculosis more efficiently and differentiate into myofibroblasts up on bacterial stimulation.

PubMed

Verma, Subash Chand; Agarwal, Pooja; Krishnan, Manju Y

2016-03-01

Keeping with their classical role in wound healing, fibroblasts of the lung take part in the resolution of tubercular granulomas. They are totally absent in nascent granulomas, but surround necrotizing granulomas, and are the majority of cells in healed granulomas. Lung fibroblasts may become infected with Mycobacterium tuberculosis (Mtb). Two previous studies suggested an immunomodulatory effect of fibroblasts on infected macrophages. In the present study, we looked at the role of primary mouse lung fibroblasts on naive or activated mouse bone marrow macrophages infected with Mtb and the effect of infection on fibroblast properties. We observed that with fibroblasts in the vicinity, infected naive macrophages restricted the bacterial growth, while activated macrophages turned more bactericidal with concomitant increase in nitrite production. Neutralizing IL-1α in fibroblast supernatant reduced the nitrite production by infected macrophages. Secretion of IL-6 and MCP-1 was down-regulated, while TNF-α was up-regulated in infected naive macrophages. In infected activated macrophages, the secretion of IL-6 was up-regulated, while that of MCP-1 and TNF-α was unaffected. The 'fibroblast effects' were enhanced when the fibroblasts too were infected. Mtb induced IL-1 secretion and pro-fibrotic responses by fibroblasts. Mtb-induced myofibroblast conversion was blocked by rapamycin suggesting cell signalling via mTOR. Copyright © 2015 Elsevier Ltd. All rights reserved.

Bacterial infections in alcoholic and nonalcoholic liver cirrhosis.

PubMed

Sargenti, Konstantina; Prytz, Hanne; Nilsson, Emma; Bertilsson, Sara; Kalaitzakis, Evangelos

2015-09-01

Longitudinal, population-based data on the occurrence, localization, and severity of bacterial infections over time in patients with alcoholic compared with nonalcoholic cirrhosis are limited. All patients with incident cirrhosis diagnosed in 2001-2010 (area of 600,000 inhabitants) were retrospectively identified. All bacterial infections resulting in or occurring during an inpatient hospital episode during this period were registered. The etiology of cirrhosis (alcoholic vs. nonalcoholic), infection localization, and outcome as well as bacterial resistance patterns were analyzed. Patients were followed until death, transplant, or the end of 2011. In all, 633 cirrhotics (363 alcoholic, 270 nonalcoholic) experienced a total of 398 infections (2276 patient-years). Among patients diagnosed with cirrhosis each year from 2001 to 2010, increasing trends were noted in the occurrence of infection (from 13 to 27%, P<0.001) and infection-related in-hospital mortality (from 2 to 7%, P=0.05), the latter mainly in the alcoholic group. Although alcoholic etiology was related to the occurrence of more frequent infection (Kaplan-Meier, P<0.001), this relationship was not significant after adjustment for confounders in Cox regression analysis (P=0.056). Resistance to piperacilin-tazobactam and carbapenems was more common in infections occurring in alcoholic versus nonalcoholic cirrhosis (13 vs. 5%, P=0.057 and 12 vs. 2%, P=0.009). Alcoholic etiology predicted pneumonia and infections caused by Gram-positive bacteria in multivariate analysis (P<0.05 for both). In a population-based cirrhotic cohort, bacterial infections increased over time, which, in the case of alcoholic cirrhosis, was associated with pneumonia and bacterial resistance to antibiotics. However, alcoholic etiology was not related indepedently to the occurrence of bacterial infections.

Bacterial Adherence and Dwelling Probability: Two Drivers of Early Alveolar Infection by Streptococcus pneumoniae Identified in Multi-Level Mathematical Modeling

PubMed Central

Santos, Guido; Lai, Xin; Eberhardt, Martin; Vera, Julio

2018-01-01

Pneumococcal infection is the most frequent cause of pneumonia, and one of the most prevalent diseases worldwide. The population groups at high risk of death from bacterial pneumonia are infants, elderly and immunosuppressed people. These groups are more vulnerable because they have immature or impaired immune systems, the efficacy of their response to vaccines is lower, and antibiotic treatment often does not take place until the inflammatory response triggered is already overwhelming. The immune response to bacterial lung infections involves dynamic interactions between several types of cells whose activation is driven by intracellular molecular networks. A feasible approach to the integration of knowledge and data linking tissue, cellular and intracellular events and the construction of hypotheses in this area is the use of mathematical modeling. For this paper, we used a multi-level computational model to analyse the role of cellular and molecular interactions during the first 10 h after alveolar invasion of Streptococcus pneumoniae bacteria. By “multi-level” we mean that we simulated the interplay between different temporal and spatial scales in a single computational model. In this instance, we included the intracellular scale of processes driving lung epithelial cell activation together with the scale of cell-to-cell interactions at the alveolar tissue. In our analysis, we combined systematic model simulations with logistic regression analysis and decision trees to find genotypic-phenotypic signatures that explain differences in bacteria strain infectivity. According to our simulations, pneumococci benefit from a high dwelling probability and a high proliferation rate during the first stages of infection. In addition to this, the model predicts that during the very early phases of infection the bacterial capsule could be an impediment to the establishment of the alveolar infection because it impairs bacterial colonization. PMID:29868515

Bacterial Adherence and Dwelling Probability: Two Drivers of Early Alveolar Infection by Streptococcus pneumoniae Identified in Multi-Level Mathematical Modeling.

PubMed

Santos, Guido; Lai, Xin; Eberhardt, Martin; Vera, Julio

2018-01-01

Pneumococcal infection is the most frequent cause of pneumonia, and one of the most prevalent diseases worldwide. The population groups at high risk of death from bacterial pneumonia are infants, elderly and immunosuppressed people. These groups are more vulnerable because they have immature or impaired immune systems, the efficacy of their response to vaccines is lower, and antibiotic treatment often does not take place until the inflammatory response triggered is already overwhelming. The immune response to bacterial lung infections involves dynamic interactions between several types of cells whose activation is driven by intracellular molecular networks. A feasible approach to the integration of knowledge and data linking tissue, cellular and intracellular events and the construction of hypotheses in this area is the use of mathematical modeling. For this paper, we used a multi-level computational model to analyse the role of cellular and molecular interactions during the first 10 h after alveolar invasion of Streptococcus pneumoniae bacteria. By "multi-level" we mean that we simulated the interplay between different temporal and spatial scales in a single computational model. In this instance, we included the intracellular scale of processes driving lung epithelial cell activation together with the scale of cell-to-cell interactions at the alveolar tissue. In our analysis, we combined systematic model simulations with logistic regression analysis and decision trees to find genotypic-phenotypic signatures that explain differences in bacteria strain infectivity. According to our simulations, pneumococci benefit from a high dwelling probability and a high proliferation rate during the first stages of infection. In addition to this, the model predicts that during the very early phases of infection the bacterial capsule could be an impediment to the establishment of the alveolar infection because it impairs bacterial colonization.

Neutrophils are important in early control of lung infection by Yersinia pestis.

PubMed

Laws, Thomas R; Davey, Martin S; Titball, Richard W; Lukaszewski, Roman

2010-04-01

In this paper we evaluate the role of neutrophils in pneumonic plague. Splenic neutrophils from naïve BALB/c mice were found to reduce numbers of culturable Yersinia pestis strain GB in suspension. A murine, BALB/c, intranasal model of pneumonic plague was used in conjunction with in vivo neutrophil ablation, using the GR-1 antibody. This treatment reduced neutrophil numbers without affecting other leukocyte numbers. Neutrophil ablated mice exhibited increased bacterial colonisation of the lung 24h post infection. Furthermore, exposure of Y. pestis to human neutrophils resulted in a 5-fold reduction in the number of viable bacterial cells, whereas, PBMCs had no effect. Crown Copyright 2010. Published by Elsevier SAS. All rights reserved.

Common bacterial skin infections.

PubMed

Trent, J T; Federman, D; Kirsner, R S

2001-08-01

Skin infections account for a significant portion of dermatologic disease, often resulting in or as a consequence of a disruption in the skin's integrity. This article covers the presentation, diagnosis, and treatment of the more common bacterial infections. The infections presented herein include impetigo, ecthyma, folliculitis, carbuncles/furuncles, cellulitis, toxic shock syndrome, and ecthyma gangrenosum. Once a diagnosis is made, treatment is based on the culture and antibiotic sensitivities of the offending organisms.

Effect of exposure to diesel exhaust particles on the susceptibility of the lung to infection.

PubMed

Castranova, V; Ma, J Y; Yang, H M; Antonini, J M; Butterworth, L; Barger, M W; Roberts, J; Ma, J K

2001-08-01

There are at least three mechanisms by which alveolar macrophages play a critical role in protecting the lung from bacterial or viral infections: production of inflammatory cytokines that recruit and activate lung phagocytes, production of antimicrobial reactive oxidant species, and production of interferon (an antiviral agent). In this article we summarize data concerning the effect of exposure to diesel exhaust particles on these alveolar macrophage functions and the role of adsorbed organic chemicals compared to the carbonaceous core in the toxicity of diesel particles. In vitro exposure of rat alveolar macrophages to diesel exhaust particles decreased the ability of lipopolysaccharide (LPS), a bacterial product] to stimulate the production of inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha). Methanol extract exhibited this potential but methanol-washed diesel particles did not. Exposure of rats to diesel exhaust particles by intratracheal instillation also decreased LPS-induced TNF-alpha and IL-1 production from alveolar macrophages. In contrast, carbon black did not exhibit this inhibitory effect. Exposure of rats to diesel exhaust particles by inhalation decreased the ability of alveolar macrophages to produce antimicrobial reactive oxidant species in response to zymosan (a fungal component). In contrast, exposure to coal dust increased zymosan-stimulated oxidant production. In vivo exposure to diesel exhaust particles but not to carbon black decreased the ability of the lungs to clear bacteria. Inhalation exposure of mice to diesel exhaust particles but not to coal dust depressed the ability of the lung to produce the antiviral agent interferon and increased viral multiplication in the lung. These results support the hypothesis that exposure to diesel exhaust particles increases the susceptibility of the lung to infection by depressing the antimicrobial potential of alveolar macrophages. This inhibitory effect appears

Effect of exposure to diesel exhaust particles on the susceptibility of the lung to infection.

PubMed Central

Castranova, V; Ma, J Y; Yang, H M; Antonini, J M; Butterworth, L; Barger, M W; Roberts, J; Ma, J K

2001-01-01

There are at least three mechanisms by which alveolar macrophages play a critical role in protecting the lung from bacterial or viral infections: production of inflammatory cytokines that recruit and activate lung phagocytes, production of antimicrobial reactive oxidant species, and production of interferon (an antiviral agent). In this article we summarize data concerning the effect of exposure to diesel exhaust particles on these alveolar macrophage functions and the role of adsorbed organic chemicals compared to the carbonaceous core in the toxicity of diesel particles. In vitro exposure of rat alveolar macrophages to diesel exhaust particles decreased the ability of lipopolysaccharide (LPS), a bacterial product] to stimulate the production of inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha). Methanol extract exhibited this potential but methanol-washed diesel particles did not. Exposure of rats to diesel exhaust particles by intratracheal instillation also decreased LPS-induced TNF-alpha and IL-1 production from alveolar macrophages. In contrast, carbon black did not exhibit this inhibitory effect. Exposure of rats to diesel exhaust particles by inhalation decreased the ability of alveolar macrophages to produce antimicrobial reactive oxidant species in response to zymosan (a fungal component). In contrast, exposure to coal dust increased zymosan-stimulated oxidant production. In vivo exposure to diesel exhaust particles but not to carbon black decreased the ability of the lungs to clear bacteria. Inhalation exposure of mice to diesel exhaust particles but not to coal dust depressed the ability of the lung to produce the antiviral agent interferon and increased viral multiplication in the lung. These results support the hypothesis that exposure to diesel exhaust particles increases the susceptibility of the lung to infection by depressing the antimicrobial potential of alveolar macrophages. This inhibitory effect appears

Aspirin-triggered resolvin D1 reduces pneumococcal lung infection and inflammation in a viral and bacterial coinfection pneumonia model.

PubMed

Wang, Hao; Anthony, Desiree; Yatmaz, Selcuk; Wijburg, Odilia; Satzke, Catherine; Levy, Bruce; Vlahos, Ross; Bozinovski, Steven

2017-09-15

Formyl peptide receptor 2/lipoxin A 4 (LXA 4 ) receptor (Fpr2/ALX) co-ordinates the transition from inflammation to resolution during acute infection by binding to distinct ligands including serum amyloid A (SAA) and Resolvin D1 (RvD1). Here, we evaluated the proresolving actions of aspirin-triggered RvD1 (AT-RvD1) in an acute coinfection pneumonia model. Coinfection with Streptococcus pneumoniae and influenza A virus (IAV) markedly increased pneumococcal lung load and neutrophilic inflammation during the resolution phase. Fpr2/ALX transcript levels were increased in the lungs of coinfected mice, and immunohistochemistry identified prominent Fpr2/ALX immunoreactivity in bronchial epithelial cells and macrophages. Levels of circulating and lung SAA were also highly increased in coinfected mice. Therapeutic treatment with exogenous AT-RvD1 during the acute phase of infection (day 4-6 post-pneumococcal inoculation) significantly reduced the pneumococcal load. AT-RvD1 also significantly reduced neutrophil elastase (NE) activity and restored total antimicrobial activity in bronchoalveolar lavage (BAL) fluid (BALF) of coinfected mice. Pneumonia severity, as measured by quantitating parenchymal inflammation or alveolitis was significantly reduced with AT-RvD1 treatment, which also reduced the number of infiltrating lung neutrophils and monocytes/macrophages as assessed by flow cytometry. The reduction in distal lung inflammation in AT-RvD1-treated mice was not associated with a significant reduction in inflammatory and chemokine mediators. In summary, we demonstrate that in the coinfection setting, SAA levels were persistently increased and exogenous AT-RvD1 facilitated more rapid clearance of pneumococci in the lungs, while concurrently reducing the severity of pneumonia by limiting excessive leukocyte chemotaxis from the infected bronchioles to distal areas of the lungs. © 2017 The Author(s).

Interleukin-12 Therapy Reduces the Number of Immune Cells and Pathology in Lungs of Mice Infected with Mycobacterium tuberculosis

PubMed Central

Nolt, Dawn; Flynn, JoAnne L.

2004-01-01

Alternate modalities for the treatment of Mycobacterium tuberculosis are needed due to the rise in numbers of immunosuppressed individuals at risk for serious disease and the increasing prevalence of multidrug-resistant isolates. Interleukin-12 (IL-12) has been shown to improve immune responses against M. tuberculosis infection in both humans and mice. Previous studies using high-dose IL-12 in various disease models reported a paradoxical immunosuppression. We demonstrate here that exogenous administration of IL-12 for 8 weeks after an aerosolized low dose of M. tuberculosis results in increased survival and decreased pulmonary bacterial loads for CD4-T-cell-deficient mice, most likely due to an early increase in gamma interferon. IL-12 treatment did not impair or enhance the ability of the wild-type mice to control infection, as measured by bacterial numbers. Two novel findings are reported here regarding exogenous IL-12 therapy for M. tuberculosis infections: (i) IL-12 treatment resulted in decreased numbers of immune cells and reduced frequencies of lymphocytes (CD8+, CD4+, and NK cells) in the lungs of infected mice and (ii) IL-12 therapy reduced the pathology of M. tuberculosis-infected lungs, as granulomas were smaller and less numerous. These studies support an immunoregulatory role for IL-12 in tuberculosis. PMID:15102810

Lung abscess from Staphylococcus aureus after varicella infection in a 3-month-old infant.

PubMed

Aygun, Deniz; Aygun, Fatih; Kılınc, Ayse A; Cam, Halit; Cokugras, Haluk; Camcıoglu, Yıldız

Varicella is a common, highly contagious viral infection of childhood. Varicella is a usually benign and self-limited disease, but it can be complicated by severe bacterial infections, especially in immunocompromised hosts. In this study, we describe a previously healthy 3-months-old infant who was admitted with high fever, cough, and respiratory distress, who had a history of varicella infection three weeks before, with exposure from her adolescent, unvaccinated sister. A lung abscess caused by Staphylococcus aureus complicating the varicella infection was discovered. The patient was aggressively treated with drainage of the abscess and intravenous antibiotics and had a good recovery. Copyright © 2016 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

Risk factors and outcome of bacterial infections in cirrhosis

PubMed Central

Bruns, Tony; Zimmermann, Henning W; Stallmach, Andreas

2014-01-01

Viable and non-viable pathological bacterial translocation promote a self-perpetuating circle of dysfunctional immune activation and systemic inflammation facilitating infections and organ failure in advanced cirrhosis. Bacterial infections and sepsis are now recognized as a distinct stage in the natural progression of chronic liver disease as they accelerate organ failure and contribute to the high mortality observed in decompensated cirrhosis. The increasing knowledge of structural, immunological and hemodynamic pathophysiology in advanced cirrhosis has not yet translated into significantly improved outcomes of bacterial infections over the last decades. Therefore, early identification of patients at the highest risk for developing infections and infection-related complications is required to tailor the currently available measures of surveillance, prophylaxis and therapy to the patients in need in order to improve the detrimental outcome of bacterial infections in cirrhosis. PMID:24627590

Cigarette Smoke Exposure Exacerbates Lung Inflammation and Compromises Immunity to Bacterial Infection

PubMed Central

Lugade, Amit A.; Bogner, Paul N.; Thatcher, Thomas H.; Sime, Patricia J.; Phipps, Richard P.; Thanavala, Yasmin

2014-01-01

The detrimental impact of tobacco on human health is clearly recognized and despite aggressive efforts to prevent smoking, close to one billion individuals worldwide continue to smoke. People with chronic obstructive pulmonary disease (COPD) are susceptible to recurrent respiratory infections with pathogens, including non-typeable Haemophilus influenzae (NTHI), yet the reasons for this increased susceptibility are poorly understood. As mortality rapidly increases with multiple exacerbations, development of protective immunity is critical to improving patient survival. Acute NTHI infection has been studied in the context of cigarette smoke exposure, but this is the first study to investigate chronic infection and the generation of adaptive immune responses to NTHI following chronic smoke exposure. After chronic NTHI infection, mice that had previously been exposed to cigarette smoke developed increased lung inflammation and compromised adaptive immunity relative to air-exposed controls. Importantly, NTHI-specific T cells from mice exposed to cigarette smoke produced lower levels of IFN-γ and IL-4, and B cells produced reduced levels of antibodies against outer membrane lipoprotein P6, with impaired IgG1, IgG2a and IgA class-switching. However, production of IL-17, which is associated with neutrophilic inflammation, was enhanced. Interestingly, cigarette smoke exposed mice exhibited a similar defect in the generation of adaptive immunity following immunization with P6. Our study has conclusively demonstrated that cigarette smoke exposure has a profound suppressive effect on the generation of adaptive immune responses to NTHI and suggests the mechanism by which prior cigarette smoke exposure predisposes COPD patients to recurrent infections, leading to exacerbations and contributing to mortality. PMID:24752444

Gallium scintigraphic pattern in lung CMV infections

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

Ganz, W.I.; Cohen, D.; Mallin, W.

1994-05-01

Due to extensive use of prophylactic therapy for Pneumonitis Carinii Pneumonia (PCP), Cytomegalic Viral (CMV) infection may now be the most common lung infection in AIDS patients. This study was performed to determine Gallium-67 patterns in AIDS patients with CMV. Pathology reports were reviewed in AIDS patients who had a dose of 5 to 10 mCi of Gallium-67 citrate. Analysis of images were obtained 48-72 hours later of the entire body was performed. Gallium-67 scans in 14 AIDS patients with biopsy proven CMV, were evaluated for eye, colon, adrenal, lung and renal uptake. These were compared to 40 AIDS patientsmore » without CMV. These controls had infections including PCP, Mycobacterial infections, and lymphocytic interstitial pneumonitis. 100% of CMV patients had bowel uptake greater than or equal to liver. Similar bowel activity was seen in 50% of AIDS patients without CMV. 71% had intense eye uptake which was seen in only 10% of patients without CMV. 50% of CMV patients had renal uptake compared to 5% of non-CMV cases. Adrenal uptake was suggested in 50%, however, SPECT imaging is needed for confirmation. 85% had low grade lung uptake. The low grade lung had perihilar prominence. The remaining 15% had high grade lung uptake (greater than sternum) due to superimposed PCP infection. Colon uptake is very sensitive indicator for CMV infection. However, observing eye, renal, and or adrenal uptake improved the diagnostic specificity. SPECT imaging is needed to confirm renal or adrenal abnormalities due to intense bowel activity present in 100% of cases. When high grade lung uptake is seen superimposed PCP is suggested.« less

Low pretransplant IgA level is associated with early post-lung transplant seromucous infection.

PubMed

Murthy, Sudish C; Avery, Robin K; Budev, Marie; Gupta, Sandeep; Pettersson, Gösta B; Nowicki, Edward R; Mehta, Atul; Chapman, Jeffrey T; Rajeswaran, Jeevanantham; Blackstone, Eugene H

2018-04-13

Infection is an important cause of morbidity and mortality after lung transplantation. Immunoglobulins are part of both seromucous (IgA) and serum (IgG) infection defense mechanisms. We therefore hypothesized that lower pretransplant IgA levels would be associated with more early post-lung transplant seromucous infections and greater mortality independent of IgG. From January 2000 to July 2010, 538 patients undergoing primary lung transplantation had pretransplant IgA (n = 429) and IgG (n = 488) measured as a clinical routine. Median IgA was 200 mg·dL -1 (2% < 70 mg·dL -1 , lower limit of normal); median IgG was 970 mg·dL -1 (5% < 600 mg·dL -1 ). Intensive microbiology review was used to categorize infections and their causative organisms within the first posttransplant year. In total, 397 seromucous infections were observed in 247 patients, most bacterial. Although IgA and IgG were moderately correlated (r = 0.5, P < .0001), low pretransplant IgA was a strong risk factor (P = .01) for seromucous infections, but pretransplant IgG was not (P ≥ .6). As pretransplant IgA levels fell below 200 mg·dL -1 , the risk of these posttransplant infections rose nearly linearly. Lower pretransplant levels of IgA were associated with greater posttransplant mortality to end of follow-up (P = .004), but pretransplant IgG was not (P ≥ .3). Low levels of preoperative IgA, an important immunoglobulin involved in mucosal immunologic defense, but not IgG, are associated with seromucous infections in the year after lung transplantation and increased follow-up mortality. It would appear prudent to identify patients with relative IgA deficiency at listing and to increase vigilance of monitoring for, and prophylaxis against, seromucous infection in this high-risk population. Copyright © 2018. Published by Elsevier Inc.

Hyperglycemia Impairs Neutrophil-Mediated Bacterial Clearance in Mice Infected with the Lyme Disease Pathogen.

PubMed

Javid, Ashkan; Zlotnikov, Nataliya; Pětrošová, Helena; Tang, Tian Tian; Zhang, Yang; Bansal, Anil K; Ebady, Rhodaba; Parikh, Maitry; Ahmed, Mijhgan; Sun, Chunxiang; Newbigging, Susan; Kim, Yae Ram; Santana Sosa, Marianna; Glogauer, Michael; Moriarty, Tara J

2016-01-01

Insulin-insufficient type 1 diabetes is associated with attenuated bactericidal function of neutrophils, which are key mediators of innate immune responses to microbes as well as pathological inflammatory processes. Neutrophils are central to immune responses to the Lyme pathogen Borrelia burgdorferi. The effect of hyperglycemia on host susceptibility to and outcomes of B. burgdorferi infection has not been examined. The present study investigated the impact of sustained obesity-independent hyperglycemia in mice on bacterial clearance, inflammatory pathology and neutrophil responses to B. burgdorferi. Hyperglycemia was associated with reduced arthritis incidence but more widespread tissue colonization and reduced clearance of bacterial DNA in multiple tissues including brain, heart, liver, lung and knee joint. B. burgdorferi uptake and killing were impaired in neutrophils isolated from hyperglycemic mice. Thus, attenuated neutrophil function in insulin-insufficient hyperglycemia was associated with reduced B. burgdorferi clearance in target organs. These data suggest that investigating the effects of comorbid conditions such as diabetes on outcomes of B. burgdorferi infections in humans may be warranted.

Comparison of Bacterial Burden and Cytokine Gene Expression in Golden Hamsters in Early Phase of Infection with Two Different Strains of Leptospira interrogans.

PubMed

Fujita, Rie; Koizumi, Nobuo; Sugiyama, Hiromu; Tomizawa, Rina; Sato, Ryoichi; Ohnishi, Makoto

2015-01-01

Leptospirosis, a zoonotic infection with worldwide prevalence, is caused by pathogenic spirochaetes of Leptospira spp., and exhibits an extremely broad clinical spectrum in human patients. Although previous studies indicated that specific serovars or genotypes of Leptospira spp. were associated with severe leptospirosis or its outbreak, the mechanism underlying the difference in virulence of the various Leptospira serotypes or genotypes remains unclear. The present study addresses this question by measuring and comparing bacterial burden and cytokine gene expression in hamsters infected with strains of two L. interrogans serovars Manilae (highly virulent) and Hebdomadis (less virulent). The histopathology of kidney, liver, and lung tissues was also investigated in infected hamsters. A significantly higher bacterial burden was observed in liver tissues of hamsters infected with serovar Manilae than those infected with serovar Hebdomadis (p < 0.01). The average copy number of the leptospiral genome was 1,302 and 20,559 in blood and liver, respectively, of hamsters infected with serovar Manilae and 1,340 and 4,896, respectively, in hamsters infected with serovar Hebdomadis. The expression levels of mip1alpha in blood; tgfbeta, il1beta, mip1alpha, il10, tnfalpha and cox2 in liver; and tgfbeta, il6, tnfalpha and cox2 in lung tissue were significantly higher in hamsters infected with serovar Manilae than those infected with serovar Hebdomadis (p < 0.05). In addition, infection with serovar Manilae resulted in a significantly larger number of hamsters with tnfalpha upregulation (p = 0.04). Severe distortion of tubular cell arrangement and disruption of renal tubules in kidney tissues and hemorrhage in lung tissues were observed in Manilae-infected hamsters. These results demonstrate that serovar Manilae multiplied more efficiently in liver tissues and induced significantly higher expression of genes encoding pro- and anti-inflammatory cytokines than serovar Hebdomadis

Comparison of Bacterial Burden and Cytokine Gene Expression in Golden Hamsters in Early Phase of Infection with Two Different Strains of Leptospira interrogans

PubMed Central

Fujita, Rie; Koizumi, Nobuo; Sugiyama, Hiromu; Tomizawa, Rina; Sato, Ryoichi; Ohnishi, Makoto

2015-01-01

Leptospirosis, a zoonotic infection with worldwide prevalence, is caused by pathogenic spirochaetes of Leptospira spp., and exhibits an extremely broad clinical spectrum in human patients. Although previous studies indicated that specific serovars or genotypes of Leptospira spp. were associated with severe leptospirosis or its outbreak, the mechanism underlying the difference in virulence of the various Leptospira serotypes or genotypes remains unclear. The present study addresses this question by measuring and comparing bacterial burden and cytokine gene expression in hamsters infected with strains of two L. interrogans serovars Manilae (highly virulent) and Hebdomadis (less virulent). The histopathology of kidney, liver, and lung tissues was also investigated in infected hamsters. A significantly higher bacterial burden was observed in liver tissues of hamsters infected with serovar Manilae than those infected with serovar Hebdomadis (p < 0.01). The average copy number of the leptospiral genome was 1,302 and 20,559 in blood and liver, respectively, of hamsters infected with serovar Manilae and 1,340 and 4,896, respectively, in hamsters infected with serovar Hebdomadis. The expression levels of mip1alpha in blood; tgfbeta, il1beta, mip1alpha, il10, tnfalpha and cox2 in liver; and tgfbeta, il6, tnfalpha and cox2 in lung tissue were significantly higher in hamsters infected with serovar Manilae than those infected with serovar Hebdomadis (p < 0.05). In addition, infection with serovar Manilae resulted in a significantly larger number of hamsters with tnfalpha upregulation (p = 0.04). Severe distortion of tubular cell arrangement and disruption of renal tubules in kidney tissues and hemorrhage in lung tissues were observed in Manilae-infected hamsters. These results demonstrate that serovar Manilae multiplied more efficiently in liver tissues and induced significantly higher expression of genes encoding pro- and anti-inflammatory cytokines than serovar Hebdomadis

Genes Required for Free Phage Production are Essential for Pseudomonas aeruginosa Chronic Lung Infections.

PubMed

Lemieux, Andrée-Ann; Jeukens, Julie; Kukavica-Ibrulj, Irena; Fothergill, Joanne L; Boyle, Brian; Laroche, Jérôme; Tucker, Nicholas P; Winstanley, Craig; Levesque, Roger C

2016-02-01

The opportunistic pathogen Pseudomonas aeruginosa causes chronic lung infection in patients with cystic fibrosis. The Liverpool Epidemic Strain LESB58 is highly resistant to antibiotics, transmissible, and associated with increased morbidity and mortality. Its genome contains 6 prophages and 5 genomic islands. We constructed a polymerase chain reaction (PCR)-based signature-tagged mutagenesis library of 9216 LESB58 mutants and screened the mutants in a rat model of chronic lung infection. A total of 162 mutants were identified as defective for in vivo maintenance, with 11 signature-tagged mutagenesis mutants having insertions in prophage and genomic island genes. Many of these mutants showed both diminished virulence and reduced phage production. Transcription profiling by quantitative PCR and RNA-Seq suggested that disruption of these prophages had a widespread trans-acting effect on the transcriptome. This study demonstrates that temperate phages play a pivotal role in the establishment of infection through modulation of bacterial host gene expression. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Influenza viral neuraminidase primes bacterial coinfection through TGF-β-mediated expression of host cell receptors.

PubMed

Li, Ning; Ren, Aihui; Wang, Xiaoshuang; Fan, Xin; Zhao, Yong; Gao, George F; Cleary, Patrick; Wang, Beinan

2015-01-06

Influenza infection predisposes the host to secondary bacterial pneumonia, which is a major cause of mortality during influenza epidemics. The molecular mechanisms underlying the bacterial coinfection remain elusive. Neuraminidase (NA) of influenza A virus (IAV) enhances bacterial adherence and also activates TGF-β. Because TGF-β can up-regulate host adhesion molecules such as fibronectin and integrins for bacterial binding, we hypothesized that activated TGF-β during IAV infection contributes to secondary bacterial infection by up-regulating these host adhesion molecules. Flow cytometric analyses of a human lung epithelial cell line indicated that the expression of fibronectin and α5 integrin was up-regulated after IAV infection or treatment with recombinant NA and was reversed through the inhibition of TGF-β signaling. IAV-promoted adherence of group A Streptococcus (GAS) and other coinfective pathogens that require fibronectin for binding was prevented significantly by the inhibition of TGF-β. However, IAV did not promote the adherence of Lactococcus lactis unless this bacterium expressed the fibronectin-binding protein of GAS. Mouse experiments showed that IAV infection enhanced GAS colonization in the lungs of wild-type animals but not in the lungs of mice deficient in TGF-β signaling. Taken together, these results reveal a previously unrecognized mechanism: IAV NA enhances the expression of cellular adhesins through the activation of TGF-β, leading to increased bacterial loading in the lungs. Our results suggest that TGF-β and cellular adhesins may be potential pharmaceutical targets for the prevention of coinfection.

Type II secretion system of Pseudomonas aeruginosa: in vivo evidence of a significant role in death due to lung infection.

PubMed

Jyot, Jeevan; Balloy, Viviane; Jouvion, Gregory; Verma, Amrisha; Touqui, Lhousseine; Huerre, Michel; Chignard, Michel; Ramphal, Reuben

2011-05-15

The role of toxins secreted by the type II secretion system (T2SS) of Pseudomonas aeruginosa during lung infection has been uncertain despite decades of research. Using a model of pneumonia in Toll-like receptor (TLR) 2,4(-/-) mice, we reexamined the role of the T2SS system. Flagellin-deficient mutants of P. aeruginosa, with mutations in the T2SS and/or T3SS, were used to infect mice. Mice were followed up for survival, with some killed at different intervals to study bacterial clearance, inflammatory responses, and lung pathology. Strains carrying either secretion system were lethal for mice. Double mutants were avirulent. The T3SS(+) strains killed mice within a day, and the T2SS(+) strains killed them later. Mice infected with a strain that had only the T2SS were unable to eradicate the organism from the lungs, whereas those infected with a T2SS-T3SS double deletion were able to clear this mutant. Death caused by the T2SS(+) strain was accompanied by a >50-fold increase in bacterial counts and higher numbers of viable intracellular bacteria. The T2SS of P. aeruginosa may play a role in death from pneumonia, but its action is delayed. These data suggest that antitoxin strategies against this organism will require measures against the toxins secreted by both T2SS and T3SS.

A Lung Segmental Model of Chronic Pseudomonas Infection in Sheep

PubMed Central

Collie, David; Govan, John; Wright, Steven; Thornton, Elisabeth; Tennant, Peter; Smith, Sionagh; Doherty, Catherine; McLachlan, Gerry

2013-01-01

Background Chronic lung infection with Pseudomonas aeruginosa is a major contributor to morbidity, mortality and premature death in cystic fibrosis. A new paradigm for managing such infections is needed, as are relevant and translatable animal models to identify and test concepts. We sought to improve on limitations associated with existing models of infection in small animals through developing a lung segmental model of chronic Pseudomonas infection in sheep. Methodology/Principal Findings Using local lung instillation of P. aeruginosa suspended in agar beads we were able to demonstrate that such infection led to the development of a suppurative, necrotising and pyogranulomatous pneumonia centred on the instilled beads. No overt evidence of organ or systemic compromise was apparent in any animal during the course of infection. Infection persisted in the lungs of individual animals for as long as 66 days after initial instillation. Quantitative microbiology applied to bronchoalveolar lavage fluid derived from infected segments proved an insensitive index of the presence of significant infection in lung tissue (>104 cfu/g). Conclusions/Significance The agar bead model of chronic P. aeruginosa lung infection in sheep is a relevant platform to investigate both the pathobiology of such infections as well as novel approaches to their diagnosis and therapy. Particular ethical benefits relate to the model in terms of refining existing approaches by compromising a smaller proportion of the lung with infection and facilitating longitudinal assessment by bronchoscopy, and also potentially reducing animal numbers through facilitating within-animal comparisons of differential therapeutic approaches. PMID:23874438

Lung Infections Associated with Cystic Fibrosis

PubMed Central

Lyczak, Jeffrey B.; Cannon, Carolyn L.; Pier, Gerald B.

2002-01-01

While originally characterized as a collection of related syndromes, cystic fibrosis (CF) is now recognized as a single disease whose diverse symptoms stem from the wide tissue distribution of the gene product that is defective in CF, the ion channel and regulator, cystic fibrosis transmembrane conductance regulator (CFTR). Defective CFTR protein impacts the function of the pancreas and alters the consistency of mucosal secretions. The latter of these effects probably plays an important role in the defective resistance of CF patients to many pathogens. As the modalities of CF research have changed over the decades from empirical histological studies to include biophysical measurements of CFTR function, the clinical management of this disease has similarly evolved to effectively address the ever-changing spectrum of CF-related infectious diseases. These factors have led to the successful management of many CF-related infections with the notable exception of chronic lung infection with the gram-negative bacterium Pseudomonas aeruginosa. The virulence of P. aeruginosa stems from multiple bacterial attributes, including antibiotic resistance, the ability to utilize quorum-sensing signals to form biofilms, the destructive potential of a multitude of its microbial toxins, and the ability to acquire a mucoid phenotype, which renders this microbe resistant to both the innate and acquired immunologic defenses of the host. PMID:11932230

Bacterial Infections in Children With Acute Myeloid Leukemia Receiving Ciprofloxacin Prophylaxis.

PubMed

Al Omar, Suha; Anabtawi, Nadine; Al Qasem, Wiam; Rihani, Rawad

2017-04-01

The aim of the study was to describe the incidence and type of bacterial infections associated with the use of ciprofloxacin prophylaxis as single agent in pediatric patients with acute myeloid leukemia (AML). This was a retrospective review of all patients with AML, who were treated according to the AML02 protocol between 2011 and 2015. The medical records were reviewed for any positive cultures from the initiation of the protocol until death or protocol discontinuation. Patient demographics, type of infections, type of isolated bacteria, and intensive care unit admissions were recorded. A total of 50 patients were evaluated, who were of a mean age of 8 years±5.1 (SD). We identified 77 episodes of bacterial infections in 42 (84%) patients. Among those bacterial infections, 73 episodes were with bacteremia and included 45 (62%) gram-positive bacterial infections, 24 (33%) gram-negative bacterial infections, and 4 (6%) mixed gram-negative and gram-positive bacterial infections. Coagulase-negative Staphylococcus and Viridans streptococci were the most commonly isolated bacteria in 33% and 30% of the episodes, respectively. Seventeen (45%) patients with bacteremia required intensive care unit admission. A high rate of bacterial infection was detected in patients who received the AML02 protocol, mainly gram-positive bacterial infections. The prophylactic regimen should be reconsidered for its efficacy, and other antibacterial prophylaxis may be used.

Premedication with Clarithromycin Is Effective against Secondary Bacterial Pneumonia during Influenza Virus Infection in a Pulmonary Emphysema Mouse Model.

PubMed

Harada, Tatsuhiko; Ishimatsu, Yuji; Hara, Atsuko; Morita, Towako; Nakashima, Shota; Kakugawa, Tomoyuki; Sakamoto, Noriho; Kosai, Kosuke; Izumikawa, Koichi; Yanagihara, Katsunori; Mukae, Hiroshi; Kohno, Shigeru

2016-09-01

Secondary bacterial pneumonia (SBP) during influenza increases the severity of chronic obstructive pulmonary disease (COPD) and its associated mortality. Macrolide antibiotics, including clarithromycin (CAM), are potential treatments for a variety of chronic respiratory diseases owing to their pharmacological activities, in addition to antimicrobial action. We examined the efficacy of CAM for the treatment of SBP after influenza infection in COPD. Specifically, we evaluated the effect of CAM in elastase-induced emphysema mice that were inoculated with influenza virus (strain A/PR8/34) and subsequently infected with macrolide-resistant Streptococcus pneumoniae CAM was administered to the emphysema mice 4 days prior to influenza virus inoculation. Premedication with CAM improved pathologic responses and bacterial load 2 days after S. pneumoniae inoculation. Survival rates were higher in emphysema mice than control mice. While CAM premedication did not affect viral titers or exert antibacterial activity against S. pneumoniae in the lungs, it enhanced host defense and reduced inflammation, as evidenced by the significant reductions in total cell and neutrophil counts and interferon (IFN)-γ levels in bronchoalveolar lavage fluid and lung homogenates. These results suggest that CAM protects against SBP during influenza in elastase-induced emphysema mice by reducing IFN-γ production, thus enhancing immunity to SBP, and by decreasing neutrophil infiltration into the lung to prevent injury. Accordingly, CAM may be an effective strategy to prevent secondary bacterial pneumonia in COPD patients in areas in which vaccines are inaccessible or limited. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

MicroRNA-155 regulates host immune response to postviral bacterial pneumonia via IL-23/IL-17 pathway.

PubMed

Podsiad, Amy; Standiford, Theodore J; Ballinger, Megan N; Eakin, Richard; Park, Pauline; Kunkel, Steven L; Moore, Bethany B; Bhan, Urvashi

2016-03-01

Postinfluenza bacterial pneumonia is associated with significant mortality and morbidity. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. miR-155 has recently emerged as a crucial regulator of innate immunity and inflammatory responses and is induced in macrophages during infection. We hypothesized upregulation of miR-155 inhibits IL-17 and increases susceptibility to secondary bacterial pneumonia. Mice were challenged with 100 plaque-forming units H1N1 intranasally and were infected with 10(7) colony-forming units of MRSA intratracheally at day 5 postviral challenge. Lungs were harvested 24 h later, and expression of miR-155, IL-17, and IL-23 was measured by real-time RT-PCR. Induction of miR-155 was 3.6-fold higher in dual-infected lungs compared with single infection. miR-155(-/-) mice were protected with significantly lower (4-fold) bacterial burden and no differences in viral load, associated with robust induction of IL-23 and IL-17 (2.2- and 4.8-fold, respectively) postsequential challenge with virus and bacteria, compared with WT mice. Treatment with miR-155 antagomir improved lung bacterial clearance by 4.2-fold compared with control antagomir postsequential infection with virus and bacteria. Moreover, lung macrophages collected from patients with postviral bacterial pneumonia also had upregulation of miR-155 expression compared with healthy controls, consistent with observations in our murine model. This is the first demonstration that cellular miRNAs regulate postinfluenza immune response to subsequent bacterial challenge by suppressing the IL-17 pathway in the lung. Our findings suggest that antagonizing certain microRNA might serve as a potential therapeutic strategy against secondary bacterial infection. Copyright © 2016 the American Physiological Society.

[Mold infections in lung transplants].

PubMed

Solé, Amparo; Ussetti, Piedad

2014-01-01

Invasive infections by molds, mainly Aspergillus infections, account for more than 10% of infectious complications in lung transplant recipients. These infections have a bimodal presentation: an early one, mainly invading bronchial airways, and a late one, mostly focused on lung or disseminated. The Aspergillus colonization at any time in the post-transplant period is one of the major risk factors. Late colonization, together with chronic rejection, is one of the main causes of late invasive forms. A galactomannan value of 0.5 in bronchoalveolar lavage is currently considered a predictive factor of pulmonary invasive infection. There is no universal strategy in terms of prophylaxis. Targeted prophylaxis and preemptive treatment instead of universal prophylaxis, are gaining more followers. The therapeutic drug monitoring level of azoles is highly recommended in the treatment. Monotherapy with voriconazole is the treatment of choice in invasive aspergillosis; combined antifungal therapies are only recommended in severe, disseminated, and other infections due to non-Aspergillus molds. Copyright © 2014 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

Bacterial Co-infection in Hospitalized Children with Mycoplasma pneumoniae Pneumonia.

PubMed

Song, Qing; Xu, Bao-Ping; Shen, Kun-Ling

2016-10-08

To describe the frequency and impact of bacterial co-infections in children hospitalized with Mycoplasma pneumoniae pneumonia. Retrospective, descriptive study. Tertiary-care hospital in Beijing, China. 8612 children admitted to Beijing Childrens Hospital from June 2006 to June 2014. According to the testing results of etiology we divided the cases into pure M. pneumoniae infection group and mixed bacterial infection group. We analyzed clinical features, hospital expenses and differences between these two groups. 173 (2%) of included children had bacterial coinfection. 56.2% of bacterial pathogens were identified as Streptococcus pneumoniae. The most common bacterium causing co-infection in children with M. pneumoniae pneumonia was S. pneumoniae.

Exploring bacterial infections: theoretical and experimental studies of the bacterial population dynamics and antibiotic treatment

NASA Astrophysics Data System (ADS)

Shao, Xinxian

Bacterial infections are very common in human society. Thus extensive research has been conducted to reveal the molecular mechanisms of the pathogenesis and to evaluate the antibiotics' efficacy against bacteria. Little is known, however, about the population dynamics of bacterial populations and their interactions with the host's immune system. In this dissertation, a stochatic model is developed featuring stochastic phenotypic switching of bacterial individuals to explain the single-variant bottleneck discovered in multi strain bacterial infections. I explored early events in a bacterial infection establishment using classical experiments of Moxon and Murphy on neonatal rats. I showed that the minimal model and its simple variants do not work. I proposed modifications to the model that could explain the data quantitatively. The bacterial infections are also commonly established in physical structures, as biofilms or 3-d colonies. In contrast, most research on antibiotic treatment of bacterial infections has been conducted in well-mixed liquid cultures. I explored the efficacy of antibiotics to treat such bacterial colonies, a broadly applicable method is designed and evaluated where discrete bacterial colonies on 2-d surfaces were exposed to antibiotics. I discuss possible explanations and hypotheses for the experimental results. To verify these hypotheses, we investigated the dynamics of bacterial population as 3-d colonies. We showed that a minimal mathematical model of bacterial colony growth in 3-d was able to account for the experimentally observed presence of a diffusion-limited regime. The model further revealed highly loose packing of the cells in 3-d colonies and smaller cell sizes in colonies than plancktonic cells in corresponding liquid culture. Further experimental tests of the model predictions have revealed that the ratio of the cell size in liquid culture to that in colony cultures was consistent with the model prediction, that the dead cells

Incidence and Predictors of Bacterial infection in Febrile Children with Sickle Cell Disease.

PubMed

Morrissey, Benita J; Bycroft, Thomas P; Almossawi, Ofran; Wilkey, Olufunke B; Daniels, Justin G

2015-01-01

Children with sickle cell disease are at increased risk of developing bacteremia and other serious bacterial infections. Fever is a common symptom in sickle cell disease and can also occur with sickle cell crises and viral infections. We aimed to evaluate the incidence and predictors of bacteremia and bacterial infection in children with sickle cell disease presenting with fever to a district hospital and sickle cell center in London. A retrospective analysis was performed on all attendances of children (aged under 16 years) with sickle cell disease presenting with a fever of 38.5 °C or higher over a 1-year period. Confirmed bacterial infection was defined as bacteremia, bacterial meningitis, urinary tract infection (UTI), pneumonia, osteomyelitis or other bacterial infection with positive identification of organism. Children were defined as having a suspected bacterial infection if a bacterial infection was suspected clinically, but no organism was identified. Over a 1-year period there were 88 episodes analyzed in 59 children. Bacteremia occurred in 3.4% of episodes and confirmed bacterial infection in 7.0%. Suspected bacterial infection occurred in 33.0%. One death occurred from Salmonella typhirium septicemia. C-reactive protein (CRP) level and white blood cell (WBC) count were both significantly associated with bacterial infection (p = 0.004 and 0.02, respectively.) In conclusion, bacterial infections continue to be a significant problem in children with sickle cell disease. C-reactive protein was significantly associated with bacterial infections, and could be included in clinical risk criteria for febrile children with sickle cell disease.

Diagnostic markers of serious bacterial infections in febrile infants younger than 90 days old.

PubMed

Nosrati, Adi; Ben Tov, Amir; Reif, Shimon

2014-02-01

The aim of this study was to assess correlations between demographic, clinical and laboratory characteristics and the risk of serious bacterial infection (SBI) in febrile <90-day-old infants. Medical records of all infants younger than 90 days old hospitalized at Dana-Dwek Children's Hospital (2006-2008) for evaluation of fever were retrospectively reviewed. Data on clinical, laboratory and demographic characteristics were retrieved and evaluated. Forty-eight of the 401 study infants (12%) had SBI: most of them had urinary tract infection (43 infants; 90% of all SBI), three infants had bacteremia, one had bacterial pneumonia and one had bacterial meningitis. Significant independent clinical predictors for the diagnosis of SBI included duration of fever, absence of rhinitis and the absence of lung and skin manifestations. Significant independent laboratory predictors were absolute neutrophil count (ANC), platelets, blood urea nitrogen and C-reactive protein (CRP) level. On receiver operating characteristic curve analysis, the CRP area under the curve (0.819) was significantly superior to ANC and leukocyte count. Of the clinical and laboratory variables selected for evaluation, qualitative CRP was the strongest independent predictor for diagnosing SBI and a significantly better diagnostic marker than clinical characteristics, ANC and white blood cell count. © 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.

Mycobacterium tuberculosis Cell Wall Fragments Released upon Bacterial Contact with the Human Lung Mucosa Alter the Neutrophil Response to Infection

PubMed Central

Scordo, Julia M.; Arcos, Jesús; Kelley, Holden V.; Diangelo, Lauren; Sasindran, Smitha J.; Youngmin, Ellie; Wewers, Mark D.; Wang, Shu-Hua; Balada-Llasat, Joan-Miquel; Torrelles, Jordi B.

2017-01-01

In 2016, the World Health Organization reported that one person dies of tuberculosis (TB) every 21 s. A host environment that Mycobacterium tuberculosis (M.tb) finds during its route of infection is the lung mucosa bathing the alveolar space located in the deepest regions of the lungs. We published that human lung mucosa, or alveolar lining fluid (ALF), contains an array of hydrolytic enzymes that can significantly alter the M.tb surface during infection by cleaving off parts of its cell wall. This interaction results in two different outcomes: modifications on the M.tb cell wall surface and release of M.tb cell wall fragments into the environment. Typically, one of the first host immune cells at the site of M.tb infection is the neutrophil. Neutrophils can mount an extracellular and intracellular innate immune response to M.tb during infection. We hypothesized that exposure of neutrophils to ALF-induced M.tb released cell wall fragments would prime neutrophils to control M.tb infection better. Our results show that ALF fragments activate neutrophils leading to an increased production of inflammatory cytokines and oxidative radicals. However, neutrophil exposure to these fragments reduces production of chemoattractants (i.e., interleukin-8), and degranulation, with the subsequent reduction of myeloperoxidase release, and does not induce cytotoxicity. Unexpectedly, these ALF fragment-derived modulations in neutrophil activity do not further, either positively or negatively, contribute to the intracellular control of M.tb growth during infection. However, secreted products from neutrophils primed with ALF fragments are capable of regulating the activity of resting macrophages. These results indicate that ALF-induced M.tb fragments could further contribute to the control of M.tb growth and local killing by resident neutrophils by switching on the total oxidative response and limiting migration of neutrophils to the infection site. PMID:28373877

Mycobacterium tuberculosis Cell Wall Fragments Released upon Bacterial Contact with the Human Lung Mucosa Alter the Neutrophil Response to Infection.

PubMed

Scordo, Julia M; Arcos, Jesús; Kelley, Holden V; Diangelo, Lauren; Sasindran, Smitha J; Youngmin, Ellie; Wewers, Mark D; Wang, Shu-Hua; Balada-Llasat, Joan-Miquel; Torrelles, Jordi B

2017-01-01

In 2016, the World Health Organization reported that one person dies of tuberculosis (TB) every 21 s. A host environment that Mycobacterium tuberculosis ( M.tb ) finds during its route of infection is the lung mucosa bathing the alveolar space located in the deepest regions of the lungs. We published that human lung mucosa, or alveolar lining fluid (ALF), contains an array of hydrolytic enzymes that can significantly alter the M.tb surface during infection by cleaving off parts of its cell wall. This interaction results in two different outcomes: modifications on the M.tb cell wall surface and release of M.tb cell wall fragments into the environment. Typically, one of the first host immune cells at the site of M.tb infection is the neutrophil. Neutrophils can mount an extracellular and intracellular innate immune response to M.tb during infection. We hypothesized that exposure of neutrophils to ALF-induced M.tb released cell wall fragments would prime neutrophils to control M.tb infection better. Our results show that ALF fragments activate neutrophils leading to an increased production of inflammatory cytokines and oxidative radicals. However, neutrophil exposure to these fragments reduces production of chemoattractants (i.e., interleukin-8), and degranulation, with the subsequent reduction of myeloperoxidase release, and does not induce cytotoxicity. Unexpectedly, these ALF fragment-derived modulations in neutrophil activity do not further, either positively or negatively, contribute to the intracellular control of M.tb growth during infection. However, secreted products from neutrophils primed with ALF fragments are capable of regulating the activity of resting macrophages. These results indicate that ALF-induced M.tb fragments could further contribute to the control of M.tb growth and local killing by resident neutrophils by switching on the total oxidative response and limiting migration of neutrophils to the infection site.

Epidemic of Lung Cancer in Patients With HIV Infection

PubMed Central

Winstone, Tiffany A.; Man, S. F. Paul; Hull, Mark; Montaner, Julio S.

2013-01-01

The survival of patients with HIV infection has improved dramatically over the past 20 years, largely owing to a significant reduction in opportunistic infections and AIDs-defining malignancies, such as lymphoma and Kaposi sarcoma. However, with improved survival, patients with HIV are experiencing morbidity and mortality from other (non-AIDs-defining) complications, such as solid organ malignancies. Of these, the leading cause of mortality in the HIV-infected population is lung cancer, accounting for nearly 30% of all cancer deaths and 10% of all non-HIV-related deaths. Importantly, the average age of onset of lung cancer in the HIV-infected population is 25 to 30 years earlier than that in the general population and at lower exposure to cigarette smoke. This article provides an overview of the epidemiology of lung cancer in the HIV-infected population and discusses some of the important risk factors and pathways that may enhance the risk of lung cancer in this population. PMID:23381313

IL-22 Is Essential for Lung Epithelial Repair following Influenza Infection

PubMed Central

Pociask, Derek A.; Scheller, Erich V.; Mandalapu, Sivanarayana; McHugh, Kevin J.; Enelow, Richard I.; Fattman, Cheryl L.; Kolls, Jay K.; Alcorn, John F.

2014-01-01

Influenza infection is widespread in the United States and the world. Despite low mortality rates due to infection, morbidity is common and little is known about the molecular events involved in recovery. Influenza infection results in persistent distal lung remodeling, and the mechanism(s) involved are poorly understood. Recently IL-22 has been found to mediate epithelial repair. We propose that IL-22 is critical for recovery of normal lung function and architecture after influenza infection. Wild-type and IL-22−/− mice were infected with influenza A PR8/34 H1N1 and were followed up for up to 21 days post infection. IL-22 receptor was localized to the airway epithelium in naive mice but was expressed at the sites of parenchymal lung remodeling induced by influenza infection. IL-22−/− mice displayed exacerbated lung injury compared with wild-type mice, which correlated with decreased lung function 21 days post infection. Epithelial metaplasia was observed in wild-type mice but was not evident in IL-22−/− animals that were characterized with an increased fibrotic phenotype. Gene expression analysis revealed aberrant expression of epithelial genes involved in repair processes, among changes in several other biological processes. These data indicate that IL-22 is required for normal lung repair after influenza infection. IL-22 represents a novel pathway involved in interstitial lung disease. PMID:23490254

Macrophage Autophagy and Bacterial Infections

PubMed Central

Bah, Aïcha; Vergne, Isabelle

2017-01-01

Autophagy is a well-conserved lysosomal degradation pathway that plays key roles in bacterial infections. One of the most studied is probably xenophagy, the selective capture and degradation of intracellular bacteria by lysosomes. However, the impact of autophagy goes beyond xenophagy and involves intensive cross-talks with other host defense mechanisms. In addition, autophagy machinery can have non-canonical functions such as LC3-associated phagocytosis. In this review, we intend to summarize the current knowledge on the many functions of autophagy proteins in cell defenses with a focus on bacteria–macrophage interaction. We also present the strategies developed by pathogens to evade or to exploit this machinery in order to establish a successful infection. Finally, we discuss the opportunities and challenges of autophagy manipulation in improving therapeutics and vaccines against bacterial pathogens. PMID:29163544

Predictors of serious bacterial infections in pediatric burn patients with fever.

PubMed

Vyles, David; Sinha, Madhumita; Rosenberg, David I; Foster, Kevin N; Tran, Melissa; Drachman, David

2014-01-01

To determine predictors of serious bacterial infections in pediatric burn patients with fever (core temp ≥38.5°C), the authors conducted a retrospective review of medical records of pediatric (0-18 years) patients admitted to the Arizona Burn Center between 2008 and 2011 with greater than 5% TBSA and inpatient hospitalization for ≥72 hours. The study group comprised patients with a febrile episode during their inpatient stay. Serious bacterial infection (the primary outcome variable) was defined as: bacteremia, urinary tract infection, meningitis (blood, urine, or cerebrospinal fluid culture positive for a pathogen respectively), pneumonia, line, and wound infection. A generalized estimating equation analysis was done to predict the presence or absence of serious bacterial infection. Of 1082 pediatric burn patients hospitalized during the study period, 353 met the study eligibility criteria. A total of 108 patients (30.6%) had at least one fever episode (fever group). No difference in demographic characteristics was noted between the fever and no-fever groups; significant differences were observed for: third-degree TBSA, second-degree TBSA, total operating room visits, length of stay, Injury Severity Score, and death. A total of 47.2% of the patients had one or more episodes of fever with serious bacterial infection. In a generalized estimating equation predictive model, presence of a central line, second-, and third-degree TBSA were predictive of serious bacterial infection in burn patients with fever. In this study, individual clinical variables such as tachypnea and tachycardia were not predictive of serious bacterial infections, but the presence of a central line, and larger TBSA were significant predictors of serious bacterial infections. Younger age (P =.08) and ventilator support (P =.057) also approached significance as predictors of serious bacterial infections.

HIV infection in the etiology of lung cancer: confounding, causality, and consequences.

PubMed

Kirk, Gregory D; Merlo, Christian A

2011-06-01

Persons infected with HIV have an elevated risk of lung cancer, but whether the increase simply reflects a higher smoking prevalence continues to be debated. This review summarizes existing data on the association of HIV infection and lung cancer, with particular attention to study design and adjustment for cigarette smoking. Potential mechanisms by which HIV infection may lead to lung cancer are discussed. Finally, irrespective of causality and mechanisms, lung cancer represents an important and growing problem confronting HIV-infected patients and their providers. Substantial efforts are needed to promote smoking cessation and to control lung cancer among HIV-infected populations.

Respiratory infections: pneumonia, lung abscess, and empyema.

PubMed

Puligandla, Pramod S; Laberge, Jean-Martin

2008-02-01

Pneumonia is an important clinical problem that affects children of all ages. Although effectively treated on an outpatient basis in the majority of cases, some children with respiratory infections still require hospitalization. This may be particularly true for patients with immunocompromise, for whom the lung represents the most common site of infection. Furthermore, respiratory infections represent a significant source of morbidity and mortality in this patient population. This article focuses on the clinical presentation, etiology, and treatment of childhood pneumonia, with special consideration given to the immunocompromised child. Two specific complications of pneumonia, lung abscess and empyema, are discussed.

D-lactic acid measurements in the diagnosis of bacterial infections.

PubMed Central

Smith, S M; Eng, R H; Campos, J M; Chmel, H

1989-01-01

Body fluids suspected of bacterial infection were cultured and examined for the presence of D-lactic acid, a specific bacterial metabolite. We examined 206 patients and 264 specimens. D-Lactic acid was found in concentrations of greater than or equal to 0.15 mM in 11 of 11 infected and 6 of 40 noninfected ascitic fluids, 6 of 6 infected and 4 of 33 noninfected pleural fluids, 4 of 4 infected and 0 of 13 noninfected synovial fluids, and 26 of 27 infected and 2 of 130 noninfected cerebrospinal fluids. The overall sensitivity was 79.7%, and the specificity was 99.5% when the D-lactic acid concentration was at least 0.15 mM. The most important clinical utility of the D-lactic acid measurement appears to be for patients with bacterial infection in various body compartments and in patients who have already received antimicrobial therapy. An elevation in D-lactic acid may indicate the presence of bacterial infection even when cultures are negative. PMID:2715313

Gram-Negative Bacterial Wound Infections

DTIC Science & Technology

2015-05-01

not statistically differ- ent from that of the control group . The levels (CFU/g) of bacteria in lung tissue correlated with the survival curves. The...median levels in the control and 2.5 mg/kg- treated groups were almost identical, at 9.04 and 9.07 log CFU/g, respectively. Figure 6B shows a decrease...Dunn’s multiple comparison test, found a statistically significant difference in bacterial burden when the control group was com- pared to animals

Infection rate and tissue localization of murine IL-12p40-producing monocyte-derived CD103(+) lung dendritic cells during pulmonary tuberculosis.

PubMed

Leepiyasakulchai, Chaniya; Taher, Chato; Chuquimia, Olga D; Mazurek, Jolanta; Söderberg-Naucler, Cecilia; Fernández, Carmen; Sköld, Markus

2013-01-01

Non-hematopoietic cells, including lung epithelial cells, influence host immune responses. By co-culturing primary alveolar epithelial cells and monocytes from naïve donor mice, we show that alveolar epithelial cells support monocyte survival and differentiation in vitro, suggesting a role for non-hematopoietic cells in monocyte differentiation during the steady state in vivo. CD103(+) dendritic cells (αE-DC) are present at mucosal surfaces. Using a murine primary monocyte adoptive transfer model, we demonstrate that αE-DC in the lungs and pulmonary lymph nodes are monocyte-derived during pulmonary tuberculosis. The tissue localization may influence the functional potential of αE-DC that accumulate in Mycobacterium tuberculosis-infected lungs. Here, we confirm the localization of αE-DC in uninfected mice beneath the bronchial epithelial cell layer and near the vascular wall, and show that αE-DC have a similar distribution in the lungs during pulmonary tuberculosis and are detected in the bronchoalveolar lavage fluid from infected mice. Lung DC can be targeted by M. tuberculosis in vivo and play a role in bacterial dissemination to the draining lymph node. In contrast to other DC subsets, only a fraction of lung αE-DC are infected with the bacterium. We also show that virulent M. tuberculosis does not significantly alter cell surface expression levels of MHC class II on infected cells in vivo and that αE-DC contain the highest frequency of IL-12p40(+) cells among the myeloid cell subsets in infected lungs. Our results support a model in which inflammatory monocytes are recruited into the M. tuberculosis-infected lung tissue and, depending on which non-hematopoietic cells they interact with, differentiate along different paths to give rise to multiple monocyte-derived cells, including DC with a distinctive αE-DC phenotype.

Infection Rate and Tissue Localization of Murine IL-12p40-Producing Monocyte-Derived CD103+ Lung Dendritic Cells during Pulmonary Tuberculosis

PubMed Central

Leepiyasakulchai, Chaniya; Taher, Chato; Chuquimia, Olga D.; Mazurek, Jolanta; Söderberg-Naucler, Cecilia; Fernández, Carmen; Sköld, Markus

2013-01-01

Non-hematopoietic cells, including lung epithelial cells, influence host immune responses. By co-culturing primary alveolar epithelial cells and monocytes from naïve donor mice, we show that alveolar epithelial cells support monocyte survival and differentiation in vitro, suggesting a role for non-hematopoietic cells in monocyte differentiation during the steady state in vivo. CD103+ dendritic cells (αE-DC) are present at mucosal surfaces. Using a murine primary monocyte adoptive transfer model, we demonstrate that αE-DC in the lungs and pulmonary lymph nodes are monocyte-derived during pulmonary tuberculosis. The tissue localization may influence the functional potential of αE-DC that accumulate in Mycobacterium tuberculosis-infected lungs. Here, we confirm the localization of αE-DC in uninfected mice beneath the bronchial epithelial cell layer and near the vascular wall, and show that αE-DC have a similar distribution in the lungs during pulmonary tuberculosis and are detected in the bronchoalveolar lavage fluid from infected mice. Lung DC can be targeted by M. tuberculosis in vivo and play a role in bacterial dissemination to the draining lymph node. In contrast to other DC subsets, only a fraction of lung αE-DC are infected with the bacterium. We also show that virulent M. tuberculosis does not significantly alter cell surface expression levels of MHC class II on infected cells in vivo and that αE-DC contain the highest frequency of IL-12p40+ cells among the myeloid cell subsets in infected lungs. Our results support a model in which inflammatory monocytes are recruited into the M. tuberculosis-infected lung tissue and, depending on which non-hematopoietic cells they interact with, differentiate along different paths to give rise to multiple monocyte-derived cells, including DC with a distinctive αE-DC phenotype. PMID:23861965

Fusarium Infection in Lung Transplant Patients

PubMed Central

Carneiro, Herman A.; Coleman, Jeffrey J.; Restrepo, Alejandro; Mylonakis, Eleftherios

2013-01-01

Fusarium is a fungal pathogen of immunosuppressed lung transplant patients associated with a high mortality in those with severe and persistent neutropenia. The principle portal of entry for Fusarium species is the airways, and lung involvement almost always occurs among lung transplant patients with disseminated infection. In these patients, the immunoprotective mechanisms of the transplanted lungs are impaired, and they are, therefore, more vulnerable to Fusarium infection. As a result, fusariosis occurs in up to 32% of lung transplant patients. We studied fusariosis in 6 patients following lung transplantation who were treated at Massachusetts General Hospital during an 8-year period and reviewed 3 published cases in the literature. Cases were identified by the microbiology laboratory and through discharge summaries. Patients presented with dyspnea, fever, nonproductive cough, hemoptysis, and headache. Blood tests showed elevated white blood cell counts with granulocytosis and elevated inflammatory markers. Cultures of Fusarium were isolated from bronchoalveolar lavage, blood, and sputum specimens. Treatments included amphotericin B, liposomal amphotericin B, caspofungin, voriconazole, and posaconazole, either alone or in combination. Lung involvement occurred in all patients with disseminated disease and it was associated with a poor outcome. The mortality rate in this group of patients was high (67%), and of those who survived, 1 patient was treated with a combination of amphotericin B and voriconazole, 1 patient with amphotericin B, and 1 patient with posaconazole. Recommended empirical treatment includes voriconazole, amphotericin B or liposomal amphotericin B first-line, and posaconazole for refractory disease. High-dose amphotericin B is recommended for treatment of most cases of fusariosis. The echinocandins (for example, caspofungin, micafungin, anidulafungin) are generally avoided because Fusarium species have intrinsic resistance to them. Treatment

Pathogen characteristics reveal novel antibacterial approaches for interstitial lung disease.

PubMed

Lu, Hai-Wen; Ji, Xiao-Bin; Liang, Shuo; Fan, Li-Chao; Bai, Jiu-Wu; Chen, Ke-Bing; Zhou, Yin; Li, Hui-Ping; Xu, Jin-Fu

2014-12-01

Interstitial lung disease (ILD) is a clinical disorder associated with changes of lung structure. Concurrent infection is a serious complication and one of the major factors that exacerbates ILD. Pathogen screening is a critical step in early diagnosis and proper treatment of ILD with secondary infection. Here we analyzed distribution and drug susceptibility of pathogens isolated from hospitalized ILD patients from January, 2007 to December, 2008 and compared them to bacterial drug resistance data in CHINET during the same period. The main specimens were from sputum culture, lavage fluid culture, lung biopsy tissue culture, and pleural effusion culture and bacterial or fungal cultures were performed on these specimens accordingly. Drug susceptibility was tested for positive bacterial cultures using disk diffusion (Kirby-Bauer method) and E Test strips in which results were determined based on the criteria of CLSI (2007). A total of 371 pathogen strains from ILD patients, including 306 bacterial strains and 65 fungal strains were isolated and cultured. Five main bacterial strains and their distribution were as follows: Klebsiella pneumoniae (31.7%), Pseudomonas aeruginosa (20.6%), Acinetobacter (12.7%), Enterobacter cloacae (8.2%), and Staphylococcus aureus (7.8%). The results showed that ILD patients who had anti-infection treatment tended to have Gram-negative bacteria, whether they acquired an infection in the hospital or elsewhere. Drug resistance screening indicated that aminoglycosides and carbapenems had lower antibiotic resistance rates. In addition, we found that the usage of immunosuppressants was associated with the increased infection rate and number of pathogens that were isolated. In conclusion, aminoglycosides and carbapenems may be selected as a priority for secondary infection to control ILD progression. Meanwhile, the use of anti-MRSA/MRCNS drugs may be considered for Staphylococcus infection. Copyright © 2014 Elsevier Ltd. All rights reserved.

The impact of bacterial and viral co‐infection in severe influenza

PubMed Central

Blyth, Christopher C.; Webb, Steve A. R.; Kok, Jen; Dwyer, Dominic E.; van Hal, Sebastiaan J.; Foo, Hong; Ginn, Andrew N.; Kesson, Alison M.; Seppelt, Ian; Iredell, Jonathan R.

2013-01-01

Please cite this paper as: Blyth et al. (2013) The impact of bacterial and viral co‐infection in severe influenza. Influenza and Other Respiratory Viruses 7(2) 168–176. Background  Many questions remain concerning the burden, risk factors and impact of bacterial and viral co‐infection in patients with pandemic influenza admitted to the intensive care unit (ICU). Objectives  To examine the burden, risk factors and impact of bacterial and viral co‐infection in Australian patients with severe influenza. Patients/Methods  A cohort study conducted in 14 ICUs was performed. Patients with proven influenza A during the 2009 influenza season were eligible for inclusion. Demographics, risk factors, clinical data, microbiological data, complications and outcomes were collected. Polymerase chain reaction for additional bacterial and viral respiratory pathogens was performed on stored respiratory samples. Results  Co‐infection was identified in 23·3–26·9% of patients with severe influenza A infection: viral co‐infection, 3·2–3·4% and bacterial co‐infection, 20·5–24·7%. Staphylococcus aureus was the most frequent bacterial co‐infection followed by Streptococcus pneumoniae and Haemophilus influenzae. Patients with co‐infection were younger [mean difference in age = 8·46 years (95% CI: 0·18–16·74 years)], less likely to have significant co‐morbidities (32·0% versus 66·2%, P = 0·004) and less frequently obese [mean difference in body mass index = 6·86 (95% CI: 1·77–11·96)] compared to those without co‐infection. Conclusions  Bacterial or viral co‐infection complicated one in four patients admitted to ICU with severe influenza A infection. Despite the co‐infected patients being younger and with fewer co‐morbidities, no significant difference in outcomes was observed. It is likely that co‐infection contributed to a need for ICU admission in those without other risk factors for severe influenza disease

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.

Epidemiology of bacterial hand infections.

PubMed

Houshian, Shirzad; Seyedipour, Sedigheh; Wedderkopp, Niels

2006-07-01

The aim of the study was to delineate and update the bacteriological spectrum, characterize patterns and sites of injury, evaluate laboratory tests and possible causes of complications in patients with bacterial hand infections. All hand infections operated on in the department of orthopedics at Odense University Hospital during the period 1992-2001 were reviewed retrospectively. A standard protocol was used to collect data for each patient. We also examined all laboratory reports and recorded the identity of the etiologic organism, if known, for all cases of bacterial hand infections. Four hundred and eighteen patients (296 men and 122 women) with hand infections were operated on between 1992 and 2001 in our department. The median age of the patients was 40 years (range 1-93). The average interval from primary injury to operation was 10 days (range 1-50). The etiology was laceration/puncture in 35%. The site of infection was subcutaneous in 45% followed by tendon, joint and bone in 27, 18 and 5%, respectively. The bacteria isolated from the patients showed that 184 cultures (44%) were pure Staphylococcus aureus followed by 49 cultures (11.7%) of mixed organisms. Body temperature and C-reactive protein (CRP) were normal in three quarters of all patients with hand infections in our series. However the erythrocyte sedimentation rate (ESR) was elevated in 50% of the patients and was a significantly better test for infection in this study than CRP (p = 0.002). Neither the severity of infection nor the etiology of infection was related in any way to the initial temperature, CRP or ESR in this study. Complications were noted in 14.8% of all patients, and were especially related to diabetes, and mixed infection. Despite modern antibiotics, hand infections with a variety of organisms continue to be a source of morbidity and possible long-term disability. Most hand infections are the result of minor wounds that have been neglected. A complete history and physical

CFTR and lung homeostasis

PubMed Central

Matalon, Sadis

2014-01-01

CFTR is a cAMP-activated chloride and bicarbonate channel that is critical for lung homeostasis. Decreases in CFTR expression have dire consequences in cystic fibrosis (CF) and have been suggested to be a component of the lung pathology in chronic obstructive pulmonary disease. Decreases or loss of channel function often lead to mucus stasis, chronic bacterial infections, and the accompanying chronic inflammatory responses that promote progressive lung destruction, and, eventually in CF, lung failure. Here we discuss CFTR's functional role airway surface liquid hydration and pH, in regulation of other channels such as the epithelial sodium channel, and in regulating inflammatory responses in the lung. PMID:25381027

Nasopharyngeal polymicrobial colonization during health, viral upper respiratory infection and upper respiratory bacterial infection.

PubMed

Xu, Qingfu; Wischmeyer, Jareth; Gonzalez, Eduardo; Pichichero, Michael E

2017-07-01

We sought to understand how polymicrobial colonization varies during health, viral upper respiratory infection (URI) and acute upper respiratory bacterial infection to understand differences in infection-prone vs. non-prone patients. Nasopharyngeal (NP) samples were collected from 74 acute otitis media (AOM) infection-prone and 754 non-prone children during 2094 healthy visits, 673 viral URI visits and 631 AOM visits. Three otopathogens Streptococcus pneumoniae (Spn), Nontypeable Haemophilus influenzae (NTHi), and Moraxella catarrhalis (Mcat) were identified by culture. NP colonization rates of multiple otopathogens during health were significantly lower than during viral URI, and during URI they were lower than at onset of upper respiratory bacterial infection in both AOM infection-prone and non-prone children. AOM infection-prone children had higher polymicrobial colonization rates than non-prone children during health, viral URI and AOM. Polymicrobial colonization rates of AOM infection-prone children during health were equivalent to that of non-prone children during viral URI, and during viral URI were equivalent to that of non-prone during AOM infection. Spn colonization was positively associated with NTHi and Mcat colonization during health, but negatively during AOM infection. The infection-prone patients more frequently have multiple potential bacterial pathogens in the NP than the non-prone patients. Polymicrobial interaction in the NP differs during health and at onset of infection. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Anti-inflammatory effect of thalidomide alone or in combination with augmentin in Klebsiella pneumoniae B5055 induced acute lung infection in BALB/c mice.

PubMed

Kumar, Vijay; Chhibber, Sanjay

2008-09-11

Thalidomide (alpha-naphtylimidoglutarimide), a psychoactive drug that readily crosses blood-brain barrier, has been shown to exhibit anti-inflammatory, anti-angiogenic, immunomodulatory properties through a mechanism that is not fully established. Keeping these properties in mind, we tried to find out the anti-inflammatory properties of thalidomide in mouse model of acute inflammation by introducing K. pneumoniae B5055 in BALB/c mice via intranasal route. The intranasal instillation of bacteria in this mouse model of acute pneumonia induced inflammation accompanied with significant increase in neutrophil infiltration in the lungs and also increased production of mediators of inflammation (i.e. malondialdehyde, myeloperoxidase and nitric oxide) in the lung tissue. The animals, which received thalidomide alone orally or in combination with augmentin, 30 min prior to bacterial instillation into the lungs via intranasal route, showed significant (P<0.05) decrease in neutrophil influx into the lungs and there was significant (P<0.05) decrease in the production of malondialdehyde, nitric oxide and myeloperoxidase activity. But the augmentin treatment alone did not decrease the malondialdehyde, myeloperoxidase and nitric oxide significantly (P>0.05) as compared to the control group. We therefore conclude that thalidomide ameliorates lung inflammation induced by K. pneumoniae B5055 without significantly (P<0.05) decreasing the bacterial load in the lung tissue whereas augmentin takes care of bacterial proliferation. Hence, it can be used as an adjunct therapy along with antibiotics as an anti-inflammatory or an immunomodulatory agent in case of acute lung infection.

Neutrophilic NLRP3 inflammasome-dependent IL-1β secretion regulates the γδT17 cell response in respiratory bacterial infections.

PubMed

Hassane, M; Demon, D; Soulard, D; Fontaine, J; Keller, L E; Patin, E C; Porte, R; Prinz, I; Ryffel, B; Kadioglu, A; Veening, J-W; Sirard, J-C; Faveeuw, C; Lamkanfi, M; Trottein, F; Paget, C

2017-07-01

Traditionally regarded as simple foot soldiers of the innate immune response limited to the eradication of pathogens, neutrophils recently emerged as more complex cells endowed with a set of immunoregulatory functions. Using a model of invasive pneumococcal disease, we highlighted an unexpected key role for neutrophils as accessory cells in innate interleukin (IL)-17A production by lung resident Vγ6Vδ1 + T cells via nucleotide-binding oligomerization domain receptor, pyrin-containing 3 (NLRP3) inflammasome-dependent IL-1β secretion. In vivo activation of the NLRP3 inflammasome in neutrophils required both host-derived and bacterial-derived signals. Elaborately, it relies on (i) alveolar macrophage-secreted TNF-α for priming and (ii) subsequent exposure to bacterial pneumolysin for activation. Interestingly, this mechanism can be translated to human neutrophils. Our work revealed the cellular and molecular dynamic events leading to γδT17 cell activation, and highlighted for the first time the existence of a fully functional NLRP3 inflammasome in lung neutrophils. This immune axis thus regulates the development of a protective host response to respiratory bacterial infections.

Novel Prevention Strategies for Bacterial Infections in Cirrhosis

PubMed Central

Yan, Kathleen; Garcia-Tsao, Guadalupe

2016-01-01

Introduction Bacterial infections are a serious complication of cirrhosis, as they can lead to decompensation, multiple organ failure, and/or death. Preventing infections is therefore very relevant. Because gut bacterial translocation is their main pathogenic mechanism, prevention of infections is mostly based on the use of orally administered poorly absorbed antibiotics such as norfloxacin (selective intestinal decontamination). However, antibiotic prophylaxis leads to antibiotic resistance, limiting therapy and increasing morbidity and mortality. Prevention of bacterial infections in cirrhosis should therefore move away from antibiotics. Areas Covered This review focuses on various potentially novel methods to prevent infections in cirrhosis focusing on non-antibiotic strategies. The use of probiotics, nonselective intestinal decontamination with rifaximin, prokinetics and beta-blockers or fecal microbiota transplant as means of targeting altered gut microbiota, bile acids and FXR agonists are all potential alternatives to selective intestinal decontamination. Prokinetics and beta-blockers can improve intestinal motility, while bile acids and FXR agonists help by improving the intestinal barrier. Finally, granulocyte colony stimulating factor (G-CSF) and statins are emerging therapeutic strategies that may improve immune dysfunction in cirrhosis. Expert Opinion Evidence for these strategies has been restricted to animal studies and proof-of concept studies but we expect this to change in coming years. PMID:26799197

Host-Pathogen Interactions and Chronic Lung Allograft Dysfunction.

PubMed

Belperio, John; Palmer, Scott M; Weigt, S Sam

2017-09-01

Lung transplantation is now considered to be a therapeutic option for patients with advanced-stage lung diseases. Unfortunately, due to post-transplant complications, both infectious and noninfectious, it is only a treatment and not a cure. Infections (e.g., bacterial, viral, and fungal) in the immunosuppressed lung transplant recipient are a common cause of mortality post transplant. Infections have more recently been explored as factors contributing to the risk of chronic lung allograft dysfunction (CLAD). Each major class of infection-(1) bacterial (Staphylococcus aureus and Pseudomonas aeruginosa); (2) viral (cytomegalovirus and community-acquired respiratory viruses); and (3) fungal (Aspergillus)-has been associated with the development of CLAD. Mechanistically, the microbe seems to be interacting with the allograft cells, stimulating the induction of chemokines, which recruit recipient leukocytes to the graft. The recipient leukocyte interactions with the microbe further up-regulate chemokines, amplifying the influx of allograft-infiltrating mononuclear cells. These events can promote recipient leukocytes to interact with the allograft, triggering an alloresponse and graft dysfunction. Overall, interactions between the microbe-allograft-host immune system alters chemokine production, which, in part, plays a role in the pathobiology of CLAD and mortality due to CLAD.

Predicting serious bacterial infection in young children with fever without apparent source.

PubMed

Bleeker, S E; Moons, K G; Derksen-Lubsen, G; Grobbee, D E; Moll, H A

2001-11-01

The aim of this study was to design a clinical rule to predict the presence of a serious bacterial infection in children with fever without apparent source. Information was collected from the records of children aged 1-36 mo who attended the paediatric emergency department because of fever without source (temperature > or = 38 degrees C and no apparent source found after evaluation by a general practitioner or history by a paediatrician). Serious bacterial infection included bacterial meningitis, sepsis, bacteraemia, pneumonia, urinary tract infection, bacterial gastroenteritis, osteomyelitis and ethmoiditis. Using multivariate logistic regression and the area under the receiver operating characteristic curve (ROC area), the diagnostic value of predictors for serious bacterial infection was judged, resulting in a risk stratification. Twenty-five percent of the 231 patients enrolled in the study (mean age 1.1 y) had a serious bacterial infection. Independent predictors from history and examination included duration of fever, poor micturition, vomiting, age, temperature < 36.7 degrees C or > or = 40 degrees C at examination, chest-wall retractions and poor peripheral circulation (ROC area: 0.75). Independent predictors from laboratory tests were white blood cell count, serum C-reactive protein and the presence of >70 white blood cells in urinalysis (ROC area: 0.83). The risk stratification for serious bacterial infection ranged from 6% to 92%. The probability of a serious bacterial infection in the individual patient with fever without source can be estimated more precisely by using a limited number of symptoms, signs and laboratory tests.

Acute Sleep Deprivation Enhances Post-Infection Sleep and Promotes Survival during Bacterial Infection in Drosophila

PubMed Central

Kuo, Tzu-Hsing; Williams, Julie A.

2014-01-01

Study Objectives: Sleep is known to increase as an acute response to infection. However, the function of this behavioral response in host defense is not well understood. To address this problem, we evaluated the effect of acute sleep deprivation on post-infection sleep and immune function in Drosophila. Setting: Laboratory. Participants: Drosophila melanogaster. Methods and Results: Flies were subjected to sleep deprivation before (early DEP) or after (late DEP) bacterial infection. Relative to a non-deprived control, flies subjected to early DEP had enhanced sleep after infection as well as increased bacterial clearance and survival outcome. Flies subjected to late DEP experienced enhanced sleep following the deprivation period, and showed a modest improvement in survival outcome. Continuous DEP (early and late DEP) throughout infection also enhanced sleep later during infection and improved survival. However, improved survival in flies subjected to late or continuous DEP did not occur until after flies had experienced sleep. During infection, both early and late DEP enhanced NFκB transcriptional activity as measured by a luciferase reporter (κB-luc) in living flies. Early DEP also increased NFκB activity prior to infection. Flies that were deficient in expression of either the Relish or Dif NFκB transcription factors showed normal responses to early DEP. However, the effect of early DEP on post-infection sleep and survival was abolished in double mutants, which indicates that Relish and Dif have redundant roles in this process. Conclusions: Acute sleep deprivation elevated NFκB-dependent activity, increased post-infection sleep, and improved survival during bacterial infection. Citation: Kuo TH, Williams JA. Acute sleep deprivation enhances post-infection sleep and promotes survival during bacterial infection in Drosophila. SLEEP 2014;37(5):859-869. PMID:24790264

Bone marrow-derived cells participate in stromal remodeling of the lung following acute bacterial pneumonia in mice.

PubMed

Serikov, Vladimir B; Mikhaylov, Viatcheslav M; Krasnodembskay, Anna D; Matthay, Michael A

2008-01-01

Bone marrow-derived cells (BMDC) have been shown to graft injured tissues, differentiate in specialized cells, and participate in repair. The importance of these processes in acute lung bacterial inflammation and development of fibrosis is unknown. The goal of this study was to investigate the temporal sequence and lineage commitment of BMDC in mouse lungs injured by bacterial pneumonia. We transplanted GFP-tagged BMDC into 5-Gy-irradiated C57BL/6 mice. After 3 months of recovery, mice were subjected to LD(50) intratracheal instillation of live E. coli (controls received saline) which produced pneumonia and subsequent areas of fibrosis. Lungs were investigated by immunohistology for up to 6 months. At the peak of lung inflammation, the predominant influx of BMDC were GFP(+) leukocytes. Postinflammatory foci of lung fibrosis were evident after 1-2 months. The fibrotic foci in lung stroma contained clusters of GFP(+) CD45(+) cells, GFP(+) vimentin-positive cells, and GFP(+) collagen I-positive fibroblasts. GFP(+) endothelial or epithelial cells were not identified. These data suggest that following 5-Gy irradiation and acute bacterial pneumonia, BMDC may temporarily participate in lung postinflammatory repair and stromal remodeling without long-term engraftment as specialized endothelial or epithelial cells.

Practical aspects of bacterial skin infections in children.

PubMed

Tunnessen, W W

1985-07-01

Bacterial skin infections are a common reason for children to be examined by a pediatrician. Streptococci and staphylococci are responsible for the great majority of the infections. Because of the variety of lesions produced by these bacteria, there is support for dividing impetigo into "traditional" crusted and bullous forms. Two important forms of cellulitis--facial and periorbital--have potential for serious systemic consequences. The bacterial etiology and treatment of cellulitis, animal bites, and puncture wounds of the foot require special attention for successful outcome.

Evaluation of procalcitonin and neopterin level in serum of patients with acute bacterial infection.

PubMed

Pourakbari, Babak; Mamishi, Setareh; Zafari, Javid; Khairkhah, Hanieh; Ashtiani, Mohammad H; Abedini, Masomeh; Afsharpaiman, Shahla; Rad, Soroush Seifi

2010-01-01

Fever as a common presenting complaint in pediatric patients can be due to various causes. Differentiating bacterial infection from other causes is important because the prompt use of antibiotics is critical in bacterial infection. Traditional markers of infection such as BT and WBC count may be unspecific and culture may be late or absent. CRP and Procalcitonin (PCT) have been considered to evaluate the evolution of infections and sepsis in patients presenting with SIRS. Neopterin has also been proposed to aid in the diagnosis of bacterial infection. In this study, we compared the value of the serum PCT, neopterin level, and WBC count for predicting bacterial infection and outcome in children with fever. 158 pediatric (2-120-month-old) patients suspected to have acute bacterial infection, based on clinical judgment in which other causes of SIRS were ruled out were included in the study. WBC count with differential was determined and PCT and neopterin levels were measured. PCT level was higher in bacterial infection and patients who were complicated or expired. Rapid PCT test is superior to neopterin and WBC count for anticipating bacterial infection, especially in ED where prompt decision making is critical.

Correlation between the neutrophil-lymphocyte count ratio and bacterial infection in patient with human immunodeficiency virus

NASA Astrophysics Data System (ADS)

Kusnadi, D.; Liwang, M. N. I.; Katu, S.; Mubin, A. H.; Halim, R.

2018-03-01

Parameters for starting antibiotic therapy such as CRP andleukocytosis are considered non-specific. Previous studies have shown the Neutrophil-Lymphocyte Count Ratio (NLCR) can serve as the basis of bacterial infection, the level of infection, and the basis of antibiotic therapy. Compared with the Procalcitonin parameter, this NLCR is rapid, an inexpensive and requires no additional sampling. To determine the correlation between The Neutrophil-LymphocyteCount Ratio to bacterial infection in HIV patients. This study was a cross-sectional observational approach to HIV subject at Wahidin Sudirohusodo and Hasanuddin University Hospital. The subjects performed routine blood, microbiology test,and blood Procalcitonin levels tests. Then performed NLCR calculations based on routine blood results. The subjects then grouped the presence or absence of bacterial infection.In 146 study subjects, there were 78 (53.4%) with bacterial infections and 68 (46.6%) without bacterial infection as controls. Subjects with bacterial infections had higher total neutrophils (84.83) compared with non-bacterial infections. Subjects with bacterial infections had total lymphocytes with an average of 8.51 lower than non-bacterial infections. Subjects with bacterial infections had higher NLCR values with an average of 12.80. The Neutrophil-Lymphocyte Count Ratio can become a marker of bacterial infection in HIV patients.

Effects and molecular mechanisms of intrauterine infection/inflammation on lung development.

PubMed

Pan, Jiarong; Zhan, Canyang; Yuan, Tianming; Wang, Weiyan; Shen, Ying; Sun, Yi; Wu, Tai; Gu, Weizhong; Chen, Lihua; Yu, Huimin

2018-05-10

Intrauterine infection/inflammation plays an important role in the development of lung injury and bronchopulmonary dysplasia (BPD) in preterm infants, While a multifactorial genesis is likely, mechanisms involved in BPD after intrauterine infection/inflammation are largely unknown. Recent studies have suggested microRNAs (miRNAs) are likely to play a role. Therefore, this study aimed to study the effects and mechanisms of intrauterine infection/inflammation on lung development, and to identify miRNAs related to lung injury and BPD. An animal model of intrauterine infection/inflammation was established with pregnant SD rats endocervically inoculated with E.coli. The fetal and neonatal rats were observed at embryonic day (E) 17, 19, 21 and postnatal day (P) 1, 3, 7, 14, respectively. Body weight, lung weight, the expression levels of NLRP3, TNF-α, IL-lβ, IL-6, VEGF, Collagen I, SP-A, SP-B and SP-C in the lung tissues of fetal and neonatal rats were measured. Expression profiles of 1218 kinds of miRNAs in the lungs of neonatal rats were detected by miRNA microarray technique. Target genes of the identified miRNAs were predicted through online software. Intrauterine infection/inflammation compromised not only weight development but also lung development of the fetal and neonatal rats. The results showed significantly increased expression of NLRP3, TNF-α, IL-1β, IL-6, Collagen I, and significantly decreased expression of VEGF, SP-A, SP-B and SP-C in the fetal and neonatal rat lung tissues in intrauterine infection group compared to the control group at different observation time point (P < 0.05). Forty-three miRNAs with significant differential expression were identified. Possible target genes regulated by the identified miRNAs are very rich. Intrauterine infection/inflammation results in lung histological changes which are very similar to those observed in BPD. Possible mechanisms may include NLRP3 inflammasome activation followed by inflammatory cytokines

Infection, inflammation, and lung function decline in infants with cystic fibrosis.

PubMed

Pillarisetti, Naveen; Williamson, Elizabeth; Linnane, Barry; Skoric, Billy; Robertson, Colin F; Robinson, Phil; Massie, John; Hall, Graham L; Sly, Peter; Stick, Stephen; Ranganathan, Sarath

2011-07-01

Better understanding of evolution of lung function in infants with cystic fibrosis (CF) and its association with pulmonary inflammation and infection is crucial in informing both early intervention studies aimed at limiting lung damage and the role of lung function as outcomes in such studies. To describe longitudinal change in lung function in infants with CF and its association with pulmonary infection and inflammation. Infants diagnosed after newborn screening or clinical presentation were recruited prospectively. FVC, forced expiratory volume in 0.5 seconds (FEV(0.5)), and forced expiratory flows at 75% of exhaled vital capacity (FEF(75)) were measured using the raised-volume technique, and z-scores were calculated from published reference equations. Pulmonary infection and inflammation were measured in bronchoalveolar lavage within 48 hours of lung function testing. Thirty-seven infants had at least two successful repeat lung function measurements. Mean (SD) z-scores for FVC were -0.8 (1.0), -0.9 (1.1), and -1.7 (1.2) when measured at the first visit, 1-year visit, or 2-year visit, respectively. Mean (SD) z-scores for FEV(0.5) were -1.4 (1.2), -2.4 (1.1), and -4.3 (1.6), respectively. In those infants in whom free neutrophil elastase was detected, FVC z-scores were 0.81 lower (P=0.003), and FEV(0.5) z-scores 0.96 lower (P=0.001), respectively. Significantly greater decline in FEV(0.5) z-scores occurred in those infected with Staphylococcus aureus (P=0.018) or Pseudomonas aeruginosa (P=0.021). In infants with CF, pulmonary inflammation is associated with lower lung function, whereas pulmonary infection is associated with a greater rate of decline in lung function. Strategies targeting pulmonary inflammation and infection are required to prevent early decline in lung function in infants with CF.

Efficacy of bacteriophage therapy in a model of Burkholderia cenocepacia pulmonary infection

PubMed Central

Carmody, Lisa A.; Gill, Jason J.; Summer, Elizabeth J.; Sajjan, Uma S.; Gonzalez, Carlos F.; Young, Ryland F.; LiPuma, John J.

2009-01-01

The therapeutic potential of bacteriophage (phage) in a mouse model of acute B. cenocepacia pulmonary infection was assessed. Phage were administered by either intranasal (i.n.) inhalation or intraperitoneal (i.p.) injection. Bacterial density, macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-α (TNFα) levels were significantly reduced in lungs of mice treated with i.p. phage. No significant differences in lung bacterial density or MIP-2 levels were found between untreated mice and mice treated with i.n. phage, i.p. UV-inactivated phage, or i.p. λ phage controls. Mock-infected mice treated with phage showed no significant increase in lung MIP-2 or TNFα levels compared to mock-infected / mock-treated mice. We have demonstrated the efficacy of phage therapy in an acute B. cenocepacia lung infection model. Systemic administration of phage was more effective than inhalational administration, suggesting that circulating phage have better access to bacteria in lung compared to topical phage. PMID:20001604

Bacterial infection causes stress-induced memory dysfunction in mice.

PubMed

Gareau, Mélanie G; Wine, Eytan; Rodrigues, David M; Cho, Joon Ho; Whary, Mark T; Philpott, Dana J; Macqueen, Glenda; Sherman, Philip M

2011-03-01

The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.

Bacteria meets influenza A virus: A bioluminescence mouse model of Escherichia coli O157:H7 following influenza A virus/Puerto Rico/8/34 (H1N1) strain infection.

PubMed

Wang, Zhongyi; Chi, Hang; Wang, Xiwen; Li, Wenliang; Li, Zhiping; Li, Jiaming; Fu, Yingying; Lu, Bing; Xia, Zhiping; Qian, Jun; Liu, Linna

2018-01-01

Objective To develop a bioluminescence-labelled bacterial infection model to monitor the colonization and clearance process of Escherichia coli O157:H7 in the lungs of mice following influenza A virus/Puerto Rico/8/34 (H1N1) strain (IAV/PR8) infection. Methods BALB/c mice were administered IAV/PR8 or 0.01 M phosphate-buffered saline (PBS; pH 7.4) intranasally 4 days prior to intranasal administration of 1 × 10 7 colony-forming units (CFU) of E. coli O157:H7-lux. Whole-body bioluminescent signals were monitored at 10 min, 4 h, 8 h, 12 h, 16 h and 24 h post-bacterial infection. Lung bioluminescent signals and bacterial load (CFU/g) were monitored at 4 h, 8 h, 12 h, 16 h and 24 h post-bacterial infection. Results Prior IAV/PR8 infection of mice resulted in a higher level of bacterial colonization and a lower rate of bacterial clearance from the lungs compared with mice treated with PBS. There were also consistent findings between the bioluminescence imaging and the CFU measurements in terms of identifying bacterial colonization and monitoring the clearance dynamics of E. coli O157:H7-lux in mouse lungs. Conclusion This novel bioluminescence-labelled bacterial infection model rapidly detected bacterial colonization of the lungs and monitored the clearance dynamics of E. coli O157:H7-lux following IAV/PR8 infection.

Lung Microbiome for Clinicians. New Discoveries about Bugs in Healthy and Diseased Lungs

PubMed Central

Rom, William N.; Weiden, Michael D.

2014-01-01

Microbes are readily cultured from epithelial surfaces of the skin, mouth, and colon. In the last 10 years, culture-independent DNA-based techniques demonstrated that much more complex microbial communities reside on most epithelial surfaces; this includes the lower airways, where bacterial culture had failed to reliably demonstrate resident bacteria. Exposure to a diverse bacterial environment is important for adequate immunological development. The most common microbes found in the lower airways are also found in the upper airways. Increasing abundance of oral characteristic taxa is associated with increased inflammatory cells and exhaled nitric oxide, suggesting that the airway microbiome induces an immunological response in the lung. Furthermore, rhinovirus infection leads to outgrowth of Haemophilus in patients with chronic obstructive pulmonary disease, and human immunodeficiency virus–infected subjects have more Tropheryma whipplei in the lower airway, suggesting a bidirectional interaction in which the host immune defenses also influence the microbial niche. Quantitative and/or qualitative changes in the lung microbiome may be relevant for disease progression and exacerbations in a number of pulmonary diseases. Future investigations with longitudinal follow-up to understand the dynamics of the lung microbiome may lead to the development of new therapeutic targets. PMID:24460444

Epidemic Pseudomonas aeruginosa infection in patients with cystic fibrosis is not a risk factor for poor clinical Outcomes following lung transplantation.

PubMed

Pritchard, Julia; Thakrar, Mitesh V; Somayaji, Ranjani; Surette, Michael G; Rabin, Harvey R; Helmersen, Doug; Lien, Dale; Purighalla, Swathi; Waddell, Barbara; Parkins, Michael D

2016-05-01

Epidemic strains of Pseudomonas aeruginosa (ePA) causing infection in cystic fibrosis (CF) have been commonly identified from clinics around the world. ePA disproportionally impacts CF patient pre-transplant outcomes manifesting in increased exacerbation frequency, worsened treatment burden and increased rate of lung function decline, and disproportionally leads to death and/or transplantation. As other CF factors such as pre-transplant infection with multi-resistant organisms, and isolation of P. aeruginosa in the post transplant graft, may impact post-transplant outcomes, we sought to determine if infection with ePA similarly adversely impact post-transplant outcomes. Between 1991-2014, 53 CF patients from our center received lung transplants. Bacterial strain typing was performed retrospectively on isolates collected prior to transplantation. Comprehensive chart reviews were performed to obtain baseline patient characteristics and post-transplant outcomes. Of the 53 transplanted patients, 57% of patients were infected with ePA prior to transplant; the other 43% of patients had unique strains of P. aeruginosa. Mean age at transplant was 29.0years for ePA and 33.3years for unique (p=0.04). There were no differences in overall survival (HR=0.75, 95% CI 0.31-1.79), bronchiolitis obliterans syndrome (BOS) free survival (HR 1.43, 95% CI 0.54-4.84) or all other assessed outcomes including exacerbation frequency, chronic renal failure, acute cellular rejections, Aspergillus infection, airway stenosis, and post-transplant lymphoproliferative disorder. Unlike pre-transplant outcomes, CF patients infected with ePA do not experience worse post-transplant outcomes than those infected with unique strains. Therefore, lung transplantation should be considered for all patients with P. aeruginosa infection and end stage lung disease, irrespective of infection with ePA. Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Infections in liver and lung transplant recipients: a national prospective cohort.

PubMed

Gagliotti, Carlo; Morsillo, Filomena; Moro, Maria Luisa; Masiero, Lucia; Procaccio, Francesco; Vespasiano, Francesca; Pantosti, Annalisa; Monaco, Monica; Errico, Giulia; Ricci, Andrea; Grossi, Paolo; Nanni Costa, Alessandro

2018-03-01

Infections are a major complication of solid organ transplants (SOTs). This study aimed to describe recipients' characteristics, and the frequency and etiology of infections and transplant outcome in liver and lung SOTs, and to investigate exposures associated to infection and death in liver transplant recipients. The study population included recipients of SOTs performed in Italy during a 1-year period in ten Italian lung transplant units and eight liver transplant units. Data on comorbidities, infections, retransplantation, and death were prospectively collected using a web-based system, with a 6-month follow-up. The cumulative incidence of infection was 31.7% and 47.8% in liver and lung transplants, respectively, with most infections occurring within the first month after transplantation. Gram-negatives, which were primarily multidrug-resistant, were the most frequent cause of infection. Death rates were 0.42 per 1000 recipient-days in liver transplants and 1.41 per 1000 recipient-days in lung transplants. Infection after SOT in adult liver recipients is associated to an increased risk of death (OR = 13.25; p-value < 0.001). Given the frequency of infection caused by multidrug-resistant microorganisms in SOT recipients in Italy and the heavy impact of infections on the transplant outcome, the reinforcement of surveillance and control activities to prevent the transmission of multidrug-resistant microorganisms in SOT recipients represents a priority. The implementation of the study protocol in liver and lung transplant units and the sharing of results have increased the awareness about the threat due to antimicrobial resistance in the country.

Concomitant Bacterial Meningitis in Infants With Urinary Tract Infection.

PubMed

Thomson, Joanna; Cruz, Andrea T; Nigrovic, Lise E; Freedman, Stephen B; Garro, Aris C; Ishimine, Paul T; Kulik, Dina M; Uspal, Neil G; Grether-Jones, Kendra L; Miller, Aaron S; Schnadower, David; Shah, Samir S; Aronson, Paul L; Balamuth, Fran

2017-09-01

To determine age-stratified prevalence of concomitant bacterial meningitis in infants ≤60 days with a urinary tract infection, we performed a 23-center, retrospective study of 1737 infants with urinary tract infection. Concomitant bacterial meningitis was rare, but more common in infants 0-28 days of age [0.9%; 95% confidence interval (CI): 0.4%-1.9%) compared with infants 29-60 days of age (0.2%; 95% CI: 0%-0.8%).

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.

Bacterial infections and hepatic encephalopathy in liver cirrhosis-prophylaxis and treatment.

PubMed

Piotrowski, Damian; Boroń-Kaczmarska, Anna

2017-09-01

Infections are common among patients with liver cirrhosis. They occur more often in cirrhotic patient groups than in the general population and result in higher mortality. One reason for this phenomenon is bacterial translocation from the intestinal lumen that occurs as a consequence of intestinal bacterial overgrowth, increased permeability and decreased motility. The most common infections in cirrhotic patients are spontaneous bacterial peritonitis and urinary tract infections, followed by pneumonia, skin and soft tissue infections. Intestinal bacterial overgrowth is also responsible for hyperammonemia, which leads to hepatic encephalopathy. All of these complications make this group of patients at high risk for mortality. The role of antibiotics in liver cirrhosis is to treat and in some cases to prevent the development of infectious complications. Based on our current knowledge, antibiotic prophylaxis should be administered to patients with gastrointestinal hemorrhage, low ascitic fluid protein concentration combined with liver or renal failure, and spontaneous bacterial peritonitis as a secondary prophylaxis, as well as after hepatic encephalopathy episodes (also as a secondary prophylaxis). In some cases, the use of non-antibiotic prophylaxis can also be considered. Current knowledge of the treatment of infections allows the choice of a preferred antibiotic for empiric therapy depending on the infection location and whether the source of the disease is nosocomial or community-acquired. Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.

Outcome of influenza infection managed with oseltamivir in lung transplant recipients.

PubMed

Ison, Michael G; Sharma, Amita; Shepard, Jo-Anne O; Wain, John C; Ginns, Leo C

2008-03-01

Influenza causes significant morbidity and mortality in lung transplant recipients and likely predisposes to obliterative bronchiolitis. Neuraminidase inhibitors shorten the duration of symptoms and virus shedding and the number of antibiotic-requiring complications in ambulatory immunocompetent patients, although the efficacy of these agents in lung transplant recipients has not been assessed previously. In this study, 9 lung transplant patients who were treated with oseltamivir for influenza infections were identified and analyzed retrospectively. Oseltamivir was well tolerated. Infection resolved in all patients and there were no deaths. Two patients developed pneumonia shortly after their influenza infection and both responded to antibiotic therapy. None of the patients had persistent abnormalities noted on chest imaging and most did not show significant changes on pulmonary function testing. Two patients with the lowest pulmonary function test (PFT) values pre-infection had persistent defects after infection. Oseltamivir is well tolerated in lung transplant recipients and may reduce the risk of complications, although further studies are warranted.

LAG3 Expression in Active Mycobacterium tuberculosis Infections

PubMed Central

Phillips, Bonnie L.; Mehra, Smriti; Ahsan, Muhammad H.; Selman, Moises; Khader, Shabaana A.; Kaushal, Deepak

2016-01-01

Mycobacterium tuberculosis (MTB) is a highly successful pathogen because of its ability to persist in human lungs for long periods of time. MTB modulates several aspects of the host immune response. Lymphocyte-activation gene 3 (LAG3) is a protein with a high affinity for the CD4 receptor and is expressed mainly by regulatory T cells with immunomodulatory functions. To understand the function of LAG3 during MTB infection, a nonhuman primate model of tuberculosis, which recapitulates key aspects of natural human infection in rhesus macaques (Macaca mulatta), was used. We show that the expression of LAG3 is highly induced in the lungs and particularly in the granulomatous lesions of macaques experimentally infected with MTB. Furthermore, we show that LAG3 expression is not induced in the lungs and lung granulomas of animals exhibiting latent tuberculosis infection. However, simian immunodeficiency virus–induced reactivation of latent tuberculosis infection results in an increased expression of LAG3 in the lungs. This response is not observed in nonhuman primates infected with non-MTB bacterial pathogens, nor with simian immunodeficiency virus alone. Our data show that LAG3 was expressed primarily on CD4+ T cells, presumably by regulatory T cells but also by natural killer cells. The expression of LAG3 coincides with high bacterial burdens and changes in the host type 1 helper T-cell response. PMID:25549835

The α-Tocopherol Form of Vitamin E Reverses Age-Associated Susceptibility to Streptococcus pneumoniae Lung Infection by Modulating Pulmonary Neutrophil Recruitment

PubMed Central

Ghanem, Elsa N. Bou; Clark, Stacie; Du, Xiaogang; Wu, Dayong; Camilli, Andrew; Leong, John M.; Meydani, Simin N.

2016-01-01

Streptococcus pneumoniae infections are an important cause of morbidity and mortality in older patients. Uncontrolled neutrophil-driven pulmonary inflammation exacerbates this disease. To test whether the α-tocopherol (α-Toc) form of vitamin E, a regulator of immunity, can modulate neutrophil responses as a preventive strategy to mitigate the age-associated decline in resistance to S. pneumoniae, young (4 mo) and old (22–24 mo) C57BL/6 mice were fed a diet containing 30-PPM (control) or 500-PPM (supplemented) α-Toc for 4 wk and intratracheally infected with S. pneumoniae. Aged mice fed a control diet were exquisitely more susceptible to S. pneumoniae than young mice. At 2 d postinfection, aged mice suffered 1000-fold higher pulmonary bacterial burden, 2.2-fold higher levels of neutrophil recruitment to the lung, and a 2.25-fold higher rate of lethal septicemia. Strikingly, α-Toc supplementation of aged mice resulted in a 1000-fold lower bacterial lung burden and full control of infection. This α-Toc–induced resistance to pneumococcal challenge was associated with a 2-fold fewer pulmonary neutrophils, a level comparable to S. pneumoniae–challenged, conventionally fed young mice. α-Toc directly inhibited neutrophil egress across epithelial cell monolayers in vitro in response to pneumococci or hepoxilin-A3, an eicosanoid required for pneumococcus-elicited neutrophil trans-epithelial migration. α-Toc altered expression of multiple epithelial and neutrophil adhesion molecules involved in migration, including CD55, CD47, CD18/CD11b, and ICAM-1. These findings suggest that α-Toc enhances resistance of aged mice to bacterial pneumonia by modulating the innate immune response, a finding that has potential clinical significance in combating infection in aged individuals through nutritional intervention. PMID:25512603

Urinary tract infections and bacterial prostatitis in men.

PubMed

Wagenlehner, Florian M E; Weidner, Wolfgang; Pilatz, Adrian; Naber, Kurt G

2014-02-01

The purpose of this review is to highlight advances in research on urinary tract infections (UTIs) and bacterial prostatitis in men in the preceding year. The antiseptic properties of the prostate secretions might be an important factor for prevention of recurrency. Risk factors for UTI in men include prostate enlargement and urological interventions, such as transrectal prostate biopsy. Preventive treatment of prostate enlargement has been demonstrated to reduce frequency of UTI. Ensuing infections after prostate biopsy, such as UTI and bacterial prostatitis, are increasing due to increasing rates of fluoroquinolone resistance. The increasing global antibiotic resistance also significantly affects management of UTI in men, and therefore calls for alternative strategies.Apart from prevention of complicating factors leading to UTI, a more thorough understanding of the pathophysiology may play a more important role in the future, to define new targets for treatment. Interesting results that might interfere with the intracellular mucosal bacterial load in the bladder wall have been found in the last years. UTI in men and bacterial prostatitis are currently underrepresented in the medical literature. Increasing antibacterial resistance calls for novel strategies in the prevention and management of UTI and bacterial prostatitis in men.

Bacterial and Pneumocystis Infections in the Lungs of Gene-Knockout Rabbits with Severe Combined Immunodeficiency

PubMed Central

Song, Jun; Wang, Guoshun; Hoenerhoff, Mark J.; Ruan, Jinxue; Yang, Dongshan; Zhang, Jifeng; Yang, Jibing; Lester, Patrick A.; Sigler, Robert; Bradley, Michael; Eckley, Samantha; Cornelius, Kelsey; Chen, Kong; Kolls, Jay K.; Peng, Li; Ma, Liang; Chen, Yuqing Eugene; Sun, Fei; Xu, Jie

2018-01-01

Using the CRISPR/Cas9 gene-editing technology, we recently produced a number of rabbits with mutations in immune function genes, including FOXN1, PRKDC, RAG1, RAG2, and IL2RG. Seven founder knockout rabbits (F0) and three male IL2RG null (−/y) F1 animals demonstrated severe combined immunodeficiency (SCID), characterized by absence or pronounced hypoplasia of the thymus and splenic white pulp, and absence of immature and mature T and B-lymphocytes in peripheral blood. Complete blood count analysis showed severe leukopenia and lymphocytopenia accompanied by severe neutrophilia. Without prophylactic antibiotics, the SCID rabbits universally succumbed to lung infections following weaning. Pathology examination revealed severe heterophilic bronchopneumonia caused by Bordetella bronchiseptica in several animals, but a consistent feature of lung lesions in all animals was a severe interstitial pneumonia caused by Pneumocystis oryctolagi, as confirmed by histological examination and PCR analysis of Pneumocystis genes. The results of this study suggest that these SCID rabbits could serve as a useful model for human SCID to investigate the disease pathogenesis and the development of gene and drug therapies. PMID:29593714

Viral Infection of Human Lung Macrophages Increases PDL1 Expression via IFNβ

PubMed Central

Staples, Karl J.; Nicholas, Ben; McKendry, Richard T.; Spalluto, C. Mirella; Wallington, Joshua C.; Bragg, Craig W.; Robinson, Emily C.; Martin, Kirstin; Djukanović, Ratko; Wilkinson, Tom M. A.

2015-01-01

Lung macrophages are an important defence against respiratory viral infection and recent work has demonstrated that influenza-induced macrophage PDL1 expression in the murine lung leads to rapid modulation of CD8+ T cell responses via the PD1 receptor. This PD1/PDL1 pathway may downregulate acute inflammatory responses to prevent tissue damage. The aim of this study was to investigate the mechanisms of PDL1 regulation by human macrophages in response to viral infection. Ex-vivo viral infection models using influenza and RSV were established in human lung explants, isolated lung macrophages and monocyte-derived macrophages (MDM) and analysed by flow cytometry and RT-PCR. Incubation of lung explants, lung macrophages and MDM with X31 resulted in mean cellular infection rates of 18%, 18% and 29% respectively. Viral infection significantly increased cell surface expression of PDL1 on explant macrophages, lung macrophages and MDM but not explant epithelial cells. Infected MDM induced IFNγ release from autologous CD8+ T cells, an effect enhanced by PDL1 blockade. We observed increases in PDL1 mRNA and IFNβ mRNA and protein release by MDM in response to influenza infection. Knockdown of IFNβ by siRNA, resulted in a 37.5% reduction in IFNβ gene expression in response to infection, and a significant decrease in PDL1 mRNA. Furthermore, when MDM were incubated with IFNβ, this cytokine caused increased expression of PDL1 mRNA. These data indicate that human macrophage PDL1 expression modulates CD8+ cell IFNγ release in response to virus and that this expression is regulated by autologous IFNβ production. PMID:25775126

Viral infection of human lung macrophages increases PDL1 expression via IFNβ.

PubMed

Staples, Karl J; Nicholas, Ben; McKendry, Richard T; Spalluto, C Mirella; Wallington, Joshua C; Bragg, Craig W; Robinson, Emily C; Martin, Kirstin; Djukanović, Ratko; Wilkinson, Tom M A

2015-01-01

Lung macrophages are an important defence against respiratory viral infection and recent work has demonstrated that influenza-induced macrophage PDL1 expression in the murine lung leads to rapid modulation of CD8+ T cell responses via the PD1 receptor. This PD1/PDL1 pathway may downregulate acute inflammatory responses to prevent tissue damage. The aim of this study was to investigate the mechanisms of PDL1 regulation by human macrophages in response to viral infection. Ex-vivo viral infection models using influenza and RSV were established in human lung explants, isolated lung macrophages and monocyte-derived macrophages (MDM) and analysed by flow cytometry and RT-PCR. Incubation of lung explants, lung macrophages and MDM with X31 resulted in mean cellular infection rates of 18%, 18% and 29% respectively. Viral infection significantly increased cell surface expression of PDL1 on explant macrophages, lung macrophages and MDM but not explant epithelial cells. Infected MDM induced IFNγ release from autologous CD8+ T cells, an effect enhanced by PDL1 blockade. We observed increases in PDL1 mRNA and IFNβ mRNA and protein release by MDM in response to influenza infection. Knockdown of IFNβ by siRNA, resulted in a 37.5% reduction in IFNβ gene expression in response to infection, and a significant decrease in PDL1 mRNA. Furthermore, when MDM were incubated with IFNβ, this cytokine caused increased expression of PDL1 mRNA. These data indicate that human macrophage PDL1 expression modulates CD8+ cell IFNγ release in response to virus and that this expression is regulated by autologous IFNβ production.

Differences of serum procalcitonin levels between bacterial infection and flare in systemic lupus erythematosus patients

NASA Astrophysics Data System (ADS)

Patrick, J.; Marpaung, B.; Ginting, Y.

2018-03-01

Differentiate bacterial infections from flare in SLE patients is difficult to do because clinical symptoms of infection is similar to flare. SLE patients with infection require antibiotic therapy with decreased doses of immunosuppressant while in flare diseases require increased immunosuppressant. Procalcitonin (PCT), a biological marker, increased in serum patients with bacterial infections and expected to be a solution of problem. The aim of this study was to examine the function of PCT serum as marker to differentiate bacterial infection and flare in SLE patients. This cross-sectional study was conducted in Adam Malik Hospital from January-July 2017. We examined 80 patients SLE flare (MEX-SLEDAI>5), screen PCT and culture according to focal infection. Data were statistically analyzed. 80 SLE patients divided into 2 groups: bacterial infection group (31 patients) and non-infection/flare group (49 patients). Median PCT levels of bacterial infection group was 1.66 (0.04-8.45)ng/ml while flare group was 0.12 (0.02-0.81)ng/ml. There was significant difference of serum Procalcitonin level between bacterial infection and flare group in SLE patients (p=0.001). Procalcitonin serum levels can be used as a biomarker to differentiate bacterial infections and flare in SLE patients.

Lung cancer in HIV infected patients: facts, questions and challenges

PubMed Central

Cadranel, J; Garfield, D; Lavolé, A; Wislez, M; Milleron, B; Mayaud, C

2006-01-01

AIDS related mortality has fallen sharply in industrialised countries since 1996 following the introduction of highly active antiretroviral therapy. This has been accompanied by an increase in the proportion of deaths attributable to non‐AIDS defining solid tumours, especially lung cancer. The risk of developing lung cancer seems to be higher in HIV infected subjects than in the general population of the same age, partly because the former tend more frequently to be smokers and, especially, intravenous drug users. The carcinogenic role of the antiretroviral nucleoside drugs and their interaction with smoking needs to be examined. Interestingly, there is no clear relationship between the degree of immunosuppression and the risk of lung cancer, so the reason for the increased risk is unknown. The mean age of HIV infected patients at the time of lung cancer diagnosis is 45 years and most are symptomatic. Lung cancer is diagnosed when locally advanced or metastatic (stage III–IV) in 75–90% of cases, similar to patients with unknown HIV status. Adenocarcinoma is the most frequent histological type. The prognosis is worse in HIV infected patients than in the general lung cancer population. Efficacy and toxicity data for chemotherapy and radiation therapy are few and imprecise. Surgery remains the treatment of choice for localised disease in patients with adequate pulmonary function and general good health, regardless of immune status. Prospective clinical trials are needed to define the optimal detection and treatment strategies for lung cancer in HIV infected patients. PMID:17071836

Anti-Pseudomonas aeruginosa IgY antibodies augment bacterial clearance in a murine pneumonia model.

PubMed

Thomsen, K; Christophersen, L; Bjarnsholt, T; Jensen, P Ø; Moser, C; Høiby, N

2016-03-01

Oral prophylactic therapy by gargling with pathogen-specific egg yolk immunoglobulins (IgY) may reduce the initial airway colonization with Pseudomonas aeruginosa in cystic fibrosis (CF) patients. IgY antibodies impart passive immunization and we investigated the effects of anti-P. aeruginosa IgY antibodies on bacterial eradication in a murine pneumonia model. P. aeruginosa pneumonia was established in Balb/c mice and the effects of prophylactic IgY administration on lung bacteriology, clinical parameters and subsequent inflammation were compared to controls. Prophylactic administration of IgY antibodies targeting P. aeruginosa significantly reduced the bacterial burden by 2-log 24h post-infection compared to controls and was accompanied by significantly reduced clinical symptom scores and successive inflammatory cytokine profile indicative of diminished lung inflammation. Passive immunization by anti-P. aeruginosa IgY therapy facilitates promptly bacterial clearance and moderates inflammation in P. aeruginosa lung infection and may serve as an adjunct to antibiotics in reducing early colonization. Copyright © 2015. Published by Elsevier B.V.

Neonatal Fc Receptor Regulation of Lung Immunoglobulin and CD103+ Dendritic Cells Confers Transient Susceptibility to Tuberculosis.

PubMed

Vogelzang, Alexis; Lozza, Laura; Reece, Stephen T; Perdomo, Carolina; Zedler, Ulrike; Hahnke, Karin; Oberbeck-Mueller, Dagmar; Dorhoi, Anca; Kaufmann, Stefan H E

2016-10-01

The neonatal Fc receptor (FcRn) extends the systemic half-life of IgG antibodies by chaperoning bound Fc away from lysosomal degradation inside stromal and hematopoietic cells. FcRn also transports IgG across mucosal barriers into the lumen, and yet little is known about how FcRn modulates immunity in the lung during homeostasis or infection. We infected wild-type (WT) and FcRn-deficient (fcgrt(-/-)) mice with Pseudomonas aeruginosa or Mycobacterium tuberculosis to investigate whether recycling and transport of IgG via FcRn influences innate and adaptive immunity in the lung in response to bacterial infection. We found that FcRn expression maintains homeostatic IgG levels in lung and leads to preferential secretion of low-affinity IgG ligands into the lumen. Fcgrt(-/-) animals exhibited no evidence of developmental impairment of innate immunity in the lung and were able to efficiently recruit neutrophils in a model of acute bacterial pneumonia. Although local humoral immunity in lung increased independently of the presence of FcRn during tuberculosis, there was nonetheless a strong impact of FcRn deficiency on local adaptive immunity. We show that the quantity and quality of IgG in airways, as well as the abundance of dendritic cells in the lung, are maintained by FcRn. FcRn ablation transiently enhanced local T cell immunity and neutrophil recruitment during tuberculosis, leading to a lower bacterial burden in lung. This novel understanding of tissue-specific modulation of mucosal IgG isotypes in the lung by FcRn sheds light on the role of mucosal IgG in immune responses in the lung during homeostasis and bacterial disease. Copyright © 2016 Vogelzang et al.

Bacterial Infections in Acute-on-Chronic Liver Failure.

PubMed

Yang, Lingling; Wu, Tianzhou; Li, Jiang; Li, Jun

2018-05-01

Acute-on-chronic liver failure (ACLF) is a newly recognized clinical syndrome characterized by preexisting chronic liver disease or cirrhosis with organ failure and high 28-day mortality (50-90%). Bacterial infections (BIs) play pivotal roles in the development and progression of ACLF either as a main precipitating event or a specific complication. The main organisms isolated as triggering ACLF are Gram-positive bacteria, followed by Gram-negative bacteria. Spontaneous bacterial peritonitis, pneumonia, urinary tract infections, and skin infections are prevalent infections that trigger and complicate ACLF. Despite appropriate antibiotic treatment, BIs account for poor ACLF outcomes and lead to a worse clinical course and higher intensive care unit admission and short-term mortality. Early diagnosis and novel nonantibiotic methods are highly important for managing BIs. Thus, this review focuses on the epidemiology, prognosis, and diagnosis of and management strategies for BIs in ACLF patients as well as the relationship between BIs and ACLF. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Serum Procalcitonin for Differential Diagnosis of Acute Exacerbation and Bacterial Pneumonia in Patients With Interstitial Lung Disease.

PubMed

Sim, Jae Kyeom; Oh, Jee Youn; Lee, Eun Joo; Hur, Gyu Young; Lee, Seung Heon; Lee, Sung Yong; Lee, Sang Yeub; Kim, Je Hyeong; Shin, Chol; Shim, Jae Jeong; In, Kwang Ho; Kang, Kyung Ho; Min, Kyung Hoon

2016-05-01

Acute exacerbation and bacterial pneumonia are major life-threatening conditions in patients with interstitial lung disease (ILD). The rapid recognition of these 2 different conditions is important for their proper treatment. An elevated procalcitonin (PCT) level is commonly detected in patients with bacterial infections. This study assessed the usefulness of the serum PCT level as a biomarker for the differential diagnosis of acute exacerbation and bacterial pneumonia in patients with ILD. In this prospective observational study, we enrolled patients with ILD who had experienced recently progressive dyspnea and exhibited new infiltrations on chest radiographs. We classified these patients into an acute exacerbation group and a bacterial pneumonia group and compared their baseline characteristics and laboratory parameters, including the PCT level. Of 21 patients with ILD, 9 patients had bacterial pneumonia. Both the groups showed similar baseline characteristics. The bacterial pneumonia group demonstrated a high PCT level. The PCT level in the acute exacerbation group was significantly lower than that in the bacterial pneumonia group (0.05 versus 0.91ng/mL, respectively; P < 0.001). Other parameters, such as the C-reactive protein level, leukocyte count and body temperature, were also lower in the acute exacerbation group. At a cutoff value of 0.1ng/mL, the sensitivity, specificity and negative predictive values of the serum PCT level were 88.9%, 100.0% and 92.3%, respectively. These findings suggest that the serum PCT level is useful in the differential diagnosis of acute exacerbation and bacterial pneumonia in patients with ILD. Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Sirolimus alters lung pathology and viral load following influenza A virus infection.

PubMed

Alsuwaidi, Ahmed R; George, Junu A; Almarzooqi, Saeeda; Hartwig, Stacey M; Varga, Steven M; Souid, Abdul-Kader

2017-07-11

Inhibitors of mTOR, such as sirolimus, have been shown to induce thymus involution and inflammatory lung disease in mice. The latter effect supports the role of this serine/threonine kinase in ameliorating lung inflammation. Other studies have shown sirolimus reduces/delays lung disease associated with various strains of influenza A virus (IAV). Thus, the effects of mTOR inhibitors on influenza infection deserve further studies. Here, we examined the changes in lung viral copies, pathology and pulmonary function associated with IAV (A/PR/8/34) infection in mice treated with sirolimus. Body weight loss peaked between days 6-11 post-infection and was more severe in IAV-infected mice that were administered sirolimus as compared to mice that received IAV alone (p = 0.030). Natural log viral gene copies, mean ± SD per mg lung tissue, in IAV-infected mice that were administered sirolimus were 17.31 ± 1.27 on day 4, 19.31 ± 7.46 on day 10, and 0 on day 25. The corresponding number of copies in mice that received IAV alone were 18.56 ± 0.95 on day 4 (p = 0.132), 1.52 ± 1.39 on day 10 (p = 0.008), and 0 on day 25. Lung pathology was evident on days 4, 10, and 25 post infection, with mean ± SD inflammatory score of 9.0 ± 4.5 in IAV-infected mice that were administered sirolimus, as compared to 11.5 ± 4.5 (p = 0.335) in mice received IAV alone (maximum score, 26.0). Impaired lung function was evident in IAV-infected mice on days 4 and 10, as demonstrated by increased airway resistance and decreased compliance. In this model, the effects of sirolimus on influenza infection included severe weight loss and modified viral replication, respiratory function and lung inflammation. The adverse events associated with sirolimus treatment are consistent with its potent immunosuppressive activity and, thus, preclude its use in IAV infection.

Acute sleep deprivation enhances post-infection sleep and promotes survival during bacterial infection in Drosophila.

PubMed

Kuo, Tzu-Hsing; Williams, Julie A

2014-05-01

Sleep is known to increase as an acute response to infection. However, the function of this behavioral response in host defense is not well understood. To address this problem, we evaluated the effect of acute sleep deprivation on post-infection sleep and immune function in Drosophila. Laboratory. Drosophila melanogaster. Flies were subjected to sleep deprivation before (early DEP) or after (late DEP) bacterial infection. Relative to a non-deprived control, flies subjected to early DEP had enhanced sleep after infection as well as increased bacterial clearance and survival outcome. Flies subjected to late DEP experienced enhanced sleep following the deprivation period, and showed a modest improvement in survival outcome. Continuous DEP (early and late DEP) throughout infection also enhanced sleep later during infection and improved survival. However, improved survival in flies subjected to late or continuous DEP did not occur until after flies had experienced sleep. During infection, both early and late DEP enhanced NFκB transcriptional activity as measured by a luciferase reporter (κB-luc) in living flies. Early DEP also increased NFκB activity prior to infection. Flies that were deficient in expression of either the Relish or Dif NFκB transcription factors showed normal responses to early DEP. However, the effect of early DEP on post-infection sleep and survival was abolished in double mutants, which indicates that Relish and Dif have redundant roles in this process. Acute sleep deprivation elevated NFκB-dependent activity, increased post-infection sleep, and improved survival during bacterial infection.

Bacterial Infection of Fly Ovaries Reduces Egg Production and Induces Local Hemocyte Activation

PubMed Central

Brandt, Stephanie M.; Schneider, David S.

2009-01-01

Summary Morbidity, the state of being diseased, is an important aspect of pathogenesis that has gone relatively unstudied in fruit flies. Our interest is in characterizing how bacterial pathogenesis affects various physiologies of the fly. We chose to examine the fly ovary because we found bacterial infection had a striking effect on fly reproduction. We observed decreased egg laying after bacterial infection that correlated with increased bacterial virulence. We also found that bacteria colonized the ovary in a previously undescribed manner; bacteria were found in the posterior of the ovary, adjacent to the lateral oviduct. This local infection in the ovary resulted in melanization and activation of the cellular immune response at the site of infection. PMID:17400292

[Preoperatiove Airway Bacterial Colonization: the Missing Link between Non-small Cell Lung Cancer Following Lobectomy and Postoperative Pneumonia?

PubMed

Gao, Ke; Lai, Yutian; Huang, Jian; Wang, Yifan; Wang, Xiaowei; Che, Guowei

2017-04-20

Surgical procedure is the main method of treating lung cancer. Meanwhile, postoperative pneumonia (POP) is the major cause of perioperative mortality in lung cancer surgery. The preoperative pathogenic airway bacterial colonization is an independent risk factor causing postoperative pulmonary complications (PPC). This cross-sectional study aimed to explore the relationship between preoperative pathogenic airway bacterial colonization and POP in lung cancer and to identify the high-risk factors of preoperative pathogenic airway bacterial colonization. A total of 125 patients with non-small cell lung cancer (NSCLC) underwent thoracic surgery in six hospitals of Chengdu between May 2015 and January 2016. Preoperative pathogenic airway bacterial colonization was detected in all patients via fiber bronchoscopy. Patients' PPC, high-risk factors, clinical characteristics, and the serum surfactant protein D (SP-D) level were also analyzed. The incidence of preoperative pathogenic airway bacterial colonization among NSCLC patients was 15.2% (19/125). Up to 22 strains were identified in the colonization positive group, with Gram-negative bacteria being dominant (86.36%, 19/22). High-risk factors of pathogenic airway bacterial colonization were age (≥75 yr) and smoking index (≥400 cigarettes/year). PPC incidence was significantly higher in the colonization-positive group (42.11%, 8/19) than that in the colonization-negative group (16.04%, 17/106)(P=0.021). POP incidence was significantly higher in the colonization-positive group (26.32%, 5/19) than that in the colonization-negative group (6.60%, 7/106)(P=0.019). The serum SP-D level of patients in the colonization-positive group was remarkably higher than that in the colonization-negative group [(31.25±6.09) vs (28.17±5.23)](P=0.023). The incidence of preoperative pathogenic airway bacterial colonization among NSCLC patients with POP was 41.67% (5/12). This value was 3.4 times higher than that among the patients without

Association of RNA Biosignatures With Bacterial Infections in Febrile Infants Aged 60 Days or Younger.

PubMed

Mahajan, Prashant; Kuppermann, Nathan; Mejias, Asuncion; Suarez, Nicolas; Chaussabel, Damien; Casper, T Charles; Smith, Bennett; Alpern, Elizabeth R; Anders, Jennifer; Atabaki, Shireen M; Bennett, Jonathan E; Blumberg, Stephen; Bonsu, Bema; Borgialli, Dominic; Brayer, Anne; Browne, Lorin; Cohen, Daniel M; Crain, Ellen F; Cruz, Andrea T; Dayan, Peter S; Gattu, Rajender; Greenberg, Richard; Hoyle, John D; Jaffe, David M; Levine, Deborah A; Lillis, Kathleen; Linakis, James G; Muenzer, Jared; Nigrovic, Lise E; Powell, Elizabeth C; Rogers, Alexander J; Roosevelt, Genie; Ruddy, Richard M; Saunders, Mary; Tunik, Michael G; Tzimenatos, Leah; Vitale, Melissa; Dean, J Michael; Ramilo, Octavio

Young febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. Analysis of host expression patterns ("RNA biosignatures") in response to infections may provide an alternative diagnostic approach. To assess whether RNA biosignatures can distinguish febrile infants aged 60 days or younger with and without serious bacterial infections. Prospective observational study involving a convenience sample of febrile infants 60 days or younger evaluated for fever (temperature >38° C) in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type. RNA biosignatures compared with cultures for discriminating febrile infants with and without bacterial infections and infants with bacteremia from those without bacterial infections. Bacterial infection confirmed by culture. Performance of RNA biosignatures was compared with routine laboratory screening tests and Yale Observation Scale (YOS) scores. Of 1883 febrile infants (median age, 37 days; 55.7% boys), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections-including 32 with bacteremia and 15 with urinary tract infections-and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set with 87% (95% CI, 73%-95%) sensitivity and 89% (95% CI, 81%-93%) specificity. Ten classifier genes distinguished infants with bacteremia from those without bacterial infections in the test set with 94% (95% CI, 70

Bacterial infections in HIV-infected children admitted with severe acute malnutrition in Durban, South Africa.

PubMed

Archary, Moherndran; Adler, Hugh; La Russa, Philip; Mahabeer, Prasha; Bobat, Raziya A

2017-02-01

Bacterial infections in HIV-infected children admitted with severe acute malnutrition (SAM) contribute to higher mortality and poorer outcomes. This study describes the spectrum of bacterial infections in antiretroviral treatment (ART)-naïve, HIV-infected children admitted with SAM. Between July 2012 and February 2015, 82 children were prospectively enrolled in the King Edward VIII Hospital, Durban. Specimens obtained on and during admission for microbiological evaluation, if clinically indicated, included blood, urine (obtained by catheterisation or suprapubic aspiration), induced sputum and cerebrospinal fluid. All positive bacterial cultures between admission and 30 days after enrollment were documented and characterised into samples taken either within 2 days of admission (infections on admission) or within 2-30 days of admission (hospital-acquired infections, HAIs). On admission, 67% of patients had abnormal white blood cell counts (WBCC) (>12 or <4 × 10 9 /L) and 70% had elevated CRP; 65% were classified as severely immunosuppressed according to the WHO immunological classification. 1 A pathogen was isolated on the admission blood culture in four patients (6%) and in 27% of urine specimens. HAIs were predominately Gram-negative (39/43), and 39.5% were extended-spectrum β-lactamase-positive. Mortality was not significantly associated with isolation of a bacterial pathogen. Routine pre-hospital administration of antibiotics as per the Integrated Management of Childhood Illness (IMCI) guidelines may be responsible for the low rates of positive admission blood cultures. HAIs with drug-resistant Gram-negative organisms are an area of concern and strategies to improve the prevention of HAIs in this vulnerable population are urgently needed.

[Scedosporium apiospermum disseminated infection in a single lung transplant recipient].

PubMed

Solé, Amparo

2011-01-01

Scedosporium spp. are filamentous fungi, and the 2 most important species are Scedosporium prolificans and Scedosporium apiospermum. S. apiospermum accounts for approximately 25% of non-Aspergillus filamentous fungi infections in organ transplant recipients. Scedosporium can colonize the sinuses and airways of lung recipients with underlying pulmonary diseases, such as bronchiectasis or cystic fibrosis before transplant, and develop invasive disease after lung transplantation. In fact, invasive diseases caused by S. apiospermum have been reported only rarely, in single lung transplant recipients and cystic fibrosis transplant patients. The treatment of scedosporiasis is complicated due to the difficulty in early diagnosis together with inherent resistance to amphotericin B. A case of disseminated S. apiospermum infection after single lung transplant in a patient with pulmonary fibrosis is reported. Leg mycetoma was the initial sign of this disseminated infection. In this case report, current treatment options are discussed, and a review of the literature of previously published cases of lung transplants is made. One conclusion based on this case is the risk of emergent molds related to antifungal prophylaxis. In addition, colonization by Scedosporium in transplant recipients should not be ignored, and target prophylaxis or suppressive therapy should be considered in all those cases with residual lesions in native lung or chronic rejection in transplanted lungs. Copyright © 2011 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

Lung abscess in a child secondary to Mycoplasma pneumoniae infection.

PubMed

Ruffini, E; De Petris, L; Candelotti, P; Tulli, M; Sabatini, M R; Luciani, L; Carlucci, A

2014-01-01

We present a case of a lung abscess in a child 6-year-old admitted with a history of right hemithorax pain lasting for 15 days and the onset of mild fever in the last two days. Etiological research showed positivity of IgM antibodies to Mycoplasma pneumoniae after seven days of admission. The child has been successfully treated with antibiotic therapy, without the use of macrolides, for a duration of 4 weeks. Our study suggests that the Mycoplasma pneumoniae infection may predispose to severe infections, such as lung abscess, caused by typical respiratory pathogens. The reported case of lung abscess is one of the few reported in the literature in the modern antibiotic era and is the first preceded by Mycoplasma pneumoniae infection.

The impact of rifaximin in the prevention of bacterial infections in cirrhosis.

PubMed

Mariani, M; Zuccaro, V; Patruno, S F A; Scudeller, L; Sacchi, P; Lombardi, A; Vecchia, M; Columpsi, P; Marone, P; Filice, G; Bruno, R

2017-03-01

Bacterial infections are a leading factor in the progression from compensated to decompensated cirrhosis, with consequent worsening of the prognosis, and concerted efforts have been made to reduce infections and improve the survival rate of these patients. We retrospectively investigated the rate of infections in hospitalized cirrhotic patients under treatment with rifaximin. We enrolled 649 patients whose clinical and personal data, prescribed therapy, microbiological findings and laboratory tests were collected from previous discharge letters and our institution database. The efficacy of rifaximin in preventing several types infection was evaluated by comparing outcomes for rifaximin-treated patients vs patients receiving no antibiotic treatment. The risk of developing selected bacterial infections was significantly lower in patients treated with rifaximin (OR 0.29; 95% CI 0.20-0.40, p < 0.001). Continuous treatment with rifaximin may prevent bacterial infections in cirrhotic patients.

[EFFECTIVENESS OF FULLERENE-(TRIS-AMINOCAPRONIC ACID) HYDRATE IN THE MODEL OF EXPERIMENTAL VIRAL-BACTERIAL PNEUMONIA OF MICE].

PubMed

Falynskova, I N; Leonova, E I; Fedyakina, I T; Makhmudova, N R; Lepekha, L N; Mikhailova, N A; Rasnetsov, L D; Zverev, V V; Leneva, I A

2015-01-01

Study the effectiveness of the substance and various drug formulations of fullerene-(tris-aminocapronic acid) hydrate (FTAAH onwards) in the model of experimental viral-bacterial pneumonia of mice. BALB/c mice were infected with influenza virus A/California/04/2009 and subsequently infected with Staphylococcus aureus. The animals were treated after viral infection with the substance and various drug forms of FTAAH, as well as comparative preparations--oseltamivir and arbidol. Therapy effectiveness was evaluated by clinical indicators (survival, lifespan, animal mass decrease reduction), virological (virus titer), microbiological (density of bacteria in lungs) parameters, confirmed by pathomorphological characteristics of lungs. FTAAH therapy in injectable form was effective in the model of a combined viral-bacterial pneumonia of mice by all the studied criteria: treatment increased mice survival, reduced the decrease of their body weight, resulted in a reduction of virus titers and density of bacteria in lungs, that correlated with the data from morphological study and signs of bronchopneumonia resolution in mice. FTAAH therapy in rectal form depended on animal infection schemes, as well as preparation dose, increasing with its increase. FTAAH substance is effective in the model of experimental viral-bacterial pneumonia of mice.

LAG3 expression in active Mycobacterium tuberculosis infections.

PubMed

Phillips, Bonnie L; Mehra, Smriti; Ahsan, Muhammad H; Selman, Moises; Khader, Shabaana A; Kaushal, Deepak

2015-03-01

Mycobacterium tuberculosis (MTB) is a highly successful pathogen because of its ability to persist in human lungs for long periods of time. MTB modulates several aspects of the host immune response. Lymphocyte-activation gene 3 (LAG3) is a protein with a high affinity for the CD4 receptor and is expressed mainly by regulatory T cells with immunomodulatory functions. To understand the function of LAG3 during MTB infection, a nonhuman primate model of tuberculosis, which recapitulates key aspects of natural human infection in rhesus macaques (Macaca mulatta), was used. We show that the expression of LAG3 is highly induced in the lungs and particularly in the granulomatous lesions of macaques experimentally infected with MTB. Furthermore, we show that LAG3 expression is not induced in the lungs and lung granulomas of animals exhibiting latent tuberculosis infection. However, simian immunodeficiency virus-induced reactivation of latent tuberculosis infection results in an increased expression of LAG3 in the lungs. This response is not observed in nonhuman primates infected with non-MTB bacterial pathogens, nor with simian immunodeficiency virus alone. Our data show that LAG3 was expressed primarily on CD4(+) T cells, presumably by regulatory T cells but also by natural killer cells. The expression of LAG3 coincides with high bacterial burdens and changes in the host type 1 helper T-cell response. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Comparison of Bacterial Community Composition of Primary and Persistent Endodontic Infections Using Pyrosequencing.

PubMed

Tzanetakis, Giorgos N; Azcarate-Peril, M Andrea; Zachaki, Sophia; Panopoulos, Panos; Kontakiotis, Evangelos G; Madianos, Phoebus N; Divaris, Kimon

2015-08-01

Elucidating the microbial ecology of endodontic infections (EIs) is a necessary step in developing effective intracanal antimicrobials. The aim of the present study was to investigate the bacterial composition of symptomatic and asymptomatic primary and persistent infections in a Greek population using high-throughput sequencing methods. 16S amplicon pyrosequencing of 48 root canal bacterial samples was conducted, and sequencing data were analyzed using an oral microbiome-specific and a generic (Greengenes) database. Bacterial abundance and diversity were examined by EI type (primary or persistent), and statistical analysis was performed by using non-parametric and parametric tests accounting for clustered data. Bacteroidetes was the most abundant phylum in both infection groups. Significant, albeit weak associations of bacterial diversity were found, as measured by UniFrac distances with infection type (analyses of similarity, R = 0.087, P = .005) and symptoms (analyses of similarity, R = 0.055, P = .047). Persistent infections were significantly enriched for Proteobacteria and Tenericutes compared with primary ones; at the genus level, significant differences were noted for 14 taxa, including increased enrichment of persistent infections for Lactobacillus, Streptococcus, and Sphingomonas. More but less abundant phyla were identified using the Greengenes database; among those, Cyanobacteria (0.018%) and Acidobacteria (0.007%) were significantly enriched among persistent infections. Persistent infections showed higher phylogenetic diversity (PD) (asymptomatic: PD = 9.2, standard error [SE] = 1.3; symptomatic: PD = 8.2, SE = 0.7) compared with primary infections (asymptomatic: PD = 5.9, SE = 0.8; symptomatic: PD = 7.4, SE = 1.0). The present study revealed a high bacterial diversity of EI and suggests that persistent infections may have more diverse bacterial communities than primary infections. Copyright © 2015 American Association of Endodontists. Published by

Persistent bacterial infections, antibiotic tolerance, and the oxidative stress response

PubMed Central

Grant, Sarah Schmidt; Hung, Deborah T.

2013-01-01

Certain bacterial pathogens are able to evade the host immune system and persist within the human host. The consequences of persistent bacterial infections potentially include increased morbidity and mortality from the infection itself as well as an increased risk of dissemination of disease. Eradication of persistent infections is difficult, often requiring prolonged or repeated courses of antibiotics. During persistent infections, a population or subpopulation of bacteria exists that is refractory to traditional antibiotics, possibly in a non-replicating or metabolically altered state. This review highlights the clinical significance of persistent infections and discusses different in vitro models used to investigate the altered physiology of bacteria during persistent infections. We specifically focus on recent work establishing increased protection against oxidative stress as a key element of the altered physiologic state across different in vitro models and pathogens. PMID:23563389

Secondary Bacterial Infections Associated with Influenza Pandemics

PubMed Central

Morris, Denise E.; Cleary, David W.; Clarke, Stuart C.

2017-01-01

Lower and upper respiratory infections are the fourth highest cause of global mortality (Lozano et al., 2012). Epidemic and pandemic outbreaks of respiratory infection are a major medical concern, often causing considerable disease and a high death toll, typically over a relatively short period of time. Influenza is a major cause of epidemic and pandemic infection. Bacterial co/secondary infection further increases morbidity and mortality of influenza infection, with Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus reported as the most common causes. With increased antibiotic resistance and vaccine evasion it is important to monitor the epidemiology of pathogens in circulation to inform clinical treatment and development, particularly in the setting of an influenza epidemic/pandemic. PMID:28690590

A human lung xenograft mouse model of Nipah virus infection.

PubMed

Valbuena, Gustavo; Halliday, Hailey; Borisevich, Viktoriya; Goez, Yenny; Rockx, Barry

2014-04-01

Nipah virus (NiV) is a member of the genus Henipavirus (family Paramyxoviridae) that causes severe and often lethal respiratory illness and encephalitis in humans with high mortality rates (up to 92%). NiV can cause Acute Lung Injury (ALI) in humans, and human-to-human transmission has been observed in recent outbreaks of NiV. While the exact route of transmission to humans is not known, we have previously shown that NiV can efficiently infect human respiratory epithelial cells. The molecular mechanisms of NiV-associated ALI in the human respiratory tract are unknown. Thus, there is an urgent need for models of henipavirus infection of the human respiratory tract to study the pathogenesis and understand the host responses. Here, we describe a novel human lung xenograft model in mice to study the pathogenesis of NiV. Following transplantation, human fetal lung xenografts rapidly graft and develop mature structures of adult lungs including cartilage, vascular vessels, ciliated pseudostratified columnar epithelium, and primitive "air" spaces filled with mucus and lined by cuboidal to flat epithelium. Following infection, NiV grows to high titers (10(7) TCID50/gram lung tissue) as early as 3 days post infection (pi). NiV targets both the endothelium as well as respiratory epithelium in the human lung tissues, and results in syncytia formation. NiV infection in the human lung results in the production of several cytokines and chemokines including IL-6, IP-10, eotaxin, G-CSF and GM-CSF on days 5 and 7 pi. In conclusion, this study demonstrates that NiV can replicate to high titers in a novel in vivo model of the human respiratory tract, resulting in a robust inflammatory response, which is known to be associated with ALI. This model will facilitate progress in the fundamental understanding of henipavirus pathogenesis and virus-host interactions; it will also provide biologically relevant models for other respiratory viruses.

Retrospective study of bacterial infective arthritis in 31 dogs.

PubMed

Clements, D N; Owen, M R; Mosley, J R; Carmichael, S; Taylor, D J; Bennett, D

2005-04-01

To characterise the presenting signs and pathological changes of canine bacterial infective arthritis in 31 dogs, and to document the response to different treatment regimens. Risk factors that may predispose joints to bacterial infective arthritis and influence the success of treatment were also investigated. A retrospective review of cases of bacterial infective arthritis that were presented to three university veterinary referral hospitals over a five-year period (January 1997 to January 2002) was performed. The elbow joint (38 per cent) and stifle joint (44 per cent) were most commonly affected. Radiographic changes consistent with pre-existing osteoarthritis were identified in 14 joints, which had no history of previous surgery (articular or periarticular) or penetrating wound. No significant difference (P = 0.78) was identified between the outcome of combined surgical and medical management, and medical management alone. There were trends for poorer outcomes with increased bodyweight of the dog, longer duration of lameness and a higher nucleated cell count of the affected joint fluid at presentation. The overall infection rate for articular surgical procedures at one institution was 1-3 per cent. Medical and/or surgical management were usually successful in resolving infection (94 per cent). However, they were frequently unsuccessful in restoring full joint function; this may in part have been due to the nature of the underlying joint

Preponderance of bacterial isolates in urine of HIV-positive malaria-infected pregnant women with urinary tract infection.

PubMed

Ako-Nai, Kwashie Ajibade; Ebhodaghe, Blessing Itohan; Osho, Patrick; Adejuyigbe, Ebun; Adeyemi, Folasade Mubiat; Kassim, Olakunle O

2014-12-15

This study examined HIV and malaria co-infection as a risk factor for urinary tract infections (UTIs) in pregnancy. The study group included 74 pregnant women, 20 to 42 years of age, who attended the antenatal clinic at the Specialist Hospital at Akure, Ondo State, Nigeria. Forty-four of the pregnant women were either HIV seropositive with malaria infection (HIV+Mal+) or HIV seropositive without malaria (HIV+Mal-). The remaining thirty pregnant women served as controls and included women HIV seronegative but with malaria (HIV-Mal+) and women HIV seronegative without malaria. UTI was indicated by a bacterial colony count of greater than 10⁵/mL of urine, using cysteine lactose electrolyte deficient medium (CLED) as the primary isolation medium. Bacterial isolates were characterized using convectional bacteriological methods, and antibiotics sensitivity tests were carried out using the disk diffusion method. A total of 246 bacterial isolates were recovered from the cultures, with a mean of 3.53 isolates per subject. Women who were HIV+Mal+ had the most diverse group of bacterial isolates and the highest frequency of UTIs. The bacterial isolates from the HIV+Mal+ women also showed the highest degree of antibiotic resistance. While pregnancy and HIV infection may each represent a risk factor for UTI, HIV and malaria co-infection may increase its frequency in pregnancy. The higher frequency of multiple antibiotic resistance observed among the isolates, particularly isolates from HIV+Mal+ subjects, poses a serious public health concern as these strains may aggravate the prognosis of both UTI and HIV infection.

Increased Sleep Promotes Survival during a Bacterial Infection in Drosophila

PubMed Central

Kuo, Tzu-Hsing; Williams, Julie A.

2014-01-01

Study Objectives: The relationship between sleep and immune function is not well understood at a functional or molecular level. We therefore used a genetic approach in Drosophila to manipulate sleep and evaluated effects on the ability of flies to fight bacterial infection. Setting: Laboratory. Participants: Drosophila melanogaster. Methods and Results: We used a genetic approach to transiently alter neuronal excitability in the mushroom body, a region in the central brain that is known to regulate sleep. Flies with increased sleep for up to two days prior to a bacterial infection showed increased resistance to the infection and improved survival. These flies also had increased expression levels of a subset of anti-microbial peptide mRNA prior to infection, as well as increased NFκB activity during infection as indicated by in vivo luciferase reporter activity. In contrast, flies that experienced reduced sleep for up to two days prior to infection had no effect on survival or on NFκB activity during infection. However, flies with reduced sleep showed an altered defense mechanism, such that resistance to infection was increased, but at the expense of reduced tolerance. This effect was dependent on environmental condition. Conclusions: Increasing sleep enhanced activity of an NFκB transcription factor, increased resistance to infection, and strongly promoted survival. Together, these findings support the hypothesis that sleep is beneficial to the host by maintaining a robust immune system. Citation: Kuo TH, Williams JA. Increased sleep promotes survival during a bacterial infection in Drosophila. SLEEP 2014;37(6):1077-1086. PMID:24882902

New insights into valve-related intramural and intracellular bacterial diversity in infective endocarditis

PubMed Central

Feder, Stefan; Lehmann, Stefanie; Kullnick, Yvonne; Buschmann, Tilo; Blumert, Conny; Horn, Friedemann; Neuhaus, Jochen; Neujahr, Ralph; Bagaev, Erik; Hagl, Christian; Pichlmaier, Maximilian; Rodloff, Arne Christian; Gräber, Sandra; Kirsch, Katharina; Sandri, Marcus; Kumbhari, Vivek; Behzadi, Armirhossein; Behzadi, Amirali; Correia, Joao Carlos; Mohr, Friedrich Wilhelm

2017-01-01

Aims In infective endocarditis (IE), a severe inflammatory disease of the endocardium with an unchanged incidence and mortality rate over the past decades, only 1% of the cases have been described as polymicrobial infections based on microbiological approaches. The aim of this study was to identify potential biodiversity of bacterial species from infected native and prosthetic valves. Furthermore, we compared the ultrastructural micro-environments to detect the localization and distribution patterns of pathogens in IE. Material and methods Using next-generation sequencing (NGS) of 16S rDNA, which allows analysis of the entire bacterial community within a single sample, we investigated the biodiversity of infectious bacterial species from resected native and prosthetic valves in a clinical cohort of 8 IE patients. Furthermore, we investigated the ultrastructural infected valve micro-environment by focused ion beam scanning electron microscopy (FIB-SEM). Results Biodiversity was detected in 7 of 8 resected heart valves. This comprised 13 bacterial genera and 16 species. In addition to 11 pathogens already described as being IE related, 5 bacterial species were identified as having a novel association. In contrast, valve and blood culture-based diagnosis revealed only 4 species from 3 bacterial genera and did not show any relevant antibiotic resistance. The antibiotics chosen on this basis for treatment, however, did not cover the bacterial spectra identified by our amplicon sequencing analysis in 4 of 8 cases. In addition to intramural distribution patterns of infective bacteria, intracellular localization with evidence of bacterial immune escape mechanisms was identified. Conclusion The high frequency of polymicrobial infections, pathogen diversity, and intracellular persistence of common IE-causing bacteria may provide clues to help explain the persistent and devastating mortality rate observed for IE. Improved bacterial diagnosis by 16S rDNA NGS that increases the

Spontaneous bacterial and fungal infections in genetically engineered mice: Is Escherichia coli an emerging pathogen in laboratory mouse?

PubMed

Benga, Laurentiu; Benten, W Peter M; Engelhardt, Eva; Gougoula, Christina; Sager, Martin

2015-01-01

The impact of particular microbes on genetically engineered mice depends on the genotype and the environment. Infections resulting in clinical disease have an obvious impact on animal welfare and experimentation. In this study, we investigated the bacterial and fungal aetiology of spontaneous clinical disease of infectious origin among the genetically engineered mice from our institution in relation to their genotype. A total of 63 mice belonging to 33 different mice strains, from severe immunodeficient to wild-type, were found to display infections as the primary cause leading to their euthanasia. The necropsies revealed abscesses localized subcutaneously as well as in the kidney, preputial glands, seminal vesicles, in the uterus, umbilicus or in the lung. In addition, pneumonia, endometritis and septicaemia cases were recorded. Escherichia coli was involved in 21 of 44 (47.72%) of the lesions of bacterial origin, whereas [Pasteurella] pneumotropica was isolated from 19 of 44 (43.18%) cases. The infections with the two agents mentioned above included three cases of mixed infection with both pathogens. Staphylococcus aureus was considered responsible for five of 44 (11.36%) cases whereas Enterobacter cloacae was found to cause lesions in two of 44 (4.54%) mice. Overall, 16 of the 44 (36.36%) cases of bacterial aetiology affected genetically engineered mice without any explicit immunodeficiency or wild-type strains. The remaining 19 cases of interstitial pneumonia were caused by Pneumocystis murina. In conclusion, the susceptibility of genetically modified mice to opportunistic infections has to be regarded with precaution, regardless of the type of genetic modification performed. Beside the classical opportunists, such as [Pasteurella] pneumotropica and Staphylococcus aureus, Escherichia coli should as well be closely monitored to evaluate whether it represents an emerging pathogen in the laboratory mouse.

Enhanced Mucosal Antibody Production and Protection against Respiratory Infections Following an Orally Administered Bacterial Extract

PubMed Central

Pasquali, Christian; Salami, Olawale; Taneja, Manisha; Gollwitzer, Eva S.; Trompette, Aurelien; Pattaroni, Céline; Yadava, Koshika; Bauer, Jacques; Marsland, Benjamin J.

2014-01-01

Secondary bacterial infections following influenza infection are a pressing problem facing respiratory medicine. Although antibiotic treatment has been highly successful over recent decades, fatalities due to secondary bacterial infections remain one of the leading causes of death associated with influenza. We have assessed whether administration of a bacterial extract alone is sufficient to potentiate immune responses and protect against primary infection with influenza, and secondary infections with either Streptococcus pneumoniae or Klebsiella pneumoniae in mice. We show that oral administration with the bacterial extract, OM-85, leads to a maturation of dendritic cells and B-cells characterized by increases in MHC II, CD86, and CD40, and a reduction in ICOSL. Improved immune responsiveness against influenza virus reduced the threshold of susceptibility to secondary bacterial infections, and thus protected the mice. The protection was associated with enhanced polyclonal B-cell activation and release of antibodies that were effective at neutralizing the virus. Taken together, these data show that oral administration of bacterial extracts provides sufficient mucosal immune stimulation to protect mice against a respiratory tract viral infection and associated sequelae. PMID:25593914

Influenza-induced type I interferon enhances susceptibility to gram-negative and gram-positive bacterial pneumonia in mice.

PubMed

Lee, Benjamin; Robinson, Keven M; McHugh, Kevin J; Scheller, Erich V; Mandalapu, Sivanarayana; Chen, Chen; Di, Y Peter; Clay, Michelle E; Enelow, Richard I; Dubin, Patricia J; Alcorn, John F

2015-07-15

Suppression of type 17 immunity by type I interferon (IFN) during influenza A infection has been shown to enhance susceptibility to secondary bacterial pneumonia. Although this mechanism has been described in coinfection with gram-positive bacteria, it is unclear whether similar mechanisms may impair lung defense against gram-negative infections. Furthermore, precise delineation of the duration of type I IFN-associated susceptibility to bacterial infection remains underexplored. Therefore, we investigated the effects of preceding influenza A virus infection on subsequent challenge with the gram-negative bacteria Escherichia coli or Pseudomonas aeruginosa and the temporal association between IFN expression with susceptibility to Staphylococcus aureus challenge in a mouse model of influenza and bacterial coinfection. Here we demonstrate that preceding influenza A virus led to increased lung E. coli and P. aeruginosa bacterial burden, which was associated with suppression of type 17 immunity and attenuation of antimicrobial peptide expression. Enhanced susceptibility to S. aureus coinfection ceased at day 14 of influenza infection, when influenza-associated type I IFN levels had returned to baseline levels, further suggesting a key role for type I IFN in coinfection pathogenesis. These findings further implicate type I IFN-associated suppression of type 17 immunity and antimicrobial peptide production as a conserved mechanism for enhanced susceptibility to both gram-positive and gram-negative bacterial coinfection during influenza infection. Copyright © 2015 the American Physiological Society.

Infection of orthopedic implants with emphasis on bacterial adhesion process and techniques used in studying bacterial-material interactions

PubMed Central

Ribeiro, Marta; Monteiro, Fernando J.; Ferraz, Maria P.

2012-01-01

Staphylococcus comprises up to two-thirds of all pathogens in orthopedic implant infections and they are the principal causative agents of two major types of infection affecting bone: septic arthritis and osteomyelitis, which involve the inflammatory destruction of joint and bone. Bacterial adhesion is the first and most important step in implant infection. It is a complex process influenced by environmental factors, bacterial properties, material surface properties and by the presence of serum or tissue proteins. Properties of the substrate, such as chemical composition of the material, surface charge, hydrophobicity, surface roughness and the presence of specific proteins at the surface, are all thought to be important in the initial cell attachment process. The biofilm mode of growth of infecting bacteria on an implant surface protects the organisms from the host immune system and antibiotic therapy. The research for novel therapeutic strategies is incited by the emergence of antibiotic-resistant bacteria. This work will provide an overview of the mechanisms and factors involved in bacterial adhesion, the techniques that are currently being used studying bacterial-material interactions as well as provide insight into future directions in the field. PMID:23507884

Lung Infections in Systemic Rheumatic Disease: Focus on Opportunistic Infections.

PubMed

Di Franco, Manuela; Lucchino, Bruno; Spaziante, Martina; Iannuccelli, Cristina; Valesini, Guido; Iaiani, Giancarlo

2017-01-29

Systemic rheumatic diseases have significant morbidity and mortality, due in large part to concurrent infections. The lung has been reported among the most frequent sites of infection in patients with rheumatic disease, who are susceptible to developing pneumonia sustained both by common pathogens and by opportunistic microorganisms. Patients with rheumatic disease show a peculiar vulnerability to infectious complications. This is due in part to intrinsic disease-related immune dysregulation and in part to the immunosuppressive treatments. Several therapeutic agents have been associated to a wide spectrum of infections, complicating the management of rheumatic diseases. This review discusses the most frequent pulmonary infections encountered in rheumatic diseases, focusing on opportunistic agents, consequent diagnostic challenges and appropriate therapeutic strategies.

Critical role of CXCL4 in the lung pathogenesis of influenza (H1N1) respiratory infection.

PubMed

Guo, L; Feng, K; Wang, Y C; Mei, J J; Ning, R T; Zheng, H W; Wang, J J; Worthen, G S; Wang, X; Song, J; Li, Q H; Liu, L D

2017-11-01

Annual epidemics and unexpected pandemics of influenza are threats to human health. Lung immune and inflammatory responses, such as those induced by respiratory infection influenza virus, determine the outcome of pulmonary pathogenesis. Platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) has an immunoregulatory role in inflammatory diseases. Here we show that CXCL4 is associated with pulmonary influenza infection and has a critical role in protecting mice from fatal H1N1 virus respiratory infection. CXCL4 knockout resulted in diminished viral clearance from the lung and decreased lung inflammation during early infection but more severe lung pathology relative to wild-type mice during late infection. Additionally, CXCL4 deficiency decreased leukocyte accumulation in the infected lung with markedly decreased neutrophil infiltration into the lung during early infection and extensive leukocyte, especially lymphocyte accumulation at the late infection stage. Loss of CXCL4 did not affect the activation of adaptive immune T and B lymphocytes during the late stage of lung infection. Further study revealed that CXCL4 deficiency inhibited neutrophil recruitment to the infected mouse lung. Thus the above results identify CXCL4 as a vital immunoregulatory chemokine essential for protecting mice against influenza A virus infection, especially as it affects the development of lung injury and neutrophil mobilization to the inflamed lung.

Hyperglycemia impedes lung bacterial clearance in a murine model of cystic fibrosis-related diabetes

PubMed Central

Hunt, William R.; Zughaier, Susu M.; Guentert, Dana E.; Shenep, Melissa A.; Koval, Michael; McCarty, Nael A.

2013-01-01

Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity associated with cystic fibrosis (CF), impacting more than half of patients over age 30. CFRD is clinically significant, portending accelerated decline in lung function, more frequent pulmonary exacerbations, and increased mortality. Despite the profound morbidity associated with CFRD, little is known about the underlying CFRD-related pulmonary pathology. Our aim was to develop a murine model of CFRD to explore the hypothesis that elevated glucose in CFRD is associated with reduced lung bacterial clearance. A diabetic phenotype was induced in gut-corrected CF transmembrane conductance regulator (CFTR) knockout mice (CFKO) and their CFTR-expressing wild-type littermates (WT) utilizing streptozotocin. Mice were subsequently challenged with an intratracheal inoculation of Pseudomonas aeruginosa (PAO1) (75 μl of 1–5 × 106 cfu/ml) for 18 h. Bronchoalveolar lavage fluid was collected for glucose concentration and cell counts. A portion of the lung was homogenized and cultured as a measure of the remaining viable PAO1 inoculum. Diabetic mice had increased airway glucose compared with nondiabetic mice. The ability to clear bacteria from the lung was significantly reduced in diabetic WT mice and control CFKO mice. Critically, bacterial clearance by diabetic CFKO mice was significantly more diminished compared with nondiabetic CFKO mice, despite an even more robust recruitment of neutrophils to the airways. This finding that CFRD mice boast an exaggerated, but less effective, inflammatory cell response to intratracheal PAO1 challenge presents a novel and useful murine model to help identify therapeutic strategies that promote bacterial clearance in CFRD. PMID:24097557

Connexin 26 facilitates gastrointestinal bacterial infection in vitro.

PubMed

Simpson, Charlotte; Kelsell, David P; Marchès, Olivier

2013-01-01

Escherichia coli, including enteropathogenic E. coli (EPEC), represents the most common cause of diarrhoea worldwide and is therefore a serious public health burden. Treatment for gastrointestinal pathogens is hindered by the emergence of multiple antibiotic resistance, leading to the requirement for the development of new therapies. A variety of mechanisms act in combination to mediate gastrointestinal-bacterial-associated diarrhoea development. For example, EPEC infection of enterocytes induces attaching and effacing lesion formation and the disruption of tight junctions. An alternative enteric pathogen, Shigella flexneri, manipulates the expression of Connexin 26 (Cx26), a gap junction protein. S. flexneri can open Cx26 hemichannels allowing the release of ATP, whereas HeLa cells expressing mutant gap-junction-associated Cx26 are less susceptible to cellular invasion by S. flexneri than cells expressing wild-type (WT) Cx26. We have investigated further the link between Cx26 expression and gastrointestinal infection by using EPEC and S. flexneri as in vitro models of infection. In this study, a significant reduction in EPEC adherence was observed in cells expressing mutant Cx26 compared with WT Cx26. Furthermore, a significant reduction in both cellular invasion by S. flexneri and adherence by EPEC was demonstrated in human intestinal cell lines following treatment with Cx26 short interfering RNA. These in vitro results suggest that the loss of functional Cx26 expression provides improved protection against gastrointestinal bacterial pathogens. Thus, Cx26 represents a potential therapeutic target for gastrointestinal bacterial infection.

HIV infection is associated with an increased risk for lung cancer, independent of smoking.

PubMed

Kirk, Gregory D; Merlo, Christian; O' Driscoll, Peter; Mehta, Shruti H; Galai, Noya; Vlahov, David; Samet, Jonathan; Engels, Eric A

2007-07-01

Human immunodeficiency virus (HIV)-infected persons have an elevated risk for lung cancer, but whether the increase reflects solely their heavy tobacco use remains an open question. The Acquired Immunodeficiency Syndrome (AIDS) Link to the Intravenous Experience Study has prospectively observed a cohort of injection drug users in Baltimore, Maryland, since 1988, using biannual collection of clinical, laboratory, and behavioral data. Lung cancer deaths were identified through linkage with the National Death Index. Cox proportional hazards regression was used to examine the effect of HIV infection on lung cancer risk, controlling for smoking status, drug use, and clinical variables. Among 2086 AIDS Link to the Intravenous Experience Study participants observed for 19,835 person-years, 27 lung cancer deaths were identified; 14 of the deaths were among HIV-infected persons. All but 1 (96%) of the patients with lung cancer were smokers, smoking a mean of 1.2 packs per day. Lung cancer mortality increased during the highly active antiretroviral therapy era, compared with the pre-highly active antiretroviral therapy period (mortality rate ratio, 4.7; 95% confidence interval, 1.7-16). After adjusting for age, sex, smoking status, and calendar period, HIV infection was associated with increased lung cancer risk (hazard ratio, 3.6; 95% confidence interval, 1.6-7.9). Preexisting lung disease, particularly noninfectious diseases and asthma, displayed trends for increased lung cancer risk. Illicit drug use was not associated with increased lung cancer risk. Among HIV-infected persons, smoking remained the major risk factor; CD4 cell count and HIV load were not strongly associated with increased lung cancer risk, and trends for increased risk with use of highly active antiretroviral therapy were not significant. HIV infection is associated with significantly increased risk for developing lung cancer, independent of smoking status.

Immunodeficiency, AIDS-related pneumonia, and risk of lung cancer among HIV-infected individuals.

PubMed

Marcus, Julia L; Leyden, Wendy A; Chao, Chun R; Horberg, Michael A; Klein, Daniel B; Quesenberry, Charles P; Towner, William J; Silverberg, Michael J

2017-04-24

The objective is to clarify the role of immunodeficiency and pneumonia in elevated lung cancer risk among HIV-infected individuals. Cohort study of HIV-infected and HIV-uninfected adults in a large integrated healthcare system in California during 1996-2011. We used Poisson models to obtain rate ratios for lung cancer associated with HIV infection, overall and stratified by recent CD4 cells/μl (HIV-uninfected as reference group), with χ tests for trends across CD4 strata. Fully adjusted models included demographics, cancer risk factors (smoking, drug/alcohol abuse, overweight/obesity), and prior pneumonia. Among 24 768 HIV-infected and 257 600 HIV-uninfected individuals, the lung cancer rate per 100 000 person-years was 66 (n = 80 events) for HIV-infected and 33 (n = 506 events) for HIV-uninfected individuals [rate ratio 2.0, 95% confidence interval (CI): 1.7-2.2]. Overall, HIV-infected individuals were at increased risk of lung cancer after adjustment for demographics and cancer risk factors (rate ratio 1.4, 95% CI: 1.1-1.7), but not after additional adjustment for pneumonia (rate ratio 1.2, 95% CI: 0.9-1.6). Lower CD4 cell counts were associated with higher risk of lung cancer in unadjusted and demographics-adjusted models (P < 0.001 for all), but this trend did not remain after adjustment for cancer risk factors and pneumonia. Compared with HIV-uninfected individuals, HIV-infected individuals with CD4 less than 200 cells/μl were not at increased risk of lung cancer in fully adjusted models. The increased lung cancer risk among HIV patients is attributable to differences in demographics, risk factors such as smoking, and history of pneumonia. Immunodeficiency does not appear to have an independent effect on lung cancer risk.

Infectious pulmonary complications in lung transplant recipients.

PubMed

Chan, Kevin M; Allen, Samuel A

2002-12-01

Pulmonary infections are the most common cause of morbidity in the lung transplant population. Prompt recognition and treatment is necessary to prevent poor outcomes. An understanding of the temporal relationship between immunosuppression and the risk for developing infection can assist the clinician with appropriate treatment. Bacterial pneumonia is common within the first 4 months after transplantation whereas cytomegalovirus (CMV) infection or disease becomes prevalent after the discontinuation of prophylaxis in at-risk patients. Fungal infections, especially aspergillosis, can be fatal if not treated early and the risk for infection is present throughout the transplant period. Community-acquired viral infections present with upper-respiratory symptoms and wheezing that may lead to a chronic decline in lung function. Suspicion of a pulmonary infection in these immunosuppressed individuals should lead to an urgent diagnostic bronchoscopy and empiric antimicrobial therapy. Copyright 2002, Elsevier Science (USA). All rights reserved.

Disparities in the treatment and outcomes of lung cancer among HIV-infected individuals

PubMed Central

Suneja, Gita; Shiels, Meredith S.; Melville, Sharon K.; Williams, Melanie A.; Rengan, Ramesh; Engels, Eric A.

2013-01-01

Objectives HIV-infected people have elevated risk for lung cancer and higher mortality following cancer diagnosis than HIV-uninfected individuals. It is unclear whether HIV-infected individuals with lung cancer receive similar cancer treatment as HIV-uninfected individuals. Design/methods We studied adults more than 18 years of age with lung cancer reported to the Texas Cancer Registry (N = 156 930) from 1995 to 2009. HIV status was determined by linkage with the Texas enhanced HIV/AIDS Reporting System. For nonsmall cell lung cancer (NSCLC) cases, we identified predictors of cancer treatment using logistic regression. We used Cox regression to evaluate effects of HIV and cancer treatment on mortality. Results Compared with HIV-uninfected lung cancer patients (N = 156 593), HIV-infected lung cancer patients (N = 337) were more frequently young, black, men, and with non-Hispanic distant stage disease. HIV-infected NSCLC patients less frequently received cancer treatment than HIV-uninfected patients [60.3 vs. 77.5%; odds ratio 0.39, 95% confidence interval (CI) 0.30–0.52, after adjustment for diagnosis year, age, sex, race, stage, and histologic subtype]. HIV infection was associated with higher lung cancer-specific mortality (hazard ratio 1.34, 95% CI 1.15–1.56, adjusted for demographics and tumor characteristics). Inclusion of cancer treatment in adjusted models slightly attenuated the effect of HIV on lung cancer-specific mortality (hazard ratio 1.25; 95% CI 1.06–1.47). Also, there was a suggestion that HIV was more strongly associated with mortality among untreated than among treated patients (adjusted hazard ratio 1.32 vs. 1.16, P-interaction = 0.34). Conclusion HIV-infected NSCLC patients were less frequently treated for lung cancer than HIV-uninfected patients, which may have affected survival. PMID:23079809

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.

Procalcitonin as a Biomarker of Bacterial Infection in Sickle Cell Vaso-Occlusive Crisis

PubMed Central

Patel, Dilip Kumar; Mohapatra, Manoj Kumar; Thomas, Ancil George; Patel, Siris; Purohit, Prasanta

2014-01-01

Sickle cell anaemia (SCA) patients with vaso-occlusive crisis (VOC) have signs of inflammation and it is often difficult to diagnose a bacterial infection in them. This study was undertaken to evaluate the role of serum procalcitonin (PCT) as a biomarker of bacterial infection in acute sickle cell vaso-occlusive crisis. Hundred homozygous SCA patients were studied at Sickle Cell Clinic and Molecular Biology Laboratory, V.S.S. Medical College, Burla, Odisha, India. All the patients were divided into three categories namely category-A (VOC/ACS with SIRS but without evidence of bacterial infection - 66 patients), category-B (VOC/ACS with SIRS and either proven or suspected bacterial infection - 24 patients) and category-C (SCA patients in steady state without VOC/ACS or SIRS - 10 patients). Complete blood count, C-reactive protein (CRP) estimation and PCT measurement were done in all the patients. There was no significant difference in TLC and CRP values between category-A and B. In category-A, the PCT level was <0.5 ng/mL in 83.3% and 0.5–2 ng/mL in 16.7% of cases. In category-B, all the patients had PCT value >0.5 ng/mL with 87.5% of patients having >2 ng/mL. In category-C, PCT value was <0.5 ng/mL. PCT had a high sensitivity (100%) and negative predictive value (100%) for bacterial infection at a cutoff value of 0.5 ng/mL; whereas the specificity is excellent at a cut-off value of 2 ng/mL. SCA patients with VOC/ACS and SIRS having a PCT level of <0.5 ng/mL have a low probability of bacterial infection whereas PCT value of >2 ng/mL is indicative of bacterial infection necessitating early antimicrobial therapy. PMID:24678395

Role of Honey in Topical and Systemic Bacterial Infections.

PubMed

Hussain, Muhammad Barkaat

2018-01-01

The development of bacterial resistance to antibiotics has made it more difficult and expensive to treat infections. Honey is getting worldwide attention as a topical therapeutic agent for wound infections and potential future candidate for systemic infections. The purpose of this review was to summarise different antibacterial bio-active compounds in honey, their synergistic interaction and their clinical implications in topical and systemic infections. In addition, contemporary testing methods for evaluating peroxide and non-peroxide antibacterial activity of honey were also critically appraised. MEDLINE, EMBASE, Cochrane Library, Pub Med, reference lists and databases were used to review the literature. Honey contains several unique antibacterial components. These components are believed to act on diverse bacterial targets, are broad spectrum, operate synergistically, prevent biofilm formation, and decrease production of virulence factors. Moreover, honey has the ability to block bacterial communication (quorum sensing), and therefore, it is unlikely that bacteria develop resistance against honey. Bacterial resistance against honey has not been documented so far. Unlike conventional antibiotics, honey only targets pathogenic bacteria without disturbing the growth of normal gastrointestinal flora when taken orally. It also contains prebiotics, probiotics, and zinc and enhances the growth of beneficial gut flora. The presence of such plethora of antibacterial properties in one product makes it a promising candidate not only in wound infections but also in systemic and particularly for gastrointestinal infections. Agar diffusion assay, being used for evaluating antibacterial activity of honey, is not the most appropriate and sensitive assay as it only detects non-peroxide activity when present at a higher level. Therefore, there is a need to develop more sensitive techniques that may be capable of detecting and evaluating different important components in honey as

Association of RNA Biosignatures With Bacterial Infections in Febrile Infants Aged 60 Days or Younger

PubMed Central

Mahajan, Prashant; Kuppermann, Nathan; Mejias, Asuncion; Suarez, Nicolas; Chaussabel, Damien; Casper, T. Charles; Smith, Bennett; Alpern, Elizabeth R.; Anders, Jennifer; Atabaki, Shireen M.; Bennett, Jonathan E.; Blumberg, Stephen; Bonsu, Bema; Borgialli, Dominic; Brayer, Anne; Browne, Lorin; Cohen, Daniel M.; Crain, Ellen F.; Cruz, Andrea T.; Dayan, Peter S.; Gattu, Rajender; Greenberg, Richard; Hoyle, John D.; Jaffe, David M.; Levine, Deborah A.; Lillis, Kathleen; Linakis, James G.; Muenzer, Jared; Nigrovic, Lise E.; Powell, Elizabeth C.; Rogers, Alexander J.; Roosevelt, Genie; Ruddy, Richard M.; Saunders, Mary; Tunik, Michael G.; Tzimenatos, Leah; Vitale, Melissa; Dean, J. Michael; Ramilo, Octavio

2016-01-01

IMPORTANCE Young febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. Analysis of host expression patterns (“RNA biosignatures”) in response to infections may provide an alternative diagnostic approach. OBJECTIVE To assess whether RNA biosignatures can distinguish febrile infants aged 60 days or younger with and without serious bacterial infections. DESIGN, SETTING, AND PARTICIPANTS Prospective observational study involving a convenience sample of febrile infants 60 days or younger evaluated for fever (temperature >38° C) in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type. EXPOSURE RNA biosignatures compared with cultures for discriminating febrile infants with and without bacterial infections and infants with bacteremia from those without bacterial infections. MAIN OUTCOMES AND MEASURES Bacterial infection confirmed by culture. Performance of RNA biosignatures was compared with routine laboratory screening tests and Yale Observation Scale (YOS) scores. RESULTS Of 1883 febrile infants (median age, 37 days; 55.7%boys), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections—including 32 with bacteremia and 15 with urinary tract infections—and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set with 87%(95%CI, 73%-95%) sensitivity and 89% (95%CI, 81%-93%) specificity. Ten classifier genes distinguished

Cytomegalovirus infection in living-donor and cadaveric lung transplantations.

PubMed

Ohata, Keiji; Chen-Yoshikawa, Toyofumi F; Takahashi, Koji; Aoyama, Akihiro; Motoyama, Hideki; Hijiya, Kyoko; Hamaji, Masatsugu; Menju, Toshi; Sato, Toshihiko; Sonobe, Makoto; Takakura, Shunji; Date, Hiroshi

2017-11-01

Cytomegalovirus (CMV) infection remains a major cause of morbidity after lung transplantation. Some studies have reported prognostic factors for the postoperative development of CMV infection in cadaveric lung transplantation (CLT), but no research has been performed in living-donor lobar lung transplantation (LDLLT). Therefore, we analysed the possible risk factors of post-transplant CMV infection and the differences between LDLLT and CLT. The development of CMV disease and viraemia in 110 patients undergoing lung transplantation at Kyoto University Hospital in 2008-2015 were retrospectively assessed. The prognostic factors in the development of CMV infection and the differences between LDLLT and CLT were analysed. Among 110 patients, 58 LDLLTs and 52 CLTs were performed. The 3-year freedom rates from CMV disease and viraemia were 92.0% and 58.5%, respectively. There was no difference in the development of CMV infection between LDLLT and CLT (disease: 94.6% vs 91.0%, P = 0.58 and viraemia: 59.3% vs 57.2%, P = 0.76). In preoperative anti-CMV immunoglobulin status, R-D+ recipients (recipient: negative, donor: positive) and R-D- recipients (recipient: negative, donor: negative) tended to have higher and lower cumulative incidences, respectively, of CMV infection (disease: P = 0.34 and viraemia: P = 0.24) than that with R+ recipients (recipient: seropositive). Significantly lower cumulative incidence of CMV viraemia was observed in patients receiving 12-month prophylactic medication (70.6% vs 36.8%, P < 0.001). Twenty-eight patients (25.5%) had early cessation of anti-CMV prophylaxis due to toxicity; however, the extended prophylaxis duration did not increase the incidence of early cessation (P = 0.88). These trends were seen in both LDLLT and CLT. We found that there was no difference in the development of CMV infection between LDLLT and CLT. Twelve-month prophylaxis protocol provides beneficial effect without increased toxicity also in LDLLT

Sensitivity and specificity of procalcitonin in predicting bacterial infections in patients with renal impairment.

PubMed

El-Sayed, Dena; Grotts, Jonathan; Golgert, William A; Sugar, Alan M

2014-09-01

It is unclear whether procalcitonin is an accurate predictor of bacterial infections in patients with renal impairment, although it is used as a biomarker for early diagnosis of sepsis. We determined the sensitivity, specificity, positive and negative predictive values, accuracy and best predictive value of procalcitonin for predicting bacterial infection in adult patients with severe renal impairment. Retrospective study at a single-center community teaching hospital involving 473 patients, ages 18-65, with Modification of Diet in Renal Disease eGFR ≤30 ml/min per 1.73 m(2), admitted between January 2009 and June 2012, with 660 independent hospital visits. A positive or negative culture (blood or identifiable focus of infection) was paired to the highest procalcitonin result performed 48 hours before or after collecting the culture. The sensitivity and specificity to predict bacterial infection, using a procalcitonin level threshold of 0.5 ng/mL, was 0.80 and 0.35 respectively. When isolating for presence of bacteremia, the sensitivity and specificity were 0.89 and 0.35 respectively. An equation adjusting for optimum thresholds of procalcitonin levels for predicting bacterial infection at different levels of eGFR had a sensitivity and specificity of 0.55 and 0.80 respectively. Procalcitonin is not a reliably sensitive or specific predictor of bacterial infection in patients with renal impairment when using a single threshold. Perhaps two thresholds should be employed, where below the lower threshold (i.e. 0.5 ng/mL) bacterial infection is unlikely with a sensitivity of 0.80, and above the higher threshold (i.e. 3.2 ng/mL) bacterial infection is very likely with a specificity of 0.75.

Lung cancer incidence and survival among HIV-infected and uninfected women and men.

PubMed

Hessol, Nancy A; Martínez-Maza, Otoniel; Levine, Alexandra M; Morris, Alison; Margolick, Joseph B; Cohen, Mardge H; Jacobson, Lisa P; Seaberg, Eric C

2015-06-19

To determine the lung cancer incidence and survival time among HIV-infected and uninfected women and men. Two longitudinal studies of HIV infection in the United States. Data from 2549 women in the Women's Interagency HIV Study (WIHS) and 4274 men in the Multicenter AIDS Cohort Study (MACS), all with a history of cigarette smoking, were analyzed. Lung cancer incidence rates and incidence rate ratios were calculated using Poisson regression analyses. Survival time was assessed using Kaplan-Meier and Cox proportional-hazard analyses. Thirty-seven women and 23 men developed lung cancer (46 HIV-infected and 14 HIV-uninfected) during study follow-up. In multivariable analyses, the factors that were found to be independently associated with a higher lung cancer incidence rate ratios were older age, less education, 10 or more pack-years of smoking, and a prior diagnosis of AIDS pneumonia (vs. HIV-uninfected women). In an adjusted Cox model that allowed different hazard functions for each cohort, a history of injection drug use was associated with shorter survival, and a lung cancer diagnosis after 2001 was associated with longer survival. In an adjusted Cox model restricted to HIV-infected participants, nadir CD4 lymphocyte cell count less than 200 was associated with shorter survival time. Our data suggest that pulmonary damage and inflammation associated with HIV infection may be causative for the increased risk of lung cancer. Encouraging and assisting younger HIV-infected smokers to quit and to sustain cessation of smoking is imperative to reduce the lung cancer burden in this population.

75 FR 52755 - Draft Guidance for Industry on Acute Bacterial Skin and Skin Structure Infections: Developing...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-27

...] Draft Guidance for Industry on Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for... ``Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment.'' The purpose of... antimicrobial drugs for the treatment of acute bacterial skin and skin structure infections (ABSSSI), impetigo...

Sphingosine rescues aged mice from pulmonary pseudomonas infection.

PubMed

Rice, Teresa C; Pugh, Amanda M; Seitz, Aaron P; Gulbins, Erich; Nomellini, Vanessa; Caldwell, Charles C

2017-11-01

Bacterial lung infection is a leading cause of death for those 65 y or older, often requiring intensive care unit admission and mechanical ventilation, which consumes considerable health care resources. Although administration of antibiotics is the standard of care for bacterial pneumonia, its overuse has led to the emergence of multidrug resistant organisms. Therefore, alternative strategies to help minimize the effects of bacterial pneumonia in the elderly are necessary. As studies have shown that sphingosine (SPH) has inherent bacterial killing properties, our goal was to assess whether it could act as a prophylactic treatment to protect aged mice from pulmonary infection by Pseudomonas aeruginosa. Aged (51 wk) and young (8 wk) C57Bl/6 mice were used in this study. Pulmonary SPH levels were determined by histology. SPH content of microparticles was quantified using a SPH kinase assay. Pneumonia was induced by intranasally treating mice with 10 6  Colony Forming Unit (CFU) P aeruginosa. Microparticles were isolated from young mice, whereas some were further incubated with SPH. We observed that SPH levels are reduced in the bronchial epithelial cells as well as the bronchoalveolar lavage microparticles isolated from aged mice, which correlates with a susceptibility to infection. We demonstrate that SPH or microparticle treatment can protect aged mice from pulmonary P aeruginosa infection. Finally, we observed that enriching microparticles with SPH before treatment eliminated the bacterial load in P aeruginosa-infected aged mice. These data suggest that prophylactic treatment with SPH could reduce lung bacterial infections for the at-risk elderly population. Copyright © 2017 Elsevier Inc. All rights reserved.

Work package 4 report: Broodfish testing for bacterial infections

USGS Publications Warehouse

Michel, Christian; Elliott, Diane G.; Jansson, Eva; Urdaci, Maria; Midtlyng, Paul J.

2005-01-01

This report summarises current scientific information and experience obtained with various methods for testing of salmonid broodfish or spawn for bacterial kidney disease (BKD - Renibacterium salmoninarum infection) in order to prevent vertical transmission of the organism to the offspring. Assessment is also being performed for Flavobacterium psychrophilum infections causing rainbow trout fry syndrome (RTFS) or bacterial coldwater disease (CWD), and for Piscirickettsia salmonis infection causing salmon rickettsial syndrome (SRS) in salmonid fish species. Methods for screening to document the absence of BKD in fish populations are well established. Some of them have also proven successful for testing individual fish from infected populations in order to avoid vertical transmission of the infectious agent. Several diagnostic methods for flavobacteriosis and piscirickettsiosis have also been established but none of them, as yet, has been validated for use in programmes to prevent vertical transmission of disease. Priority subjects for further research in order to improve the management and control of these vertically transmissible fish diseases are suggested.

The effect of latent adenovirus 5 infection on cigarette smoke-induced lung inflammation.

PubMed

Vitalis, T Z; Kern, I; Croome, A; Behzad, H; Hayashi, S; Hogg, J C

1998-03-01

The aim of this study was to test the hypothesis that latent adenovirus (Ad) 5 infection increases the lung inflammation that follows a single acute exposure to cigarette smoke. A recently developed model of latent adenoviral infection in guinea-pigs was used. Twelve animals were infected with Ad5 (10(8) plaque-forming units) and 12 animals were sham-infected. Thirty five days later six Ad5-infected and six sham-infected animals were exposed to the smoke from five cigarettes. The remaining animals were used as controls for both infection and smoking. As markers of inflammation, the volume fraction of macrophages, T-lymphocytes, neutrophils and eosinophils were measured by quantitative histology. We found that latent Ad5-infection alone, doubled the number of macrophages in the lung parenchyma and that smoking alone, doubled the volume fraction of neutrophils in the airway wall and the volume fraction of macrophages in the lung parenchyma. Neither viral infection nor smoking, alone, had an effect on T-lymphocytes or eosinophils. However, the combination of viral infection and smoking doubled the T-lymphocyte helper cells and quadrupled the volume fraction of macrophages in the lung parenchyma. We conclude that in guinea-pigs, latent adenovirus 5 infection increases the inflammation that follows a single acute exposure to cigarette smoke, by increasing the volume fraction of macrophages and T-lymphocyte helper cells.

Hemojuvelin regulates the innate immune response to peritoneal bacterial infection in mice.

PubMed

Wu, Qian; Shen, Yuanyuan; Tao, Yunlong; Wei, Jiayu; Wang, Hao; An, Peng; Zhang, Zhuzhen; Gao, Hong; Zhou, Tianhua; Wang, Fudi; Min, Junxia

2017-01-01

Hereditary hemochromatosis and iron imbalance are associated with susceptibility to bacterial infection; however, the underlying mechanisms are poorly understood. Here, we performed in vivo bacterial infection screening using several mouse models of hemochromatosis, including Hfe ( Hfe -/- ), hemojuvelin ( Hjv -/- ), and macrophage-specific ferroportin-1 ( Fpn1 fl/fl ; LysM-Cre + ) knockout mice. We found that Hjv -/- mice, but not Hfe -/- or Fpn1 fl/fl ; LysM-Cre + mice, are highly susceptible to peritoneal infection by both Gram-negative and Gram-positive bacteria. Interestingly, phagocytic cells in the peritoneum of Hjv -/- mice have reduced bacterial clearance, IFN-γ secretion, and nitric oxide production; in contrast, both cell migration and phagocytosis are normal. Expressing Hjv in RAW264.7 cells increased the level of phosphorylated Stat1 and nitric oxide production. Moreover, macrophage-specific Hjv knockout mice are susceptible to bacterial infection. Finally, we found that Hjv facilitates the secretion of IFN-γ via the IL-12/Jak2/Stat4 signaling pathway. Together, these findings reveal a novel protective role of Hjv in the early stages of antimicrobial defense.

Procalcitonin Identifies Cell Injury, Not Bacterial Infection, in Acute Liver Failure.

PubMed

Rule, Jody A; Hynan, Linda S; Attar, Nahid; Sanders, Corron; Korzun, William J; Lee, William M

2015-01-01

Because acute liver failure (ALF) patients share many clinical features with severe sepsis and septic shock, identifying bacterial infection clinically in ALF patients is challenging. Procalcitonin (PCT) has proven to be a useful marker in detecting bacterial infection. We sought to determine whether PCT discriminated between presence and absence of infection in patients with ALF. Retrospective analysis of data and samples of 115 ALF patients from the United States Acute Liver Failure Study Group randomly selected from 1863 patients were classified for disease severity and ALF etiology. Twenty uninfected chronic liver disease (CLD) subjects served as controls. Procalcitonin concentrations in most samples were elevated, with median values for all ALF groups near or above a 2.0 ng/mL cut-off that generally indicates severe sepsis. While PCT concentrations increased somewhat with apparent liver injury severity, there were no differences in PCT levels between the pre-defined severity groups-non-SIRS and SIRS groups with no documented infections and Severe Sepsis and Septic Shock groups with documented infections, (p = 0.169). PCT values from CLD patients differed from all ALF groups (median CLD PCT value 0.104 ng/mL, (p ≤0.001)). Subjects with acetaminophen (APAP) toxicity, many without evidence of infection, demonstrated median PCT >2.0 ng/mL, regardless of SIRS features, while some culture positive subjects had PCT values <2.0 ng/mL. While PCT appears to be a robust assay for detecting bacterial infection in the general population, there was poor discrimination between ALF patients with or without bacterial infection presumably because of the massive inflammation observed. Severe hepatocyte necrosis with inflammation results in elevated PCT levels, rendering this biomarker unreliable in the ALF setting.

Viral infection of the lungs through the eye.

PubMed

Bitko, Vira; Musiyenko, Alla; Barik, Sailen

2007-01-01

Respiratory syncytial virus (RSV) is the foremost respiratory pathogen in newborns and claims millions of lives annually. However, there has been no methodical study of the pathway(s) of entry of RSV or its interaction with nonrespiratory tissues. We and others have recently established a significant association between allergic conjunctivitis and the presence of RSV in the eye. Here we adopt a BALB/c mouse model and demonstrate that when instilled in the live murine eye, RSV not only replicated robustly in the eye but also migrated to the lung and produced a respiratory disease that is indistinguishable from the standard, nasally acquired RSV disease. Ocularly applied synthetic anti-RSV small interfering RNA prevented infection of the eye as well as the lung. RSV infection of the eye activated a plethora of ocular cytokines and chemokines with profound relevance to inflammation of the eye. Anticytokine treatments in the eye reduced ocular inflammation but had no effect on viral growth in both eye and lung, demonstrating a role of the cytokine response in ocular pathology. These results establish the eye as a major gateway of respiratory infection and a respiratory virus as a bona fide eye pathogen, thus offering novel intervention and treatment options.

Selective decontamination of the digestive tract helps prevent bacterial infections in the early postoperative period after liver transplant.

PubMed

Emre, S; Sebastian, A; Chodoff, L; Boccagni, P; Meyers, B; Sheiner, P A; Mor, E; Guy, S R; Atillasoy, E; Schwartz, M E; Miller, C M

1999-01-01

In liver transplant (LTx) recipients, gut-associated bacterial and fungal organisms produce significant postoperative morbidity and mortality. We sought to assess the role of selective digestive decontamination (SDD) in preventing postoperative infections in a large single-center cohort of liver recipients transplanted under two non-simultaneous protocols. In 212 consecutive patients transplanted between 1/1/91 and 7/31/92, SDD (gentamicin 80 mg, polymyxin B 100 mg, nystatin suspension 10 mL) was employed, starting after induction of anesthesia and continued until POD 21 (SDD Group). In 157 consecutive patients transplanted between 1/1/93 and 12/31/93, SDD was not used (non-SDD Group). Both groups received IV vancomycin and cefotaxime prophylaxis. All culture-positive infections within the first 30 days post-LTx were recorded and classified as bacterial or fungal. Infection-related mortality (patients who died of infectious complications without any technical complication) was recorded. Groups did not differ in patient demographics, United Network for Organ Sharing (UNOS) status, use of veno-venous bypass, total/warm ischemia, or length of ICU stay. Infections developed in fewer SDD patients (56/212; 26%) than non-SDD patients (69/157; 44%) (p<0.001). The incidence of gram-negative infection was less in the SDD group (11% vs. 26%, p<0. 001) as was gram-positive infection (16% vs. 26%, p<0.001). Among patients who developed infection, there was no difference between groups in infections per patient. Primary graft non-function (PNF) developed in 20 SDD patients (7/20 had infections) and 8 non-SDD patients (6/8 had infections) (p=0.06). There were no differences in incidence of fungal infections or of infection-related mortality between groups. In the SDD group, there were fewer abdominal (p<0. 001), lung (p<0.001), wound (p<0.01), and urinary tract infections (p<0.05). Use of SDD in liver recipients early after transplant was associated with significantly fewer

Sensitivity and Specificity of Procalcitonin in Predicting Bacterial Infections in Patients With Renal Impairment

PubMed Central

El-sayed, Dena; Grotts, Jonathan; Golgert, William A.; Sugar, Alan M.

2014-01-01

Background  It is unclear whether procalcitonin is an accurate predictor of bacterial infections in patients with renal impairment, although it is used as a biomarker for early diagnosis of sepsis. We determined the sensitivity, specificity, positive and negative predictive values, accuracy and best predictive value of procalcitonin for predicting bacterial infection in adult patients with severe renal impairment. Methods  Retrospective study at a single-center community teaching hospital involving 473 patients, ages 18–65, with Modification of Diet in Renal Disease eGFR ≤30 ml/min per 1.73 m2, admitted between January 2009 and June 2012, with 660 independent hospital visits. A positive or negative culture (blood or identifiable focus of infection) was paired to the highest procalcitonin result performed 48 hours before or after collecting the culture. Results  The sensitivity and specificity to predict bacterial infection, using a procalcitonin level threshold of 0.5 ng/mL, was 0.80 and 0.35 respectively. When isolating for presence of bacteremia, the sensitivity and specificity were 0.89 and 0.35 respectively. An equation adjusting for optimum thresholds of procalcitonin levels for predicting bacterial infection at different levels of eGFR had a sensitivity and specificity of 0.55 and 0.80 respectively. Conclusions  Procalcitonin is not a reliably sensitive or specific predictor of bacterial infection in patients with renal impairment when using a single threshold. Perhaps two thresholds should be employed, where below the lower threshold (i.e. 0.5 ng/mL) bacterial infection is unlikely with a sensitivity of 0.80, and above the higher threshold (i.e. 3.2 ng/mL) bacterial infection is very likely with a specificity of 0.75. PMID:25734138

Exaggerated Acute Lung Injury and Impaired Antibacterial Defenses During Staphylococcus aureus Infection in Rats with the Metabolic Syndrome

PubMed Central

Feng, Xiaomei; Maze, Mervyn; Koch, Lauren G.; Britton, Steven L.; Hellman, Judith

2015-01-01

Rats with Metabolic Syndrome (MetaS) have a dysregulated immune response to the aseptic trauma of surgery. We hypothesized that rats with MetaS would have dysregulated inflammation, increased lung injury, and less effective antibacterial defenses during Staphylococcus (S.) aureus sepsis as compared to rats without MetaS. Low capacity runner (LCR; a model of MetaS) and high capacity runner (HCR) rats were challenged intravenously with S. aureus bacteria. After 48 h, inflammatory mediators and bacteria were quantified in the blood, bronchoalveolar lavage fluid (BALF), and lung homogenates. Lungs were analyzed histologically. BALF protein and lung wet-dry ratios were quantified to assess for vascular leak. Endpoints were compared in infected LCR vs HCR rats. LCR rats had higher blood and lung S. aureus counts, as well as higher levels of IL-6 in plasma, lungs and BALF, MIP-2 in plasma and lung, and IL-17A in lungs. Conversely, LCR rats had lower levels of IL-10 in plasma and lungs. Although lactate levels, and liver and renal function tests were similar between groups, LCR rats had higher BALF protein and lung wet-dry ratios, and more pronounced acute lung injury histologically. During S. aureus bacteremia, as compared with HCR rats, LCR (MetaS) rats have heightened pro-inflammatory responses, accompanied by increased acute lung injury and vascular leak. Notably, despite an augmented pro-inflammatory phenotype, LCR rats have higher bacterial levels in their blood and lungs. The MetaS state may exacerbate lung injury and vascular leak by attenuating the inflammation-resolving response, and by weakening antimicrobial defenses. PMID:25978669

CXCR3 chemokine ligands during respiratory viral infections predict lung allograft dysfunction.

PubMed

Weigt, S S; Derhovanessian, A; Liao, E; Hu, S; Gregson, A L; Kubak, B M; Saggar, R; Saggar, R; Plachevskiy, V; Fishbein, M C; Lynch, J P; Ardehali, A; Ross, D J; Wang, H-J; Elashoff, R M; Belperio, J A

2012-02-01

Community-acquired respiratory viruses (CARV) can accelerate the development of lung allograft dysfunction, but the immunologic mechanisms are poorly understood. The chemokine receptor CXCR3 and its chemokine ligands, CXCL9, CXCL10 and CXCL11 have roles in the immune response to viruses and in the pathogenesis of bronchiolitis obliterans syndrome, the predominant manifestation of chronic lung allograft rejection. We explored the impact of CARV infection on CXCR3/ligand biology and explored the use of CXCR3 chemokines as biomarkers for subsequent lung allograft dysfunction. Seventeen lung transplant recipients with CARV infection had bronchoalveolar lavage fluid (BALF) available for analysis. For comparison, we included 34 BALF specimens (2 for each CARV case) that were negative for infection and collected at a duration posttransplant similar to a CARV case. The concentration of each CXCR3 chemokine was increased during CARV infection. Among CARV infected patients, a high BALF concentration of either CXCL10 or CXCL11 was predictive of a greater decline in forced expiratory volume in 1 s, 6 months later. CXCR3 chemokine concentrations provide prognostic information and this may have important implications for the development of novel treatment strategies to modify outcomes after CARV infection. © 2011 American Society of Transplantation and the American Society of Transplant Surgeons.

Classification and possible bacterial infection in outpatients with eczema and dermatitis in China

PubMed Central

Wang, Xin; Shi, Xiao-Dong; Li, Lin-Feng; Zhou, Ping; Shen, Yi-Wei

2017-01-01

Abstract Little is known about the classification and bacterial infection in outpatients with eczema and dermatitis in China. To investigate the prevalence of eczema and dermatitis in outpatients of dermatology clinics in China, examine classification and proportion of common types of dermatitis and the possible bacterial infection, and analyze the possible related factors. Outpatients with eczema or dermatitis from 39 tertiary hospitals of 15 provinces in mainland China from July 1 to September 30, 2014, were enrolled in this cross-sectional and multicenter study. Among 9393 enrolled outpatients, 636 patients (6.7%) were excluded because of incomplete information. The leading subtypes of dermatitis were unclassified eczema (35.5%), atopic dermatitis (13.4%), irritant dermatitis (9.2%), and widespread eczema (8.7%). Total bacterial infection rate was 52.3%, with widespread eczema, stasis dermatitis, and atopic dermatitis being the leading three (65.7%, 61.8%, and 61.4%, respectively). Clinically very likely bacterial infection has a significant positive correlation with disease duration, history of allergic disease, history of flexion dermatitis, and severe itching. Atopic dermatitis has become a common subtype of dermatitis in China. Secondary bacterial infection is common in all patients with dermatitis, and more attentions should be paid on this issue in other type of dermatitis apart from atopic dermatitis. PMID:28858126

Tyk2 as a target for immune regulation in human viral/bacterial pneumonia.

PubMed

Berg, Johanna; Zscheppang, Katja; Fatykhova, Diana; Tönnies, Mario; Bauer, Torsten T; Schneider, Paul; Neudecker, Jens; Rückert, Jens C; Eggeling, Stephan; Schimek, Maria; Gruber, Achim D; Suttorp, Norbert; Hippenstiel, Stefan; Hocke, Andreas C

2017-07-01

The severity and lethality of influenza A virus (IAV) infections is frequently aggravated by secondary bacterial pneumonia. However, the mechanisms in human lung tissue that provoke this increase in fatality are unknown and therapeutic immune modulatory options are lacking.We established a human lung ex vivo co-infection model to investigate innate immune related mechanisms contributing to the susceptibility of secondary pneumococcal pneumonia.We revealed that type I and III interferon (IFN) inhibits Streptococcus pneumoniae -induced interleukin (IL)-1β release. The lack of IL-1β resulted in the repression of bacterially induced granulocyte-macrophage colony-stimulating factor (GM-CSF) liberation. Specific inhibition of IFN receptor I and III-associated tyrosine kinase 2 (Tyk2) completely restored the S. pneumoniae -induced IL-1β-GM-CSF axis, leading to a reduction of bacterial growth. A preceding IAV infection of the human alveolus leads to a type I and III IFN-dependent blockade of the early cytokines IL-1β and GM-CSF, which are key for orchestrating an adequate innate immune response against bacteria. Their virally induced suppression may result in impaired bacterial clearance and alveolar repair.Pharmacological inhibition of Tyk2 might be a new treatment option to sustain beneficial endogenous GM-CSF levels in IAV-associated secondary bacterial pneumonia. Copyright ©ERS 2017.

Liver abscess caused by periodontal bacterial infection with Fusobacterium necrophorum.

PubMed

Yoneda, Masato; Kato, Shingo; Mawatari, Hironori; Kirikoshi, Hiroyuki; Imajo, Kento; Fujita, Koji; Endo, Hiroki; Takahashi, Hirokazu; Inamori, Masahiko; Kobayashi, Noritoshi; Kubota, Kensuke; Saito, Satoru; Tohnai, Iwai; Watanuki, Kei; Wada, Koichiro; Maeda, Shin; Nakajima, Atsushi

2011-02-01

Liver abscess is recognized as a life-threatening disease. However, even in recent years, approximately 50% of liver abscess cases are considered to be cryptogenic. Here, we report a case of liver abscess associated with periodontal bacterial infection by Fusobacterium necrophorum, which is commonly found in the oropharyngeal flora. A 36-year-old man presented with fever and contrast-enhanced abdominal computed tomography revealed multiple liver abscesses. F.necrophorum was isolated from oral smears, liver aspirates and blood samples. Liver abscesses caused by periodontal bacterial infection are rare, however, the incidence is expected to increase in the future, as periodontitis is extremely common and is on the rise as one of the most common chronic infections in the world. A systemic survey including periodontitis may be required for the exact diagnosis of the source of infection. © 2011 The Japan Society of Hepatology.

Potential role of Saudi red propolis in alleviating lung damage induced by methicillin resistant Staphylococcus aureus virulence in rats.

PubMed

Saddiq, Amna Ali; Mohamed, Azza Mostafa

2016-07-01

The aim of this study was to explore the protective impact of aqueous extract of Saudi red propolis against rat lung damage induced by the pathogenic bacteria namely methicillin resistant Staphylococcus aureus (MRSA) ATCC 6538 strain. Infected rats were received a single intraperitoneal (i.p.) injection of bacterial suspension at a dose of 1 X 10(6) CFU / 100g body weight. Results showed that oral administration of an aqueous extract of propolis (50mg/100g body weight) daily for two weeks to infected rats simultaneously with bacterial infection, effectively ameliorated the alteration of oxidative stress biomarker, malondialdehyde (MDA), as well as the antioxidant markers, glutathione peroxidase (GPx) and superoxide dismutase (SOD), in lungs of infected rats compared with infected untreated ones. Also, the used propolis extract successfully modulated the alterations in proinflammatory mediators, tumor necrosis factor-α (TNF- α) and vascular endothelial growth factor (VEGF) in serum. In addition, the propolis extract successfully modulated the oxidative DNA damage and the apoptosis biomarker, caspase 3, in lungs of S aureus infected rats compared with infected untreated animals. The biochemical results were supported by histo-pathological observation of lung tissues. In conclusion, the beneficial prophylactic role of the aqueous extract of Saudi red propolis against lung damage induced by methicillin resistant S aureus may be related to the antioxidant, anti-inflammatory, immunomodulatory and antiapoptosis of its active constituents.

Atorvastatin along with imipenem attenuates acute lung injury in sepsis through decrease in inflammatory mediators and bacterial load.

PubMed

Choudhury, Soumen; Kandasamy, Kannan; Maruti, Bhojane Somnath; Addison, M Pule; Kasa, Jaya Kiran; Darzi, Sazad A; Singh, Thakur Uttam; Parida, Subhashree; Dash, Jeevan Ranjan; Singh, Vishakha; Mishra, Santosh Kumar

2015-10-15

Lung is one of the vital organs which is affected during the sequential development of multi-organ dysfunction in sepsis. The purpose of the present study was to examine whether combined treatment with atorvastatin and imipenem could attenuate sepsis-induced lung injury in mice. Sepsis was induced by caecal ligation and puncture. Lung injury was assessed by the presence of lung edema, increased vascular permeability, increased inflammatory cell infiltration and cytokine levels in broncho-alveolar lavage fluid (BALF). Treatment with atorvastatin along with imipenem reduced the lung bacterial load and pro-inflammatory cytokines (IL-1β and TNFα) level in BALF. The markers of pulmonary edema such as microvascular leakage and wet-dry weight ratio were also attenuated. This was further confirmed by the reduced activity of MPO and ICAM-1 mRNA expression, indicating the lesser infiltration and adhesion of inflammatory cells to the lungs. Again, expression of mRNA and protein level of iNOS in lungs was also reduced in the combined treatment group. Based on the above findings it can be concluded that, combined treatment with atorvastatin and imipenem dampened the inflammatory response and reduced the bacterial load, thus seems to have promising therapeutic potential in sepsis-induced lung injury in mice. Copyright © 2015 Elsevier B.V. All rights reserved.

Bacterial urinary tract infection after solid organ transplantation in the RESITRA cohort.

PubMed

Vidal, E; Torre-Cisneros, J; Blanes, M; Montejo, M; Cervera, C; Aguado, J M; Len, O; Carratalá, J; Cordero, E; Bou, G; Muñoz, P; Ramos, A; Gurguí, M; Borrell, N; Fortún, J

2012-12-01

Urinary tract infection (UTI) is the most common infection in renal transplant patients, but it is necessary to determine the risk factors for bacterial UTI in recipients of other solid organ transplants (SOTs), as well as changes in etiology, clinical presentation, and prognosis. In total, 4388 SOT recipients were monitored in 16 transplant centers belonging to the Spanish Network for Research on Infection in Transplantation (RESITRA). The frequency and characteristics of bacterial UTI in transplant patients were obtained prospectively from the cohort (September 2003 to February 2005). A total of 192 patients (4.4%) presented 249 episodes of bacterial UTI (0.23 episodes per 1000 transplantation days); 156 patients were kidney or kidney-pancreas transplant recipients, and 36 patients were liver, heart, and lung transplant recipients. The highest frequency was observed in renal transplants (7.3%). High frequency of cystitis versus pyelonephritis without related mortality was observed in both groups. The most frequent etiology was Escherichia coli (57.8%), with 25.7% producing extended-spectrum β-lactamase (ESBL). In all transplants but renal, most cases occurred in the first month after transplantation. Cases were uniformly distributed during the first 6 months after transplantation in renal recipients. Age (odds ratio [OR] per decade 1.1, 95% confidence interval [CI] 1.02-1.17), female gender (OR 1.74, 95% CI 1.42-2.13), and the need for immediate post-transplant dialysis (OR 1.63, 95% CI 1.29-2.05) were independent variables associated with bacterial UTI in renal and kidney-pancreas recipients. The independent risk factors identified in non-renal transplants were age (OR per decade 1.79, 95% CI 1.09-3.48), female gender (OR 1.7, 95% CI 1.43-2.49), and diabetes (OR 1.02, 95% CI 1.001-1.040). UTI was frequent in renal transplants, but also not unusual in non-renal transplants. Because E. coli continues to be the most frequent etiology, the emergence of ESBL

Failure To Recruit Anti-Inflammatory CD103+ Dendritic Cells and a Diminished CD4+ Foxp3+ Regulatory T Cell Pool in Mice That Display Excessive Lung Inflammation and Increased Susceptibility to Mycobacterium tuberculosis

PubMed Central

Leepiyasakulchai, Chaniya; Ignatowicz, Lech; Pawlowski, Andrzej; Källenius, Gunilla

2012-01-01

Susceptibility to Mycobacterium tuberculosis is characterized by excessive lung inflammation, tissue damage, and failure to control bacterial growth. To increase our understanding of mechanisms that may regulate the host immune response in the lungs, we characterized dendritic cells expressing CD103 (αE integrin) (αE-DCs) and CD4+ Foxp3+ regulatory T (Treg) cells during M. tuberculosis infection. In resistant C57BL/6 and BALB/c mice, the number of lung αE-DCs increased dramatically during M. tuberculosis infection. In contrast, highly susceptible DBA/2 mice failed to recruit αE-DCs even during chronic infection. Even though tumor necrosis factor alpha (TNF-α) is produced by multiple DCs and macrophage subsets and is required for control of bacterial growth, αE-DCs remained TNF-α negative. Instead, αE-DCs contained a high number of transforming growth factor beta-producing cells in infected mice. Further, we show that Treg cells in C57BL/6 and DBA/2 mice induce gamma interferon during pulmonary tuberculosis. In contrast to resistant mice, the Treg cell population was diminished in the lungs, but not in the draining pulmonary lymph nodes (PLN), of highly susceptible mice during chronic infection. Treg cells have been reported to inhibit M. tuberculosis-specific T cell immunity, leading to increased bacterial growth. Still, despite the reduced number of lung Treg cells in DBA/2 mice, the bacterial load in the lungs was increased compared to resistant animals. Our results show that αE-DCs and Treg cells that may regulate the host immune response are increased in M. tuberculosis-infected lungs of resistant mice but diminished in infected lungs of susceptible mice. PMID:22215739

Associations of the vaginal microbiota with HIV infection, bacterial vaginosis, and demographic factors.

PubMed

Chehoud, Christel; Stieh, Daniel J; Bailey, Aubrey G; Laughlin, Alice L; Allen, Shannon A; McCotter, Kerrie L; Sherrill-Mix, Scott A; Hope, Thomas J; Bushman, Frederic D

2017-04-24

We sought to investigate the effects of HIV infection on the vaginal microbiota and associations with treatment and demographic factors. We thus compared vaginal microbiome samples from HIV-infected (HIV+) and HIV-uninfected (HIV-) women collected at two Chicago area hospitals. We studied vaginal microbiome samples from 178 women analyzed longitudinally (n = 324 samples) and collected extensive data on clinical status and demographic factors. We used 16S rRNA gene sequencing to characterize the bacterial lineages present, then UniFrac, Shannon diversity, and other measures to compare community structure with sample metadata. Differences in microbiota measures were modest in the comparison of HIV+ and HIV- samples, in contrast to several previous studies, consistent with effective antiretroviral therapy. Proportions of healthy Lactobacillus species were not higher in HIV- patients overall, but were significantly higher when analyzed within each hospital in isolation. Rates of bacterial vaginosis were higher among African-American women and HIV+ women. Bacterial vaginosis was associated with higher frequency of HIV+. Unexpectedly, African-American women were more likely to switch bacterial vaginosis status between sampling times; switching was not associated with HIV+ status. The influence of HIV infection on the vaginal microbiome was modest for this cohort of well suppressed urban American women, consistent with effective antiretroviral therapy. HIV+ was found to be associated with bacterial vaginosis. Although bacterial vaginosis has previously been associated with HIV transmission, most of the women studied here became HIV+ many years before our test for bacterial vaginosis, thus implicating additional mechanisms linking HIV infection and bacterial vaginosis.

Infected colonic mass revealing a lung adenocarcinoma.

PubMed

Doussot, Alexandre; Chalumeau, Claire; Combier, Christophe; Cheynel, Nicolas; Facy, Olivier

2013-12-01

We report the case of lung adenocarcinoma revealed by infected colonic tumor in a 62-year-old man. An en bloc surgical resection was performed with uneventful recovery. The pathologic report concluded in a right mesocolic lymph node metastases from a mildly differentiated adenocarcinoma from pulmonary origin. GI metastases of lung cancer are described in the literature and are frequently asymptomatic in patient with a known primary cancer. In this patient, the complication of the metastases revealed the primary and immunochemistry permitted to adapt the systemic chemotherapy. Copyright © 2012. Published by Elsevier Masson SAS.

Pharmacokinetics and Pharmacodynamics of Tildipirosin Against Pasteurella multocida in a Murine Lung Infection Model

PubMed Central

Zeng, Dongping; Sun, Meizhen; Lin, Zhoumeng; Li, Miao; Gehring, Ronette; Zeng, Zhenling

2018-01-01

Tildipirosin, a 16-membered-ring macrolide antimicrobial, has recently been approved for the treatment of swine respiratory disease and bovine respiratory disease. This macrolide is extensively distributed to the site of respiratory infection followed by slow elimination. Clinical efficacy has been demonstrated in cattle and swine clinical field trials. However, the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with the efficacy of tildipirosin remains undefined. The objective of this study was to develop a PK/PD model following subcutaneous injection of tildipirosin against Pasteurella multocida in a murine lung infection model. The PK studies of unbound (f) tildipirosin in plasma were determined following subcutaneous injection of single doses of 1, 2, 4, 6, and 8 mg/kg of body weight in neutropenic lung-infected mice. The PD studies were conducted over 24 h based on twenty intermittent dosing regimens, of which total daily dose ranged from 1 to 32 mg/kg and dosage intervals included 6, 8, 12, and 24 h. The minimum inhibitory concentration (MIC) of tildipirosin against P. multocida was determined in serum. The inhibitory effect Imax model was employed for PK/PD modeling. The area under the unbound concentration-time profile over 24 h to MIC (fAUC0-24 h/MIC) was the PK/PD index that best described the antibacterial activity in the murine infection model. The fAUC0-24 h/MIC targets required to achieve the bacteriostatic action, a 1-log10 kill and 2-log10 kill of bacterial counts were 19.93, 31.89, and 53.27 h, respectively. These results can facilitate efforts to define more rational designs of dosage regimens of tildipirosin using classical PK/PD concepts for the treatment of respiratory diseases in pigs and cattle. PMID:29867911

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.

Bacterial diversity in the feces of dogs with CPV infection.

PubMed

Zheng, Yun; Hao, Xiangqi; Lin, Xi; Zheng, Qingxu; Zhang, Wenyan; Zhou, Pei; Li, Shoujun

2018-04-27

Canine parvovirus (CPV) is a contagious disease in dogs that has high morbidity and mortality. In cases of infection, the pups tend to have a higher mortality and more severe clinical symptoms than the adult dogs because the dehydration is difficult for pups to bear. Following the natural infection, there is a rapid antibody response neutralizing the extracellular virus. As a result, virus titers in tissue and feces become markedly reduced. Hence, it is important to have an effective symptomatic therapy of supporting animals to survive in the early stages of CPV infection. Furthermore, the co-infection with bacteria could increase the severity of lesions and clinical signs as well. In this paper, we obtained the bacterial diversity in feces of CPV infected dogs with the enrichment of five bacteria genera (Shigella, Peptoclostridium, Peptostreptococcus, Streptococcus, Fusobacterium). These microorganisms may partly result in the intestinal pathology of the infection. In summary, the discussion of the bacterial biodiversity in feces of CPV infected dogs provides further insights into the pathology of CPV disease and the targets of developing more effective treatment strategies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Aspergillus infection in lung transplant patients: incidence and prognosis.

PubMed

Iversen, M; Burton, C M; Vand, S; Skovfoged, L; Carlsen, J; Milman, N; Andersen, C B; Rasmussen, M; Tvede, M

2007-12-01

Lung transplant recipients experience a particularly high incidence of Aspergillus infection in comparison with other solid-organ transplantations. This study was conducted to determine the incidence of Aspergillus colonisation and invasive aspergillosis, and the impact on long-term survival associated with Aspergillus infection. A retrospective study of 362 consecutive lung transplant patients from a single national centre who were transplanted 1992-2003 were studied. Twenty-seven patients were excluded due to incomplete or missing files. A total of 105/335 (31%) patients had evidence of Aspergillus infection (colonisation or invasion), including 83 (25%) patients with colonisation and 22 (6%) patients with radiographic or histological evidence of invasive disease. Most of the infections occurred within the first 3 months after transplantation. Cystic fibrosis (CF) patients had higher incidences of colonisation and invasive disease [15 (42%) and 4 (11%) of 36 patients] than non-CF patients [68 (23%) and 18 (6%) of 299 patients] (P = 0.01). Invasive aspergillosis was associated with 58% mortality after 2 years, whereas colonisation was not associated with early increased mortality but was associated with increased mortality after 5 years compared to non-infected patients (P < 0.05). An analysis of demographic factors showed that donor age [OR 1.40 per decade (95% CI 1.10-1.80)], ischaemia time [OR 1.17 per hour increase (95% CI 1.01-1.39)], and use of daclizumab versus polyclonal induction [OR 2.05 (95% CI 1.14-3.75)] were independent risk factors for Aspergillus infection. Invasive aspergillosis was associated with early and high mortality in lung transplant patients. Colonisation with Aspergillus was also associated with a significant increase in mortality after 5 years. CF patients have a higher incidence of Aspergillus infection than non-CF patients.

Associations between bacterial infections and blood pressure in pregnancy.

PubMed

Petry, Clive J; Ong, Ken K; Hughes, Ieuan A; Acerini, Carlo L; Dunger, David B

2017-10-01

To test the hypothesis that bacterial infections in pregnancy are related to maternal blood pressure. Bacterial infection was assessed using antibiotic usage as a surrogate and its association with blood pressure in pregnancy tested in the Cambridge Baby Growth Study. Antibiotic usage in pregnancy was self-reported in questionnaires. Blood pressure measurements at four time points in pregnancy were collected from the hospital notes of 622 women. Using all the available blood pressure readings (adjusted for weeks gestation) antibiotic usage was associated with a higher mean arterial blood pressure across pregnancy: antibiotics used 85(84, 87)mmHg vs. no antibiotics used 83 (83, 84) mmHg (β=2.3 (0.6, 4.0) mmHg, p=9.6×10 -3 , from 621 individuals). Further analysis revealed that antibiotic usage was associated with diastolic (β=2.3 (0.6, 4.0) mmHg; p=7.0×10 -3 ) more than systolic blood pressure (β=1.4(-0.9, 3.7)mmHg; p=0.2). The effect size associated with antibiotic usage appeared to rise slightly after the first trimester. Bacterial infection in pregnancy, as assessed by self-reported antibiotic usage, is associated with small rises in blood pressure. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Effects of copper nanoparticle exposure on host defense in a murine pulmonary infection model

PubMed Central

2011-01-01

Background Human exposure to nanoparticles (NPs) and environmental bacteria can occur simultaneously. NPs induce inflammatory responses and oxidative stress but may also have immune-suppressive effects, impairing macrophage function and altering epithelial barrier functions. The purpose of this study was to assess the potential pulmonary effects of inhalation and instillation exposure to copper (Cu) NPs using a model of lung inflammation and host defense. Methods We used Klebsiella pneumoniae (K.p.) in a murine lung infection model to determine if pulmonary bacterial clearance is enhanced or impaired by Cu NP exposure. Two different exposure modes were tested: sub-acute inhalation (4 hr/day, 5 d/week for 2 weeks, 3.5 mg/m3) and intratracheal instillation (24 hr post-exposure, 3, 35, and 100 μg/mouse). Pulmonary responses were evaluated by lung histopathology plus measurement of differential cell counts, total protein, lactate dehydrogenase (LDH) activity, and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. Results Cu NP exposure induced inflammatory responses with increased recruitment of total cells and neutrophils to the lungs as well as increased total protein and LDH activity in BAL fluid. Both inhalation and instillation exposure to Cu NPs significantly decreased the pulmonary clearance of K.p.-exposed mice measured 24 hr after bacterial infection following Cu NP exposure versus sham-exposed mice also challenged with K.p (1.4 × 105 bacteria/mouse). Conclusions Cu NP exposure impaired host defense against bacterial lung infections and induced a dose-dependent decrease in bacterial clearance in which even our lowest dose demonstrated significantly lower clearance than observed in sham-exposed mice. Thus, exposure to Cu NPs may increase the risk of pulmonary infection. PMID:21943386

[Clinical efficacy of flomoxef in neonatal bacterial infection].

PubMed

Sakata, H; Hirano, Y; Maruyama, S

1993-03-01

One hundred and seventy one neonates were treated with flomoxef (FMOX) and the clinical efficacy and safety were evaluated. The ages of the patients ranged from 0 to 28 days, and their body weights from 450 to 4300 g. Dose levels were 12.4 to 24.9 mg/kg every 8 or 12 hours for 1 to 10 days. Fifty two patients who responded to the FMOX treatment included 5 neonates with sepsis, 17 with suspected sepsis, 9 with urinary tract infections, 12 with pneumonia, 8 with intrauterine infections, and 1 with omphalitis. The other neonates could not be retrospectively diagnosed as bacterial infections. Of 52 patients, clinical results were excellent in 15, good in 34, fair in 1, and poor in 2. And the FMOX treatment was effective in 13 out of 14 patients in which causative bacteria were identified. The drug was well tolerated, but 6 neonates out of 33 over 5 days old had diarrhea. From these results, empiric treatment with FMOX against neonatal bacterial infection was as clinically useful as that of combination with ampicillin and gentamicin or cefotaxime and ampicillin in our neonatal intensive care unit. But, as this study did not include neonate with meningitis, efficacy to meningitis was not evaluated.

Bacterial pattern and antibiotic sensitivity in children and adolescents with infected atopic dermatitis

NASA Astrophysics Data System (ADS)

Samosir, C. T.; Ruslie, R. H.; Rusli, R. E.

2018-03-01

Atopic dermatitis (AD) is a pruritic and chronic inflammatory skin disease which affected approximately 20% in children. Bacterial infection is common in AD patients and correlates directly with AD severity. A cross-sectional study was conducted to evaluate the prevalence of bacterial skin infection in AD patients and its relation with severity of AD and also to study bacteria in the infected AD and its antibiotic sensitivity. Samples were 86 children and adolescents with an AD in Helvetia Community Health Center Medan from March 2016 until February 2017. Index of SCORing Atopic Dermatitis (SCORAD) was used to evaluate the severity of AD. Lesion and nonlesional skinwere swabbed to take sterile cultures. All bacteria noted and tested for antibiotic sensitivity. Datawere by using Chi-Square and Mann Whitney test with 95% CI and p-value<0.05 was considered statistically significant. Fifty-six AD patients (65.1%) were bacterial infected. There was a significant relationship between severity of AD and bacterial infection (p = 0.006). Staphylococcus aureus was the leading bacteria from all degrees of AD severity. Isolated Staphylococcus aureuswas sensitive to amoxicillin-clavulanate (93.3%), clindamycin (90%), erythromycin (90%), and gentamicin (90%), while sensitivity to tetracycline was low (20%).

Serum procalcitonin has negative predictive value for bacterial infection in active systemic lupus erythematosus.

PubMed

Bador, K M; Intan, S; Hussin, S; Gafor, A H A

2012-10-01

Previous studies in systemic lupus erythematosus (SLE) patients have produced conflicting results regarding the diagnostic utility of procalcitonin (PCT). The aim of this study was to determine predictive values of PCT and C-reactive protein (CRP) for bacterial infection in SLE patients. This was a cross-sectional study of clinic and hospitalized SLE patients with and without bacterial infection recruited over 18 months. Bacterial infection was defined as positive culture results. SLE disease activity was measured using SLEDAI. PCT and CRP were measured by automated immunoassays. Sixty-eight patients (57 females) were studied. Ten patients (15%) had infection. The areas under the receiver operating characteristic curves for PCT and CRP were not significantly different [0.797 (CI 0.614-0.979) versus 0.755 (CI 0.600-0.910)]. In lupus flare patients, PCT but not CRP was higher with infection (p = 0.019 versus 0.195). A PCT of <0.17 ng/ml ruled out infection with 94% negative predictive value (NPV). In remission patients, CRP but not PCT was elevated with infection (p = 0.036 versus 0.103). CRP < 0.57 mg/dl had 96% NPV. PCT may be a better marker to rule out bacterial infection in lupus flare but not in remission or general screening.

Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase Cα Signaling.

PubMed

Zhou, Xikun; Ye, Yan; Sun, Yuyang; Li, Xuefeng; Wang, Wenxue; Privratsky, Breanna; Tan, Shirui; Zhou, Zongguang; Huang, Canhua; Wei, Yu-Quan; Birnbaumer, Lutz; Singh, Brij B; Wu, Min

2015-08-01

Transient receptor potential channel 1 (TRPC1) is a nonselective cation channel that is required for Ca(2+) homeostasis necessary for cellular functions. However, whether TRPC1 is involved in infectious disease remains unknown. Here, we report a novel function for TRPC1 in host defense against Gram-negative bacteria. TRPC1(-/-) mice exhibited decreased survival, severe lung injury, and systemic bacterial dissemination upon infection. Furthermore, silencing of TRPC1 showed decreased Ca(2+) entry, reduced proinflammatory cytokines, and lowered bacterial clearance. Importantly, TRPC1 functioned as an endogenous Ca(2+) entry channel critical for proinflammatory cytokine production in both alveolar macrophages and epithelial cells. We further identified that bacterium-mediated activation of TRPC1 was dependent on Toll-like receptor 4 (TLR4), which induced endoplasmic reticulum (ER) store depletion. After activation of phospholipase Cγ (PLC-γ), TRPC1 mediated Ca(2+) entry and triggered protein kinase Cα (PKCα) activity to facilitate nuclear translocation of NF-κB/Jun N-terminal protein kinase (JNK) and augment the proinflammatory response, leading to tissue damage and eventually mortality. These findings reveal that TRPC1 is required for host defense against bacterial infections through the TLR4-TRPC1-PKCα signaling circuit. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

[Nocardia farcinica lung infection in a patient with cystic fibrosis and a lung transplant].

PubMed

Chacón, C F; Vicente, R; Ramos, F; Porta, J; Lopez Maldonado, A; Ansotegui, E

2015-03-01

Patients with cystic fibrosis have a higher risk of developing chronic respiratory infectious diseases. The Nocardia farcinica lung infection is rare in this group of patients, and there are limited publications about this topic. Its diagnosis is complex, due to the clinical and the radiology signs being non-specific. Identification of the agent responsible in the sputum culture is occasionally negative. It is a slow growing organism and for this reason treatment is delayed, which can lead to an increase in complications, hospitable stays, and mortality. A case is reported on a 26 year-old woman with cystic fibrosis and chronic lung colonization by Nocardia farcinica and Aspergillus fumigatus, on long-term treatment with ciprofloxacin, trimethoprim-sulfamethoxazole, and posaconazole, who was admitted to ICU after bilateral lung transplantation. The initial post-operative progress was satisfactory. After discharge, the patient showed a gradual respiratory insufficiency with new chest X-ray showing diffuse infiltrates. Initially, the agent was not seen in the sputum culture. Prompt and aggressive measures were taken, due to the high clinical suspicion of a Nocardia farcinica lung infection. Treatment with a combination of amikacin and meropenem, and later combined with linezolid, led to the disappearance of the lung infiltrates and a clinical improvement. In our case, we confirm the rapid introduction of Nocardia farcinica in the new lungs. The complex identification and the delay in treatment increased the morbimortality. There is a special need for its eradication in patients with lung transplant, due to the strong immunosuppressive treatment. Copyright © 2013 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

High specificity ZnO quantum dots for diagnosis and treatment in bacterial infection

NASA Astrophysics Data System (ADS)

Zhang, Min; Qian, Zhiyu; Gu, Yueqing

2016-03-01

Early diagnosis and effective treatment of bacterial infection has become increasingly important. Herein, we developed a fluorescent nano-probe MPA@ZnO-PEP by conjugating SiO2-stabilized ZnO quantum dot (ZnO@SiO2) with bacteria-targeting peptide PEP, which was encapsulated with MPA, a near infrared (NIR) dye. The nanoprobe MPA@ZnO-PEP showed excellent fluorescence property and could specifically distinguish bacterial infection from sterile inflammation both in vitro and in vivo. The favorable biocompatability of MPA@ZnO-PEP was verified by MTT assay. This probe was further modified with antibiotic methicillin to form the theranostic nanoparticle MPA/Met@ZnO-PEP with amplified antibacterial activity. These results promised the great potential of MPA@ZnO-PEP for efficient non-invasive early diagnosis of bacterial infections and effective bacterial-targeting therapy.

Screening host proteins required for bacterial adherence after H9N2 virus infection.

PubMed

Ma, Li-Li; Sun, Zhen-Hong; Xu, Yu-Lin; Wang, Shu-Juan; Wang, Hui-Ning; Zhang, Hao; Hu, Li-Ping; Sun, Xiao-Mei; Zhu, Lin; Shang, Hong-Qi; Zhu, Rui-Liang; Wei, Kai

2018-01-01

H9N2 subtype low pathogenic avian influenza virus (LPAIV) is distributed worldwide and causes great economic losses in the poultry industry, especially when complicated with other bacterial infections. Tissue damages caused by virus infection provide an opportunity for bacteria invasion, but this mechanism is not sufficient for low pathogenic strains. Moreover, although H9N2 virus infection was demonstrated to promote bacterial infection in several studies, its mechanism remained unclear. In this study, infection experiments in vivo and in vitro demonstrated that the adhesion of Escherichia coli (E. coli) to host cells significantly increased after H9N2 virus infection, and this increase was not caused by pathological damages. Subsequently, we constructed a late chicken embryo infection model and used proteomics techniques to analyze the expression of proteins associated with bacterial adhesion after H9N2 virus infection. A total of 279 significantly differential expressed proteins were detected through isobaric tags for relative and absolute quantitation (iTRAQ) coupled with nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) analysis. The results of Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that differentially expressed proteins were enriched in host innate immunity; cell proliferation, differentiation, and apoptosis; and pathogenicity-related signaling pathways. Finally, we screened out several proteins, such as TGF-β1, integrins, cortactin, E-cadherin, vinculin, and fibromodulin, which were probably associated with bacterial adhesion. The study analyzed the mechanism of secondary bacterial infection induced by H9N2 virus infection from a novel perspective, which provided theoretical and data support for investigating the synergistic infection mechanism between the H9N2 virus and bacteria. Copyright © 2017 Elsevier B.V. All rights reserved.

Risk of bacterial cross infection associated with inspiration through flow-based spirometers.

PubMed

Bracci, Massimo; Strafella, Elisabetta; Croce, Nicola; Staffolani, Sara; Carducci, Annalaura; Verani, Marco; Valentino, Matteo; Santarelli, Lory

2011-02-01

Bacterial contamination of spirometers has been documented in water-sealed devices, mouthpieces, and connection tubes. Little information is available about bacterial contamination of flow-based apparatuses such as turbine-type spirometers and pneumotachographs. Inspiration through contaminated equipment is a potential source of cross infection. To investigate bacteria mobilization (ie, bacteria detachment and aerosolization from the instrument) during routine spirometric testing, 2 types of flow-based spirometers were used. Bacteria mobilization during artificial inspiration through in-line filters or cardboard mouthpieces was evaluated. Nine hundred workers undergoing periodic spirometric testing were enrolled at the occupational physician office in 30 sessions of 30 subjects each. The participants were asked to perform a forced vital capacity test in a turbine-type spirometer and in an unheated pneumotachograph fitted with disposable in-line filters or cardboard mouthpieces. To evaluate bacterial mobilization, an artificial inspiration was performed and bacterial growth determined. The bacterial growth analysis was assessed after the first and the thirtieth spirometric tests of each session without disinfecting the instruments between tests. In addition, instrument bacterial contamination was evaluated. No significant bacterial mobilization and instrument contamination were found in spirometric tests executed with in-line filters. Conversely, a significant bacterial mobilization and instrument contamination were observed in tests performed with cardboard mouthpieces. Differences between the 2 spirometers were not significant. In-line filters may effectively reduce the risk of bacterial cross infection. Inspiration through flow-based spirometers fitted with disposable cardboard mouthpieces is completely safe when combined with spirometer disinfection/sterilization between subjects. Copyright © 2011 Association for Professionals in Infection Control and

Bacterial adherence in the pathogenesis of urinary tract infection: a review.

PubMed

Reid, G; Sobel, J D

1987-01-01

Bacterial adherence to the uroepithelium is recognized as an important mechanism in the initiation and pathogenesis of urinary tract infections (UTI). The uropathogens originate predominantly in the intestinal tract and initially colonize the periurethral region and ascend into the bladder, resulting in symptomatic or asymptomatic bacteriuria. Thereafter, depending on host factors and bacterial virulence factors, the organisms may further ascend and give rise to pyelonephritis. Uropathogens are selected by the presence of virulence characteristics that enable them to resist the normally efficient host defense mechanisms. Considerable progress has been made in identifying bacterial adhesins and in demonstrating bacterial receptor sites on uroepithelial surfaces. Recent studies have identified natural anti-adherence mechanisms in humans as well as possible increased susceptibility to UTI when these mechanisms are defective and when receptor density on uroepithelial cells is altered. Knowledge of bacterial adherence mechanisms may permit alternative methods of prevention and management of urinary infection, including the use of subinhibitory concentrations of antibiotics, vaccine development, nonimmune inhibition of bacterial adhesins and receptor sites, and the use of autochthonous flora, such as lactobacilli, to exclude uropathogens from colonizing the urinary tract.

Chronic Stenotrophomonas maltophilia infection and mortality or lung transplantation in cystic fibrosis patients.

PubMed

Waters, Valerie; Atenafu, Eshetu G; Lu, Annie; Yau, Yvonne; Tullis, Elizabeth; Ratjen, Felix

2013-09-01

Chronic Stenotrophomonas maltophilia infection is an independent risk factor for severe pulmonary exacerbations in cystic fibrosis (CF) patients. The goal of this study was to determine the effect of chronic S. maltophilia infection on mortality and the need for lung transplantation in a longitudinal study of children and adults with CF. This was a cohort study of CF patients from the Hospital for Sick Children and St Michael's Hospital (Toronto, Canada) from 1997 to 2008. A Cox Regression model was used to estimate the hazard ratio (HR) to time of death or lung transplantation adjusting for age, gender, genotype, pancreatic status, CF related diabetes (CFRD), forced expiratory volume in 1 s (FEV1), body mass index, number of pulmonary exacerbations, Pseudomonas aeruginosa, Burkholderia cepacia complex, Aspergillus and chronic S. maltophilia infection. A total of 687 patients were followed over the 12 year study period; 95 patients underwent a lung transplantation (of which 26 died) and an additional 49 patients died (total 144 events). In a Cox Regression model adjusting for baseline FEV1, baseline infection with B. cepacia complex (HR 1.72, 95% CI 1.09-2.71) and baseline chronic S. maltophilia infection (HR 2.80, 95% CI 1.65-4.76) were significantly associated with death or lung transplant. However, in a time-varying model, infection with B. cepacia complex and chronic S. maltophilia infection were no longer significant. Baseline chronic S. maltophilia infection is associated with an almost three-fold increased risk of death or lung transplant in CF patients. It is still unclear, however, whether chronic S. maltophilia infection is simply a marker of severity of disease and ultimate mortality or whether it is causally related to disease progression. Copyright © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Temperature variation, bacterial diversity and fungal infection dynamics in the amphibian skin.

PubMed

Longo, Ana V; Zamudio, Kelly R

2017-09-01

Host-associated bacterial communities on the skin act as the first line of defence against invading pathogens. Yet, for most natural systems, we lack a clear understanding of how temperature variability affects structure and composition of skin bacterial communities and, in turn, promotes or limits the colonization of opportunistic pathogens. Here, we examine how natural temperature fluctuations might be related to changes in skin bacterial diversity over time in three amphibian populations infected by the pathogenic fungus Batrachochytrium dendrobatidis (Bd). Our focal host species (Eleutherodactylus coqui) is a direct-developing frog that has suffered declines at some populations in the last 20 years, while others have not experienced any changes. We quantified skin bacterial alpha- and beta-diversity at four sampling time points, a period encompassing two seasons and ample variation in natural infections and environmental conditions. Despite the different patterns of infection across populations, we detected an overall increase in bacterial diversity through time, characterized by the replacement of bacterial operational taxonomic units (OTUs). Increased frog body temperatures possibly allowed the colonization of bacteria as well as the recruitment of a subset of indicator OTUs, which could have promoted the observed changes in diversity patterns. Our results suggest that natural environmental fluctuations might be involved in creating opportunities for bacterial replacement, potentially attenuating pathogen transmission and thus contributing to host persistence in E. coqui populations. © 2017 John Wiley & Sons Ltd.

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

PubMed

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

2017-03-01

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

Serum lipopolysaccharide-binding protein prediction of severe bacterial infection in cirrhotic patients with ascites.

PubMed

Albillos, Agustín; de-la-Hera, Antonio; Alvarez-Mon, Melchor

2004-05-15

Serum lipopolysaccharide-binding protein is increased in a subset of non-infected ascitic cirrhotic patients, a finding previously related to bacterial passage from the gut to the circulation without overt infection. We prospectively analysed the risk factors associated with a first episode of severe bacterial infection in 84 ascitic cirrhotics, followed up for a median of 46 weeks. The cumulative probability of such infection in patients with raised and normal lipopolysaccharide-binding protein was 32.4% and 8.0% (p=0.004), respectively. Increased lipopolysaccharide-binding protein was the only factor independently associated with severe bacterial infection in a multivariate analysis (relative risk 4.49, 95% CI 1.42-14.1). Monitoring of serum lipopolysaccharide-binding protein could, therefore, help to target cirrhotic patients with ascites for antibiotic prophylaxis.

Real-time monitoring of bacterial infection in vivo: development of bioluminescent staphylococcal foreign-body and deep-thigh-wound mouse infection models.

PubMed

Kuklin, Nelly A; Pancari, Gregory D; Tobery, Timothy W; Cope, Leslie; Jackson, Jesse; Gill, Charles; Overbye, Karen; Francis, Kevin P; Yu, Jun; Montgomery, Donna; Anderson, Annaliesa S; McClements, William; Jansen, Kathrin U

2003-09-01

Staphylococcal infections associated with catheter and prosthetic implants are difficult to eradicate and often lead to chronic infections. Development of novel antibacterial therapies requires simple, reliable, and relevant models for infection. Using bioluminescent Staphylococcus aureus, we have adapted the existing foreign-body and deep-wound mouse models of staphylococcal infection to allow real-time monitoring of the bacterial colonization of catheters or tissues. This approach also enables kinetic measurements of bacterial growth and clearance in each infected animal. Persistence of infection was observed throughout the course of the study until termination of the experiment at day 16 in a deep-wound model and day 21 in the foreign-body model, providing sufficient time to test the effects of antibacterial compounds. The usefulness of both animal models was assessed by using linezolid as a test compound and comparing bioluminescent measurements to bacterial counts. In the foreign-body model, a three-dose antibiotic regimen (2, 5, and 24 h after infection) resulted in a decrease in both luminescence and bacterial counts recovered from the implant compared to those of the mock-treated infected mice. In addition, linezolid treatment prevented the formation of subcutaneous abscesses, although it did not completely resolve the infection. In the thigh model, the same treatment regimen resulted in complete resolution of the luminescent signal, which correlated with clearance of the bacteria from the thighs.

Bacteriophage therapy to combat bacterial infections in poultry.

PubMed

Wernicki, Andrzej; Nowaczek, Anna; Urban-Chmiel, Renata

2017-09-16

Infections in poultry are an economic and health problem in Europe and worldwide. The most common infections are associated with salmonellosis, colibacillosis, campylobacteriosis, and others. The prevalence of Campylobacter-positive poultry flocks in European countries varies from 18% to 90%. In the United States, the prevalence of infected flocks is nearly 90%. A similar percentage of infection has been noted for salmonellosis (about 75-90%) and E. coli (90-95%). The occurence of Clostridium perfringens is a major problem for the poultry industry, with some estimates suggesting colonization of as many as 95% of chickens, resulting in clinical or subclinical infections. In the US, annual economic losses due to Salmonella infections run from $1.188 billion to over $11.588 billion, based on an estimated 1.92 million cases. Similar costs are observed in the case of other types of infections. In 2005 economic losses in the the poultry industry due to mortalities reached 1,000,000 USD.Infections caused by these pathogens, often through poultry products, are also a serious public health issue.The progressive increase in the number of multi-drug resistant bacteria and the complete ban on the use of antibiotics in livestock feed in the EU, as well as the partial ban in the US, have led to the growth of research on the use of bacteriophages to combat bacterial infections in humans and animals.The high success rate and safety of phage therapy in comparison with antibiotics are partly due to their specificity for selected bacteria and the ability to infect only one species, serotype or strain. This mechanism does not cause the destruction of commensal bacterial flora. Phages are currently being used with success in humans and animals in targeted therapies for slow-healing infections. They have also found application in the US in eliminating pathogens from the surface of foods of animal and plant origin. At a time of growing antibiotic resistance in bacteria and the resulting

Bacterial sexually transmitted infections among HIV-infected patients in the United States: estimates from the Medical Monitoring Project.

PubMed

Flagg, Elaine W; Weinstock, Hillard S; Frazier, Emma L; Valverde, Eduardo E; Heffelfinger, James D; Skarbinski, Jacek

2015-04-01

Bacterial sexually transmitted infections may facilitate HIV transmission. Bacterial sexually transmitted infection testing is recommended for sexually active HIV-infected patients annually and more frequently for those at elevated sexual risk. We estimated percentages of HIV-infected patients in the United States receiving at least one syphilis, gonorrhea, or chlamydia test, and repeat (≥2 tests, ≥3 months apart) tests for any of these sexually transmitted infections from mid-2008 through mid-2010. The Medical Monitoring Project collects behavioral and clinical characteristics of HIV-infected adults receiving medical care in the United States using nationally representative sampling. Sexual activity included self-reported oral, vaginal, or anal sex in the past 12 months. Participants reporting more than 1 sexual partner or illicit drug use before/during sex in the past year were classified as having elevated sexual risk. Among participants with only 1 sex partner and no drug use before/during sex, those reporting consistent condom use were classified as low risk; those reporting sex without a condom (or for whom this was unknown) were classified as at elevated sexual risk only if they considered their sex partner to be a casual partner, or if their partner was HIV-negative or partner HIV status was unknown. Bacterial sexually transmitted infection testing was ascertained through medical record abstraction. Among sexually active patients, 55% were tested at least once in 12 months for syphilis, whereas 23% and 24% received at least one gonorrhea and chlamydia test, respectively. Syphilis testing did not vary by sex/sexual orientation. Receipt of at least 3 CD4+ T-lymphocyte cell counts and/or HIV viral load tests in 12 months was associated with syphilis testing in men who have sex with men (MSM), men who have sex with women only, and women. Chlamydia testing was significantly higher in sexually active women (30%) compared with men who have sex with women only

Development of a Hybrid Tracer for SPECT and Optical Imaging of Bacterial Infections.

PubMed

Welling, Mick M; Bunschoten, Anton; Kuil, Joeri; Nelissen, Rob G H H; Beekman, Freek J; Buckle, Tessa; van Leeuwen, Fijs W B

2015-05-20

In trauma and orthopedic surgery, infection of implants has a major impact on the outcome for patients. Infections may develop either during the initial implantation or during the lifetime of an implant. Both infections, as well as aseptic loosening of the implant, are reasons for revision of the implants. Therefore, discrimination between aseptic-mechanical-loosening and septic-bacterial-loosening of implants is critical during selection of a patient-tailored treatment policy. Specific detection and visualization of infections is a challenge because it is difficult to discriminate infections from inflammation. An imaging tracer that facilitates bacterial identification in a pre- and intraoperative setting may aid the workup for patients suspicious of bacterial infections. In this study we evaluated an antimicrobial peptide conjugated to a hybrid label, which contains both a radioisotope and a fluorescent dye. After synthesis of DTPA-Cy5-UBI29-41 and-when necessary-radiolabeling with (111)In (yield 96.3 ± 2.7%), in vitro binding to various bacterial strains was evaluated using radioactivity counting and confocal fluorescence microscopy. Intramuscular bacterial infections (S. aureus or K. pneumoniae) were also visualized in vivo using a combined nuclear and fluorescence imaging system. The indium-111 was chosen as label as it has a well-defined coordination chemistry, and in pilot studies labeling DTPA-Cy5-UBI29-41 with technetium-99m, we encountered damage to the Cy5 dye after the reduction with SnCl2. As a reference, we used the validated tracer (99m)Tc-UBI29-41. Fast renal excretion of (111)In-DTPA-Cy5-UBI29-41 was observed. Target to nontarget (T/NT) ratios were highest at 2 h post injection: radioactivity counting yielded T/NT ratios of 2.82 ± 0.32 for S. aureus and 2.37 ± 0.05 for K. pneumoniae. Comparable T/NT ratios with fluorescence imaging of 2.38 ± 0.09 for S. aureus and 3.55 ± 0.31 for K. pneumoniae were calculated. Ex vivo confocal microscopy of

Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis.

PubMed

Hackstein, Carl-Philipp; Assmus, Lisa Mareike; Welz, Meike; Klein, Sabine; Schwandt, Timo; Schultze, Joachim; Förster, Irmgard; Gondorf, Fabian; Beyer, Marc; Kroy, Daniela; Kurts, Christian; Trebicka, Jonel; Kastenmüller, Wolfgang; Knolle, Percy A; Abdullah, Zeinab

2017-03-01

Patients with liver cirrhosis suffer from increased susceptibility to life-threatening bacterial infections that cause substantial morbidity. Experimental liver fibrosis in mice induced by bile duct ligation or CCl 4 application was used to characterise the mechanisms determining failure of innate immunity to control bacterial infections. In murine liver fibrosis, translocation of gut microbiota induced tonic type I interferon (IFN) expression in the liver. Such tonic IFN expression conditioned liver myeloid cells to produce high concentrations of IFN upon intracellular infection with Listeria that activate cytosolic pattern recognition receptors. Such IFN-receptor signalling caused myeloid cell interleukin (IL)-10 production that corrupted antibacterial immunity, leading to loss of infection-control and to infection-associated mortality. In patients with liver cirrhosis, we also found a prominent liver IFN signature and myeloid cells showed increased IL-10 production after bacterial infection. Thus, myeloid cells are both source and target of IFN-induced and IL-10-mediated immune dysfunction. Antibody-mediated blockade of IFN-receptor or IL-10-receptor signalling reconstituted antibacterial immunity and prevented infection-associated mortality in mice with liver fibrosis. In severe liver fibrosis and cirrhosis, failure to control bacterial infection is caused by augmented IFN and IL-10 expression that incapacitates antibacterial immunity of myeloid cells. Targeted interference with the immune regulatory host factors IL-10 and IFN reconstitutes antibacterial immunity and may be used as therapeutic strategy to control bacterial infections in patients with liver cirrhosis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Stopping bacterial adhesion: a novel approach to treating infections.

PubMed

Bavington, C; Page, C

2005-01-01

Adhesion and colonization are prerequisites for the establishment of bacterial pathogenesis. The prevention of adhesion is an attractive target for the development of new therapies in the prevention of infection. Bacteria have developed a multiplicity of adhesion mechanisms commonly targeting surface carbohydrate structures, but our ability to rationally design effective antiadhesives is critically affected by the limitations of our knowledge of the human 'glycome' and of the bacterial function in relation to it. The potential for the future development of carbohydrate-based antiadhesives has been demonstrated by a significant number of in vitro and in vivo studies. Such therapies will be particularly relevant for infections of mucosal surfaces where topical application or delivery is possible. (c) 2005 S. Karger AG, Basel

Bacterial and cellular RNAs at work during Listeria infection.

PubMed

Sesto, Nina; Koutero, Mikael; Cossart, Pascale

2014-01-01

Listeria monocytogenes is an intracellular pathogen that can enter and invade host cells. In the course of its infection, RNA-mediated regulatory mechanisms provide a fast and versatile response for both the bacterium and the host. They regulate a variety of processes, such as environment sensing and virulence in pathogenic bacteria, as well as development, cellular differentiation, metabolism and immune responses in eukaryotic cells. The aim of this article is to summarize first the RNA-mediated regulatory mechanisms that play a role in the Listeria lifestyle and in its virulence, and then the host miRNA responses to Listeria infection. Finally, we discuss the potential cross-talk between bacterial RNAs and host RNA regulatory mechanisms as new mechanisms of bacterial virulence.

Diagnosing viral and bacterial respiratory infections in acute COPD exacerbations by an electronic nose: a pilot study.

PubMed

van Geffen, Wouter H; Bruins, Marcel; Kerstjens, Huib A M

2016-06-16

Respiratory infections, viral or bacterial, are a common cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). A rapid, point-of-care, and easy-to-use tool distinguishing viral and bacterial from other causes would be valuable in routine clinical care. An electronic nose (e-nose) could fit this profile but has never been tested in this setting before. In a single-center registered trial (NTR 4601) patients admitted with AECOPD were tested with the Aeonose(®) electronic nose, and a diagnosis of viral or bacterial infection was obtained by bacterial culture on sputa and viral PCR on nose swabs. A neural network with leave-10%-out cross-validation was used to assess the e-nose data. Forty three patients were included. In the bacterial infection model, 22 positive cases were tested versus the negatives; and similarly 18 positive cases were tested in the viral infection model. The Aeonose was able to distinguish between COPD-subjects suffering from a viral infection and COPD patients without infection, showing an area under the curve (AUC) of 0.74. Similarly, for bacterial infections, an AUC of 0.72 was obtained. The Aeonose e-nose yields promising results in 'smelling' the presence or absence of a viral or bacterial respiratory infection during an acute exacerbation of COPD. Validation of these results using a new and large cohort is required before introduction into clinical practice.

Prone position for the prevention of lung infection.

PubMed

Beuret, P

2002-04-01

Pulmonary infection is frequent in brain injured patients. It has been identified as an independent predictor of unfavorable neurological outcome, calling for attempts of prevention. We recently evaluated intermittent prone positioning for the prevention of ventilator-associated pneumonia (VAP) in comatose brain injured patients, in a randomized study. 25 patients were included in the prone position (PP) group: they were positioned on prone four hours once daily until they could get up to sit in an armchair; 26 patients were included in the supine position (SP) group. The main characteristics of the patients from the two groups were similar at randomization. The primary end-point was the incidence of lung worsening, defined by an increase in the Lung Injury Score by at least one point since the time of randomization. The incidence of lung worsening was lower in the PP group (12%) than in the SP group (50%) (p=0.003). The incidence of VAP was 38.4% in the SP group and 20% in the PP group (p=0.14). There was no serious complication attributable to prone positioning. In conclusion, the beneficial effect of prone positioning for prevention of lung infection in brain injured patients is not well established. However, in those patients, prone positioning is able to avoid the worsening of pulmonary function, especially in oxygenation.

Empiric Antibiotic Therapy of Nosocomial Bacterial Infections.

PubMed

Reddy, Pramod

2016-01-01

Broad-spectrum antibiotics are commonly used by physicians to treat various infections. The source of infection and causative organisms are not always apparent during the initial evaluation of the patient, and antibiotics are often given empirically to patients with suspected sepsis. Fear of attempting cephalosporins and carbapenems in penicillin-allergic septic patients may result in significant decrease in the spectrum of antimicrobial coverage. Empiric antibiotic therapy should sufficiently cover all the suspected pathogens, guided by the bacteriologic susceptibilities of the medical center. It is important to understand the major pharmacokinetic properties of antibacterial agents for proper use and to minimize the development of resistance. In several septic patients, negative cultures do not exclude active infection and positive cultures may not represent the actual infection. This article will review the important differences in the spectrum of commonly used antibiotics for nosocomial bacterial infections with a particular emphasis on culture-negative sepsis and colonization.

The impact of pan-resistant bacterial pathogens on survival after lung transplantation in cystic fibrosis: results from a single large referral centre.

PubMed

Dobbin, C; Maley, M; Harkness, J; Benn, R; Malouf, M; Glanville, A; Bye, P

2004-04-01

Reported actuarial one-year survival for patients with cystic fibrosis (CF) after lung transplant is 55-91%. Infection is the most common cause of early death. Colonization with Burkholderia cepacia complex is associated with reduced survival and international lung transplant referral guidelines support individual unit assessment policies for patients colonized with other pan-resistant bacteria. We examined local data on survival after transplant for CF to determine the impact of colonization with pan-resistant bacteria. A retrospective review of all CF patients from Royal Prince Alfred Hospital (RPAH), Sydney, who underwent lung transplantation at St Vincent's Hospital, Sydney, 1989-2002, was performed. Sixty-five patients were listed for lung transplantation with 54 (male: female=29:25) receiving transplants. Of the 11 patients (17%) who died on the waiting list, six were colonized with pan-resistant Pseudomonas aeruginosa. Thirty of the 54 transplanted patients had at least one pan-resistant organism before transplant. In 28 this included P. aeruginosa. Overall one-year survival was 92% with a median survival of 67 months. Overall survival for the pan-resistant group (N = 30) was not significantly different to survival in those with sensitive organisms (N = 24) (Logrank chi square = 1.6, P = 0.2). Three patients colonized with B. cepacia complex pre-transplant survive at 11, 40 and 60 months post-transplant. Infection contributed to 11 of the 18 post-transplant deaths, with pre-transplant-acquired bacterial pathogens responsible in two cases. Patients continued to acquire multiresistant bacteria post-transplantation. Lung transplant survival at St Vincent's Hospital for CF adults from RPAH compares favourably with international benchmarks. Importantly, colonization with pan-resistant bacteria pre-transplant did not appear to adversely affect survival post-transplant.

Bacterial Dose-Dependent Role of G Protein-Coupled Receptor Kinase 5 in Escherichia coli-Induced Pneumonia.

PubMed

Packiriswamy, Nandakumar; Steury, Michael; McCabe, Ian C; Fitzgerald, Scott D; Parameswaran, Narayanan

2016-05-01

G protein-coupled receptor kinase 5 (GRK5) is a serine/threonine kinase previously shown to mediate polymicrobial sepsis-induced inflammation. The goal of the present study was to examine the role of GRK5 in monomicrobial pulmonary infection by using an intratracheal Escherichia coli infection model of pneumonia. We used sublethal and lethal doses of E. coli to examine the mechanistic differences between low-grade and high-grade inflammation induced by E. coli infection. With a sublethal dose of E. coli, GRK5 knockout (KO) mice exhibited higher plasma CXCL1/KC levels and enhanced lung neutrophil recruitment early after infection, and lower bacterial loads, than wild-type (WT) mice. The inflammatory response was also diminished, and resolution of inflammation advanced, in the lungs of GRK5 KO mice. In contrast to the reduced bacterial loads in GRK5 KO mice following a sublethal dose, at a lethal dose of E. coli, the bacterial burdens remained high in GRK5 KO mice relative to those in WT mice. This occurred in spite of enhanced plasma CXCL1 levels as well as neutrophil recruitment in the KO mice. But the recruited neutrophils (following high-dose infection) exhibited decreased CD11b expression and reduced reactive oxygen species production, suggesting decreased neutrophil activation or increased neutrophil exhaustion in the GRK5 KO mice. In agreement with the increased bacterial burden, KO mice showed poorer survival than WT mice following E. coli infection at a lethal dose. Overall, our data suggest that GRK5 negatively regulates CXCL1/KC levels during bacterial pneumonia but that the role of GRK5 in the clinical outcome in this model is dependent on the bacterial dose. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

HIF1α-dependent glycolysis promotes macrophage functional activities in protecting against bacterial and fungal infection.

PubMed

Li, Chunxiao; Wang, Yu; Li, Yan; Yu, Qing; Jin, Xi; Wang, Xiao; Jia, Anna; Hu, Ying; Han, Linian; Wang, Jian; Yang, Hui; Yan, Dapeng; Bi, Yujing; Liu, Guangwei

2018-02-26

Macrophages are important innate immune defense system cells in the fight against bacterial and fungal pathogenic infections. They exhibit significant plasticity, particularly with their ability to undergo functional differentiation. Additionally, HIF1α is critically involved in the functional differentiation of macrophages during inflammation. However, the role of macrophage HIF1α in protecting against different pathogenic infections remains unclear. In this study, we investigated and compared the roles of HIF1α in different macrophage functional effects of bacterial and fungal infections in vitro and in vivo. We found that bacterial and fungal infections produced similar effects on macrophage functional differentiation. HIF1α deficiency inhibited pro-inflammatory macrophage functional activities when cells were stimulated with LPS or curdlan in vitro or when mice were infected with L. monocytogenes or C. albicans in vivo, thus decreasing pro-inflammatory TNFα and IL-6 secretion associated with pathogenic microorganism survival. Alteration of glycolytic pathway activation was required for the functional differentiation of pro-inflammatory macrophages in protecting against bacterial and fungal infections. Thus, the HIF1α-dependent glycolytic pathway is essential for pro-inflammatory macrophage functional differentiation in protecting against bacterial and fungal infections.

IL-10 restrains IL-17 to limit lung pathology characteristics following pulmonary infection with Francisella tularensis live vaccine strain.

PubMed

Slight, Samantha R; Monin, Leticia; Gopal, Radha; Avery, Lyndsay; Davis, Marci; Cleveland, Hillary; Oury, Tim D; Rangel-Moreno, Javier; Khader, Shabaana A

2013-11-01

IL-10 production during intracellular bacterial infections is generally thought to be detrimental because of its role in suppressing protective T-helper cell 1 (Th1) responses. Francisella tularensis is a facultative intracellular bacterium that activates both Th1 and Th17 protective immune responses. Herein, we report that IL-10-deficient mice (Il10(-/-)), despite having increased Th1 and Th17 responses, exhibit increased mortality after pulmonary infection with F. tularensis live vaccine strain. We demonstrate that the increased mortality observed in Il10(-/-)-infected mice is due to exacerbated IL-17 production that causes increased neutrophil recruitment and associated lung pathology. Thus, although IL-17 is required for protective immunity against pulmonary infection with F. tularensis live vaccine strain, its production is tightly regulated by IL-10 to generate efficient induction of protective immunity without mediating pathology. These data suggest a critical role for IL-10 in maintaining the delicate balance between host immunity and pathology during pulmonary infection with F. tularensis live vaccine strain. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Stenotrophomonas maltophilia Virulence and Specific Variations in Trace Elements during Acute Lung Infection: Implications in Cystic Fibrosis

PubMed Central

Crocetta, Valentina; Consalvo, Ada; Zappacosta, Roberta; Di Ilio, Carmine; Di Bonaventura, Giovanni

2014-01-01

Metal ions are necessary for the proper functioning of the immune system, and, therefore, they might have a significant influence on the interaction between bacteria and host. Ionic dyshomeostasis has been recently observed also in cystic fibrosis (CF) patients, whose respiratory tract is frequently colonized by Stenotrophomonas maltophilia. For the first time, here we used an inductively mass spectrometry method to perform a spatial and temporal analysis of the pattern of changes in a broad range of major trace elements in response to pulmonary infection by S. maltophilia. To this, DBA/2 mouse lungs were comparatively infected by a CF strain and by an environmental one. Our results showed that pulmonary ionomic profile was significantly affected during infection. Infected mice showed increased lung levels of Mg, P, S, K, Zn, Se, and Rb. To the contrary, Mn, Fe, Co, and Cu levels resulted significantly decreased. Changes of element concentrations were correlated with pulmonary bacterial load and markers of inflammation, and occurred mostly on day 3 post-exposure, when severity of infection culminated. Interestingly, CF strain – significantly more virulent than the environmental one in our murine model - provoked a more significant impact in perturbing pulmonary metal homeostasis. Particularly, exposure to CF strain exclusively increased P and K levels, while decreased Fe and Mn ones. Overall, our data clearly indicate that S. maltophilia modulates pulmonary metal balance in a concerted and virulence-dependent manner highlighting the potential role of the element dyshomeostasis during the progression of S. maltophilia infection, probably exacerbating the harmful effects of the loss of CF transmembrane conductance regulator function. Further investigations are required to understand the biological significance of these alterations and to confirm they are specifically caused by S. maltophilia. PMID:24586389

Diagnostic test accuracy of a 2-transcript host RNA signature for discriminating bacterial vs viral infection in febrile children

PubMed Central

Shailes, Hannah; Eleftherohorinou, Hariklia; Hoggart, Clive J; Cebey-Lopez, Miriam; Carter, Michael J; Janes, Victoria A; Gormley, Stuart; Shimizu, Chisato; Tremoulet, Adriana H; Barendregt, Anouk M; Salas, Antonio; Kanegaye, John; Pollard, Andrew J; Faust, Saul N; Patel, Sanjay; Kuijpers, Taco; Martinon-Torres, Federico; Burns, Jane C; Coin, Lachlan JM; Levin, Michael

2018-01-01

Importance As clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment whilst bacterial infection is missed in others. Objective To identify a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children. Design Febrile children presenting to participating hospitals in UK, Spain, Netherlands and USA between 2009-2013 were prospectively recruited, comprising a discovery group and validation group. Each group was classified after microbiological investigation into definite bacterial, definite viral infection or indeterminate infection. RNA expression signatures distinguishing definite bacterial from viral infection were identified in the discovery group and diagnostic performance assessed in the validation group. Additional validation was undertaken in separate studies of children with meningococcal disease (n=24) inflammatory diseases (n=48), and on published gene expression datasets. Exposures A 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis. Main Outcomes Definite Bacterial and viral infection was confirmed by culture or molecular detection of the pathogens. Performance of the RNA signature was evaluated in the definite bacterial and viral group, and the indeterminate group. Results The discovery cohort of 240 children (median age 19 months, 62% males) included 52 with definite bacterial infection of whom 36 (69%) required intensive care; and 92 with definite viral infection of whom 32 (35%) required intensive care. 96 children had indeterminate infection. Bioinformatic analysis of RNA expression data identified a 38-transcript signature distinguishing bacterial from viral infection. A smaller (2-transcript) signature (FAM89A and IFI44L) was identified by removing highly correlated transcripts. When this 2-transcript signature was

Transcriptional response of Musca domestica larvae to bacterial infection.

PubMed

Tang, Ting; Li, Xiang; Yang, Xue; Yu, Xue; Wang, Jianhui; Liu, Fengsong; Huang, Dawei

2014-01-01

The house fly Musca domestica, a cosmopolitan dipteran insect, is a significant vector for human and animal bacterial pathogens, but little is known about its immune response to these pathogens. To address this issue, we inoculated the larvae with a mixture of Escherichia coli and Staphylococcus aureus and profiled the transcriptome 6, 24, and 48 h thereafter. Many genes known to controlling innate immunity in insects were induced following infection, including genes encoding pattern recognition proteins (PGRPs), various components of the Toll and IMD signaling pathways and of the proPO-activating and redox systems, and multiple antimicrobial peptides. Interestingly, we also uncovered a large set of novel immune response genes including two broad-spectrum antimicrobial peptides (muscin and domesticin), which might have evolved to adapt to house-fly's unique ecological environments. Finally, genes mediating oxidative phosphorylation were repressed at 48 h post-infection, suggesting disruption of energy homeostasis and mitochondrial function at the late stages of infection. Collectively, our data reveal dynamic changes in gene expression following bacterial infection in the house fly, paving the way for future in-depth analysis of M. domestica's immune system.

Bacterial Infections Change Natural History of Cirrhosis Irrespective of Liver Disease Severity.

PubMed

Dionigi, Elena; Garcovich, Matteo; Borzio, Mauro; Leandro, Gioacchino; Majumdar, Avik; Tsami, Aikaterini; Arvaniti, Vasiliki; Roccarina, Davide; Pinzani, Massimo; Burroughs, Andrew K; O'Beirne, James; Tsochatzis, Emmanuel A

2017-04-01

We assessed the prognostic significance of infections in relation to current prognostic scores and explored if infection could be considered per se a distinct clinical stage in the natural history of cirrhosis. We included consecutive patients with cirrhosis admitted to a tertiary referral liver unit for at least 48 h over a 2-year period. Diagnosis of infection was based on positive cultures or strict established criteria. We used competing risk analysis and propensity score matching for data analysis. 501 patients (63% male, 48% alcoholic liver disease, median Model of End-stage Liver Disease (MELD)=17) underwent 781 admissions over the study period. Portal hypertensive bleeding and complicated ascites were the commonest reasons of admission. The incidence of proven bacterial infection was 25.6% (60% community acquired and 40% nosocomial). Survival rates at 3, 6, 12, and 30 months were 83%, 77%, 71%, and 62% in patients without diagnosis of infection, vs. 50%, 46%, 41%, and 34% in patients with diagnosis of infection. Overall survival was independently associated with MELD score (hazards ratio (HR) 1.099), intensive care (ITU) stay (HR 1.967) and bacterial infection (HR 2.226). Bacterial infection was an independent predictor of survival even when patients who died within the first 30 days were excluded from the analysis in Cox regression (HR 2.013) and competing risk Cox models in all patients (HR 1.46) and propensity risk score-matched infected and non-infected patients (HR 1.67). Infection most likely represents a distinct prognostic stage of cirrhosis, which affects survival irrespective of disease severity, even after recovery from the infective episode.

Fungal infection by Mucorales order in lung transplantation: 4 case reports.

PubMed

Neto, F M F D; Camargo, P C L B; Costa, A N; Teixeira, R H O B; Carraro, R M; Afonso, J E; Campos, S V; Samano, M N; Fernandes, L M; Abdalla, L G; Pêgo-Fernandes, P M

2014-01-01

Mucorales is a fungus that causes systemic, highly lethal infections in immunocompromised patients. The overall mortality of pulmonary mucormycosis can reach 95%. This work is a review of medical records of 200 lung transplant recipients between the years of 2003 and 2013, in order to identify the prevalence of Mucorales in the Lung Transplantation service of Heart Institute (InCor), Hospital das Clínicas da Universidade de São Paulo, Brazil, by culture results from bronchoalveolar lavage and necropsy findings. We report 4 cases found at this analyses: 3 in patients with cystic fibrosis and 1 in a patient with bronchiectasis due to Kartagener syndrome. There were 2 unfavorable outcomes related to the presence of Mucorales, 1 by reduction of immunosuppression, another by invasive infection. Another patient died from renal and septic complications from another etiology. One patient was diagnosed at autopsy just 5 days after lung transplantation, with the Mucor inside the pulmonary vein with a precise, well-defined involvement only of donor's segment, leading to previous colonization hypothesis. There are few case reports of Mucorales infection in lung transplantation in the literature. Surveillance for the presence of Mucor can lead to timely fungal treatment and reduce morbidity and mortality in the immunocompromised patients, especially lung transplant recipients. Copyright © 2014 Elsevier Inc. All rights reserved.

Human papillomavirus 16/18 infections in lung cancer patients in Mexico.

PubMed

Badillo-Almaraz, I; Zapata-Benavides, P; Saavedra-Alonso, S; Zamora-Avila, D; Reséndez-Pérez, D; Tamez-Guerra, R; Herrera-Esparza, R; Rodríguez-Padilla, C

2013-01-01

Human papillomavirus (HPV) is an epitheliotropic, double-stranded DNA virus, and its high-risk genotypes are associated with human cancer. HPV genome has been detected in lung carcinomas in certain places around the world, including Mexico; however, the prevalence of this is unclear. In this study, we examine the frequency of high-risk HPV 16/18 in lung cancer tissues from a Mexican population. 39 lung cancer specimens were analyzed by polymerase chain reaction (PCR) using HPV GP5+/GP6+ primers and then were genotyped using specific primers to HPV 16/18. Additionally, in situ hybridization (ISH) was performed using BIO-labeled oligonucleotide probes. Our results identified 15 positive cases (38.46%) for HPV 16 and 1 positive case (2.56%) for HPV 18 by PCR. ISH showed the presence of HPV DNA in 13 of 16 (81%) samples, in agreement with the PCR results. In this study, we detected HPV 16/18 gene sequences in lung cancer samples obtained from Mexican patients by PCR and ISH. We found the highest prevalence of HPV 16 infection in lung adenocarcinomas, suggesting that HPV infection may be associated with lung cancer. However, further studies are needed to elucidate the role of HPV in lung carcinogenesis. Copyright © 2013 S. Karger AG, Basel.

The Superiority of IFN-λ as a Therapeutic Candidate to Control Acute Influenza Viral Lung Infection.

PubMed

Kim, Sujin; Kim, Min-Ji; Kim, Chang-Hoon; Kang, Ju Wan; Shin, Ha Kyung; Kim, Dong-Young; Won, Tae-Bin; Han, Doo Hee; Rhee, Chae Seo; Yoon, Joo-Heon; Kim, Hyun Jik

2017-02-01

Here, we studied the IFN-regulated innate immune response against influenza A virus (IAV) infection in the mouse lung and the therapeutic effect of IFN-λ2/3 in acute IAV lung infection. For viral infections, IAV (WS/33, H1N1, PR8 H1N1, H5N1) were inoculated into wild-type mice by intranasal delivery, and IAV mRNA level and viral titer were measured. To compare the antiviral effect of IFNs in vivo in the lung, neutralizing antibodies and recombinant IFNs were used. After intranasal inoculation of IAV into mice, viral infection peaked at 7 days postinfection, and the IAV titer also reached its peak at this time. We found that IFN-β and IFN-λ2/3 were preferentially induced after IAV infection and the IFN-λ2/3-mediated innate immune response was specifically required for the induction of IFN-stimulated genes (ISGs) transcription in the mouse respiratory tract. Neutralization of secreted IFN-λ2/3 aggravated acute IAV lung infection in mice with intact IFN-β induction; consistent with this finding, the transcription of ISGs was significantly reduced. Intranasal administration of IFN-λ2/3 significantly suppressed various strains of IAV infection, including WS/33 (H1N1), PR (H1N1), and H5N1 in the mouse lung, and was accompanied by greater up-regulation of ISGs. Taken together, our data indicate that the IFN-λ2/3-mediated innate immune response is necessary to protect the lungs from IAV infection, and intranasally delivered IFN-λ2/3 has the potential to be a useful therapeutic strategy for treating acute IAV lung infection.

Respiratory infections in patients with cystic fibrosis undergoing lung transplantation.

PubMed

Lobo, Leonard J; Noone, Peadar G

2014-01-01

Cystic fibrosis is an inherited disease characterised by chronic respiratory infections associated with bronchiectasis. Lung transplantation has helped to extend the lives of patients with cystic fibrosis who have advanced lung disease. However, persistent, recurrent, and newly acquired infections can be problematic. Classic cystic fibrosis-associated organisms, such as Staphylococcus aureus and Pseudomonas aeruginosa, are generally manageable post-transplantation, and are associated with favourable outcomes. Burkholderia cenocepacia poses particular challenges, although other Burkholderia species are less problematic. Despite concerns about non-tuberculous mycobacteria, especially Mycobacterium abscessus, post-transplantation survival has not been definitively shown to be less than average in patients with these infections. Fungal species can be prevalent before and after transplantation and are associated with high morbidity, so should be treated aggressively. Appropriate viral screening and antiviral prophylaxis are necessary to prevent infection with and reactivation of Epstein-Barr virus and cytomegalovirus and their associated complications. Awareness of drug pharmacokinetics and interactions in cystic fibrosis is crucial to prevent toxic effects and subtherapeutic or supratherapeutic drug dosing. With the large range of potential infectious organisms in patients with cystic fibrosis, infection control in hospital and outpatient settings is important. Despite its complexity, lung transplantation in the cystic fibrosis population is safe, with good outcomes if the clinician is aware of all the potential pathogens and remains vigilant by means of surveillance and proactive treatment. Copyright © 2014 Elsevier Ltd. All rights reserved.

Bacterial isolates from equine infections in western Canada (1998–2003)

PubMed Central

Clark, Chris; Greenwood, Sarah; Boison, Joe O.; Chirino-Trejo, Manuel; Dowling, Patricia M.

2008-01-01

All bacterial samples of equine origin submitted to the diagnostic laboratory at the Western College of Veterinary Medicine from January 1998 to December 2003 from either “in-clinic” or Field Service cases were accessed (1323 submissions). The most common bacterial isolates from specific presenting signs were identified, along with their in vitro antimicrobial susceptibility patterns. The most common site from which significant bacterial isolates were recovered was the respiratory tract, followed by wounds. Streptococcus zooepidemicus was the most common isolate from most infections, followed by Escherichia coli. Antimicrobial resistance was not common in the isolates and acquired antimicrobial resistance to multiple drugs was rare. The results are compared with previous published studies from other institutions and used to suggest appropriate antimicrobial treatments for equine infections in western Canada. PMID:18309745

The Role of the Microbiome in Exacerbations of Chronic Lung Diseases

PubMed Central

Dickson, Robert P.; Martinez, Fernando J.; Huffnagle, Gary B.

2014-01-01

Summary Culture-independent microbiological techniques have revealed a previously unappreciated complexity to the bacterial microbiome of the respiratory tract, forcing reconsideration of the interactions between host, bacteria and the pathogenesis of exacerbations of chronic lung disease. The composition of the lung microbiome is determined by microbial immigration, elimination, and the relative growth rates of its members; all of these change dramatically in chronic lung disease and further during exacerbations. Exacerbations lack key features of bacterial infections, including increased bacterial burden and decreased community diversity. We propose instead that exacerbations are occasions of respiratory dysbiosis: a disordered respiratory microbial ecosystem with negative effects on host biology. Respiratory dysbiosis provokes a dysregulated host immune response, which in turn alters microbial growth conditions in patient airways, further promoting dysbiosis and perpetuating a coupled cycle of inflammation and disordered microbiota. Differences in baseline respiratory microbiota may help explain the “frequent-exacerbator” phenotype observed across multiple disease states, and may provide novel targets for therapeutic intervention. PMID:25152271

M13 Virus based detection of Bacterial Infections in Living Hosts

PubMed Central

Bardhan, Neelkanth M.; Ghosh, Debadyuti; Belcher, Angela M.

2014-01-01

We report a first method for using M13 bacteriophage as a multifunctional scaffold for optically imaging bacterial infections in vivo. We demonstrate that M13 virus conjugated with hundreds of dye molecules (M13-Dye) can target and distinguish pathogenic infections of F-pili expressing and F-negative strains of E. coli. Further, in order to tune this M13-Dye complex suitable for targeting other strains of bacteria, we have used a 1-step reaction for creating an anti-bacterial antibody-M13-Dye probe. As an example, we show anti-S.aureus-M13-Dye able to target and image infections of S. aureus in living hosts, with a 3.7x increase in fluorescence over background. PMID:23576418

The interplay between regulated necrosis and bacterial infection.

PubMed

Blériot, Camille; Lecuit, Marc

2016-06-01

Necrosis has long been considered as a passive event resulting from a cell extrinsic stimulus, such as pathogen infection. Recent advances have refined this view and it is now well established that necrosis is tightly regulated at the cell level. Regulated necrosis can occur in the context of host-pathogen interactions, and can either participate in the control of infection or favor it. Here, we review the two main pathways implicated so far in bacteria-associated regulated necrosis: caspase 1-dependent pyroptosis and RIPK1/RIPK3-dependent necroptosis. We present how these pathways are modulated in the context of infection by a series of model bacterial pathogens.

Elucidation of Bacterial Pneumonia-Causing Pathogens in Patients with Respiratory Viral Infection.

PubMed

Jung, Hwa Sik; Kang, Byung Ju; Ra, Seung Won; Seo, Kwang Won; Jegal, Yangjin; Jun, Jae Bum; Jung, Jiwon; Jeong, Joseph; Jeon, Hee Jeong; Ahn, Jae Sung; Lee, Taehoon; Ahn, Jong Joon

2017-10-01

Bacterial pneumonia occurring after respiratory viral infection is common. However, the predominant bacterial species causing pneumonia secondary to respiratory viral infections other than influenza remain unknown. The purpose of this study was to know whether the pathogens causing post-viral bacterial pneumonia vary according to the type of respiratory virus. Study subjects were 5,298 patients, who underwent multiplex real-time polymerase chain reaction for simultaneous detection of respiratory viruses, among who visited the emergency department or outpatient clinic with respiratory symptoms at Ulsan University Hospital between April 2013 and March 2016. The patients' medical records were retrospectively reviewed. A total of 251 clinically significant bacteria were identified in 233 patients with post-viral bacterial pneumonia. Mycoplasma pneumoniae was the most frequent bacterium in patients aged <16 years, regardless of the preceding virus type (p=0.630). In patients aged ≥16 years, the isolated bacteria varied according to the preceding virus type. The major results were as follows (p<0.001): pneumonia in patients with influenza virus (type A/B), rhinovirus, and human metapneumovirus infections was caused by similar bacteria, and the findings indicated that Staphylococcus aureus pneumonia was very common in these patients. In contrast, coronavirus, parainfluenza virus, and respiratory syncytial virus infections were associated with pneumonia caused by gram-negative bacteria. The pathogens causing post-viral bacterial pneumonia vary according to the type of preceding respiratory virus. This information could help in selecting empirical antibiotics in patients with post-viral pneumonia. Copyright©2017. The Korean Academy of Tuberculosis and Respiratory Diseases

Elucidation of Bacterial Pneumonia-Causing Pathogens in Patients with Respiratory Viral Infection

PubMed Central

Jung, Hwa Sik; Kang, Byung Ju; Ra, Seung Won; Seo, Kwang Won; Jegal, Yangjin; Jun, Jae-Bum; Jung, Jiwon; Jeong, Joseph; Jeon, Hee-Jeong; Ahn, Jae-Sung

2017-01-01

Background Bacterial pneumonia occurring after respiratory viral infection is common. However, the predominant bacterial species causing pneumonia secondary to respiratory viral infections other than influenza remain unknown. The purpose of this study was to know whether the pathogens causing post-viral bacterial pneumonia vary according to the type of respiratory virus. Methods Study subjects were 5,298 patients, who underwent multiplex real-time polymerase chain reaction for simultaneous detection of respiratory viruses, among who visited the emergency department or outpatient clinic with respiratory symptoms at Ulsan University Hospital between April 2013 and March 2016. The patients' medical records were retrospectively reviewed. Results A total of 251 clinically significant bacteria were identified in 233 patients with post-viral bacterial pneumonia. Mycoplasma pneumoniae was the most frequent bacterium in patients aged <16 years, regardless of the preceding virus type (p=0.630). In patients aged ≥16 years, the isolated bacteria varied according to the preceding virus type. The major results were as follows (p<0.001): pneumonia in patients with influenza virus (type A/B), rhinovirus, and human metapneumovirus infections was caused by similar bacteria, and the findings indicated that Staphylococcus aureus pneumonia was very common in these patients. In contrast, coronavirus, parainfluenza virus, and respiratory syncytial virus infections were associated with pneumonia caused by gram-negative bacteria. Conclusion The pathogens causing post-viral bacterial pneumonia vary according to the type of preceding respiratory virus. This information could help in selecting empirical antibiotics in patients with post-viral pneumonia. PMID:28905531

The Rab-binding Profiles of Bacterial Virulence Factors during Infection*

PubMed Central

So, Ernest C.; Schroeder, Gunnar N.; Carson, Danielle; Mattheis, Corinna; Mousnier, Aurélie; Broncel, Malgorzata; Tate, Edward W.; Frankel, Gad

2016-01-01

Legionella pneumophila, the causative agent of Legionnaire's disease, uses its type IV secretion system to translocate over 300 effector proteins into host cells. These effectors subvert host cell signaling pathways to ensure bacterial proliferation. Despite their importance for pathogenesis, the roles of most of the effectors are yet to be characterized. Key to understanding the function of effectors is the identification of host proteins they bind during infection. We previously developed a novel tandem-affinity purification (TAP) approach using hexahistidine and BirA-specific biotinylation tags for isolating translocated effector complexes from infected cells whose composition were subsequently deciphered by mass spectrometry. Here we further advanced the workflow for the TAP approach and determined the infection-dependent interactomes of the effectors SidM and LidA, which were previously reported to promiscuously bind multiple Rab GTPases in vitro. In this study we defined a stringent subset of Rab GTPases targeted by SidM and LidA during infection, comprising of Rab1A, 1B, 6, and 10; in addition, LidA targets Rab14 and 18. Taken together, this study illustrates the power of this approach to profile the intracellular interactomes of bacterial effectors during infection. PMID:26755725

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.

New Bacterial Infection in the Prostate after Transrectal Prostate Biopsy.

PubMed

Seo, Yumi; Lee, Gilho

2018-04-23

The prostate is prone to infections. Hypothetically, bacteria can be inoculated into the prostate during a transrectal prostate biopsy (TRPB) and progress into chronic bacterial prostatitis. Therefore, we examined new bacterial infections in biopsied prostates after TRPB and whether they affect clinical characteristics in the biopsied patients. Of men whose prostate cultures have been taken prior to TRPB, 105 men with bacteria-free benign prostate pathology underwent an additional repeated prostate culture within a year after TRPB. Twenty out of 105 men (19.05%) acquired new bacteria in their naïve prostates after TRPB. Except for one single case of Escherichia coli infection, 19 men had acquired gram-positive bacteria species. Between the culture-positive and negative groups, there were no significant differences in age, serum prostate-specific antigen (PSA) level, white blood cell (WBC) counts in expressed prostatic secretion (EPS), prostate volume, symptom severities in Korean version of the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) questionnaire, and patient-specific risk factors for biopsy associated infectious complications. Additionally, the TRPB procedure increased the WBC counts in post-biopsy EPS ( P = 0.031, McNemar test), but did not increase the serum PSA level and symptoms of NIH-CPSI in 20 men who acquired new bacteria after TRPB. The TRPB procedure was significantly associated with acquiring new bacterial infections in the biopsied prostate, but these localized bacteria did not affect patients' serum PSA level and symptoms after biopsy.

Interaction of antimicrobial peptides with bacterial polysaccharides from lung pathogens.

PubMed

Herasimenka, Yury; Benincasa, Monica; Mattiuzzo, Maura; Cescutti, Paola; Gennaro, Renato; Rizzo, Roberto

2005-07-01

The interaction of two cathelicidin antimicrobial peptides, LL-37 and SMAP-29, with three bacterial polysaccharides, respectively, produced by Pseudomonas aeruginosa, Burkholderia cepacia and Klebsiella pneumoniae, was investigated to identify possible mechanisms adopted by lung pathogens to escape the action of innate immunity effectors. In vitro assays indicated that the antibacterial activity of both peptides was inhibited to a variable extent by the three polysaccharides. Circular dichroism experiments showed that these induced an alpha-helical conformation in the two peptides, with the polysaccharides from K. pneumoniae and B. cepacia showing, respectively, the highest and the lowest effect. Fluorescence measurements also indicated the presence of peptide-polysaccharide interactions. A model is proposed in which the binding of peptides to the polysaccharide molecules induces, at low polysaccharide to peptide ratios, a higher order of aggregation, due to peptide-peptide interactions. Overall, these results suggest that binding of the peptides by the polysaccharides produced by lung pathogens can contribute to the impairment of peptide-based innate defenses of airway surface.

Inhalable Antimicrobials for Treatment of Bacterial Biofilm-Associated Sinusitis in Cystic Fibrosis Patients: Challenges and Drug Delivery Approaches

PubMed Central

Kłodzińska, Sylvia Natalie; Priemel, Petra Alexandra; Rades, Thomas; Mørck Nielsen, Hanne

2016-01-01

Bacterial biofilm-associated chronic sinusitis in cystic fibrosis (CF) patients caused by Pseudomonas aeruginosa infections and the lack of available treatments for such infections constitute a critical aspect of CF disease management. Currently, inhalation therapies to combat P. aeruginosa infections in CF patients are focused mainly on the delivery of antimicrobials to the lower respiratory tract, disregarding the sinuses. However, the sinuses constitute a reservoir for P. aeruginosa growth, leading to re-infection of the lungs, even after clearing an initial lung infection. Eradication of P. aeruginosa from the respiratory tract after a first infection has been shown to delay chronic pulmonary infection with the bacteria for up to two years. The challenges with providing a suitable treatment for bacterial sinusitis include: (i) identifying a suitable antimicrobial compound; (ii) selecting a suitable device to deliver the drug to the sinuses and nasal cavities; and (iii) applying a formulation design, which will mediate delivery of a high dose of the antimicrobial directly to the site of infection. This review highlights currently available inhalable antimicrobial formulations for treatment and management of biofilm infections caused by P. aeruginosa and discusses critical issues related to novel antimicrobial drug formulation design approaches. PMID:27735846

Can procalcitonin help identify associated bacterial infection in patients with severe influenza pneumonia? A multicentre study.

PubMed

Cuquemelle, E; Soulis, F; Villers, D; Roche-Campo, F; Ara Somohano, C; Fartoukh, M; Kouatchet, A; Mourvillier, B; Dellamonica, J; Picard, W; Schmidt, M; Boulain, T; Brun-Buisson, C

2011-05-01

To determine whether procalcitonin (PCT) levels could help discriminate isolated viral from mixed (bacterial and viral) pneumonia in patients admitted to the intensive care unit (ICU) during the A/H1N1v2009 influenza pandemic. A retrospective observational study was performed in 23 French ICUs during the 2009 H1N1 pandemic. Levels of PCT at admission were compared between patients with confirmed influenzae A pneumonia associated or not associated with a bacterial co-infection. Of 103 patients with confirmed A/H1N1 infection and not having received prior antibiotics, 48 (46.6%; 95% CI 37-56%) had a documented bacterial co-infection, mostly caused by Streptococcus pneumoniae (54%) or Staphylococcus aureus (31%). Fifty-two patients had PCT measured on admission, including 19 (37%) having bacterial co-infection. Median (range 25-75%) values of PCT were significantly higher in patients with bacterial co-infection: 29.5 (3.9-45.3) versus 0.5 (0.12-2) μg/l (P < 0.01). For a cut-off of 0.8 μg/l or more, the sensitivity and specificity of PCT for distinguishing isolated viral from mixed pneumonia were 91 and 68%, respectively. Alveolar condensation combined with a PCT level of 0.8 μg/l or more was strongly associated with bacterial co-infection (OR 12.9, 95% CI 3.2-51.5; P < 0.001). PCT may help discriminate viral from mixed pneumonia during the influenza season. Levels of PCT less than 0.8 μg/l combined with clinical judgment suggest that bacterial infection is unlikely.

Bacterial communications in implant infections: a target for an intelligence war.

PubMed

Costerton, J W; Montanaro, L; Arciola, C R

2007-09-01

The status of population density is communicated among bacteria by specific secreted molecules, called pheromones or autoinducers, and the control mechanism is called "quorum-sensing". Quorum-sensing systems regulate the expression of a panel of genes, allowing bacteria to adapt to modified environmental conditions at a high density of population. The two known different quorum systems are described as the LuxR-LuxI system in gram-negative bacteria, which uses an N-acyl-homoserine lactone (AHL) as signal, and the agr system in gram-positive bacteria, which uses a peptide-tiolactone as signal and the RNAIII as effector molecules. Both in gram-negative and in gram-positive bacteria, quorum-sensing systems regulate the expression of adhesion mechanisms (biofilm and adhesins) and virulence factors (toxins and exoenzymes) depending on population cell density. In gram-negative Pseudomonas aeruginosa, analogs of signaling molecules such as furanone analogs, are effective in attenuating bacterial virulence and controlling bacterial infections. In grampositive Staphylococcus aureus, the quorum-sensing RNAIII-inhibiting peptide (RIP), tested in vitro and in animal infection models, has been proved to inhibit virulence and prevent infections. Attenuation of bacterial virulence by quorum-sensing inhibitors, rather than by bactericidal or bacteriostatic drugs, is a highly attractive concept because these antibacterial agents are less likely to induce the development of bacterial resistance.

Detection of bacterial infection by a technetium-99m-labeled peptidoglycan aptamer.

PubMed

Ferreira, Iêda Mendes; de Sousa Lacerda, Camila Maria; Dos Santos, Sara Roberta; de Barros, André Luís Branco; Fernandes, Simone Odília; Cardoso, Valbert Nascimento; de Andrade, Antero Silva Ribeiro

2017-09-01

Nuclear medicine clinicians are still waiting for the optimal scintigraphic imaging agents capable of distinguishing between infection and inflammation, and between fungal and bacterial infections. Aptamers have several properties that make them suitable for molecular imaging. In the present study, a peptidoglycan aptamer (Antibac1) was labeled with 99m Tc and evaluated by biodistribution studies and scintigraphic imaging in infection-bearing mice. Labeling with 99m Tc was performed by the direct method and the complex stability was evaluated in saline, plasma and in the molar excess of cysteine. The biodistribution and scintigraphic imaging studies with the 99m Tc-Antibac1 were carried out in two different experimental infection models: Bacterial-infected mice (S. aureus) and fungal-infected mice (C. albicans). A 99m Tc radiolabeled library, consisting of oligonucleotides with random sequences, was used as a control for both models. Radiolabeling yields were superior to 90% and 99m Tc-Antibac1 was highly stable in presence of saline, plasma, and cysteine up to 6h. Scintigraphic images of S. aureus infected mice at 1.5 and 3.0h after 99m Tc-Antibac1 injection showed target to non-target ratios of 4.7±0.9 and 4.6±0.1, respectively. These values were statistically higher than those achieved for the 99m Tc-library at the same time frames (1.6±0.4 and 1.7±0.4, respectively). Noteworthy, 99m Tc-Antibac1 and 99m Tc-library showed similar low target to non-target ratios in the fungal-infected model: 2.0±0.3 and 2.0±0.6for 99m Tc-Antibac1 and 2.1±0.3 and 1.9 ± 0.6 for 99m Tc-library, at the same times. These findings suggest that the 99m Tc-Antibac1 is a feasible imaging probe to identify a bacterial infection focus. In addition, this radiolabeled aptamer seems to be suitable in distinguishing between bacterial and fungal infection. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

M13 virus based detection of bacterial infections in living hosts.

PubMed

Bardhan, Neelkanth M; Ghosh, Debadyuti; Belcher, Angela M

2014-08-01

We report a first method for using M13 bacteriophage as a multifunctional scaffold for optically imaging bacterial infections in vivo. We demonstrate that M13 virus conjugated with hundreds of dye molecules (M13-Dye) can target and distinguish pathogenic infections of F-pili expressing and F-negative strains of E. coli. Further, in order to tune this M13-Dye complex suitable for targeting other strains of bacteria, we have used a 1-step reaction for creating an anti-bacterial antibody-M13-Dye probe. As an example, we show anti-S. aureus-M13-Dye able to target and image infections of S. aureus in living hosts, with a 3.7× increase in fluorescence over background. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Host DNA repair proteins in response to Pseudomonas aeruginosa in lung epitehlial cells and in mice

USDA-ARS?s Scientific Manuscript database

Host DNA damage and DNA repair response to bacterial infections and its significance are not fully understood. Here, we demonstrate that infection by Gram-negative bacterium P. aeruginosa significantly altered the expression and enzymatic activity of base excision DNA repair protein OGG1 in lung epi...

Multi-scale fluorescence imaging of bacterial infections in animal models

NASA Astrophysics Data System (ADS)

Bixler, Joel N.; Kong, Ying; Cirillo, Jeffrey D.; Maitland, Kristen C.

2013-03-01

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), currently affects roughly one-third of the world's population. Drug resistant strains of Mtb decrease the effectiveness of current therapeutics and demand the development of new antimicrobial therapies. In addition, the current vaccine, Bacille Calmette Guérin (BCG), has variable efficacy for disease prevention in different populations. Animal studies are often limited by the need to sacrifice at discrete time points for pathology and tissue homogenization, which greatly reduces spatial and temporal resolution. Optical imaging offers the potential for a minimally-invasive solution to imaging on a macroscopic and microscopic scale, allowing for high resolution study of infection. We have integrated a fluorescence microendoscope into a whole-animal optical imaging system, allowing for simultaneous microscopic and macroscopic imaging of tdTomato expressing BCG in vivo. A 535 nm LED was collimated and launched into a 10,000 element fiber bundle with an outer diameter of 0.66 mm. The fiber bundle can be inserted through an intra-tracheal catheter into the lung of a mouse. Fluorescence emission can either be (1) collected by the bundle and imaged onto the surface of a CCD camera for localized detection or (2) the fluorescence can be imaged by the whole animal imaging system providing macroscopic information. Results from internal localized excitation and external whole body detection indicate the potential for imaging bacterial infections down to 100 colony forming units. This novel imaging technique has the potential to allow for functional studies, enhancing the ability to assess new therapeutic agents.

Acyloxyacyl hydrolase promotes the resolution of lipopolysaccharide-induced acute lung injury

PubMed Central

Tang, Zihui; Yang, Qian; Qian, Guojun; Qian, Jing; Zeng, Wenjiao; Gu, Jie; Chu, Tianqing; Zhu, Ning; Zhang, Wenhong; Yan, Dapeng; He, Rui; Chu, Yiwei

2017-01-01

Pulmonary infection is the most common risk factor for acute lung injury (ALI). Innate immune responses induced by Microbe-Associated Molecular Pattern (MAMP) molecules are essential for lung defense but can lead to tissue injury. Little is known about how MAMP molecules are degraded in the lung or how MAMP degradation/inactivation helps prevent or ameliorate the harmful inflammation that produces ALI. Acyloxyacyl hydrolase (AOAH) is a host lipase that inactivates Gram-negative bacterial endotoxin (lipopolysaccharide, or LPS). We report here that alveolar macrophages increase AOAH expression upon exposure to LPS and that Aoah+/+ mice recover more rapidly than do Aoah-/- mice from ALI induced by nasally instilled LPS or Klebsiella pneumoniae. Aoah-/- mouse lungs had more prolonged leukocyte infiltration, greater pro- and anti-inflammatory cytokine expression, and longer-lasting alveolar barrier damage. We also describe evidence that the persistently bioactive LPS in Aoah-/- alveoli can stimulate alveolar macrophages directly and epithelial cells indirectly to produce chemoattractants that recruit neutrophils to the lung and may prevent their clearance. Distinct from the prolonged tolerance observed in LPS-exposed Aoah-/- peritoneal macrophages, alveolar macrophages that lacked AOAH maintained or increased their responses to bioactive LPS and sustained inflammation. Inactivation of LPS by AOAH is a previously unappreciated mechanism for promoting resolution of pulmonary inflammation/injury induced by Gram-negative bacterial infection. PMID:28622363

Statin Treatment and Mortality in Bacterial Infections – A Systematic Review and Meta-Analysis

PubMed Central

Björkhem-Bergman, Linda; Bergman, Peter; Andersson, Jan; Lindh, Jonatan D.

2010-01-01

Background Several studies have reported improved survival in severe bacterial infections among statin treated patients. In addition, statins have been ascribed beneficial anti-inflammatory effects. The aim of this study was to evaluate the effect of statin-treatment on mortality in patients with bacterial infections, by means of a systematic review and a meta-analysis. Methodology and Principal Findings Studies investigating the association between statin use and mortality in patients with bacterial disease were identified in a systematic literature review and a meta-analysis was performed to calculate the overall odds ratio of mortality in statin users. The literature search identified 947 citations from which 40 relevant studies were extracted. In all, 15 studies comprising 113 910 patients were included in the final analysis. Statin use was associated with a significantly (p<0.0001) reduced mortality in patients suffering from bacterial infections (OR 0.52, 95% CI 0.42–0.66). However, all studies included were of observational design and funnel plot analyses indicated influence by a possible publication bias (Egger's bias test p<0.05). When a precision estimate test was used to adjust for publication bias the effect of statin treatment was no longer significant, with an OR of 0.79 (95% CI 0.58–1.07). Conclusion/Significance According to the meta-analysis of observational studies presented here, patients on statin therapy seem to have a better outcome in bacterial infections. However, the association did not reach statistical significance after adjustment for apparent publication bias. Thus, there is a great need for randomised controlled trials investigating the possible beneficial effect of statins in bacterial infections. PMID:20502712

In vivo imaging of the pathophysiological changes and neutrophil dynamics in influenza virus-infected mouse lungs.

PubMed

Ueki, Hiroshi; Wang, I-Hsuan; Fukuyama, Satoshi; Katsura, Hiroaki; da Silva Lopes, Tiago Jose; Neumann, Gabriele; Kawaoka, Yoshihiro

2018-06-25

The pathophysiological changes that occur in lungs infected with influenza viruses are poorly understood. Here we established an in vivo imaging system that combines two-photon excitation microscopy and fluorescent influenza viruses of different pathogenicity. This approach allowed us to monitor and correlate several parameters and physiological changes including the spread of infection, pulmonary permeability, pulmonary perfusion speed, number of recruited neutrophils in infected lungs, and neutrophil motion in the lungs of live mice. Several physiological changes were larger and occurred earlier in mice infected with a highly pathogenic H5N1 influenza virus compared with those infected with a mouse-adapted human strain. These findings demonstrate the potential of our in vivo imaging system to provide novel information about the pathophysiological consequences of virus infections.

A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin: a step towards predicting bacterial killing at sites of infection.

PubMed

Sadiq, Muhammad W; Nielsen, Elisabet I; Khachman, Dalia; Conil, Jean-Marie; Georges, Bernard; Houin, Georges; Laffont, Celine M; Karlsson, Mats O; Friberg, Lena E

2017-04-01

The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors. The developed WB-PBPK model successfully characterized both the typical trends and variability of the available ciprofloxacin plasma concentration data. The WB-PBPK model was thereafter combined with a pharmacokinetic-pharmacodynamic (PKPD) model, developed based on in vitro time-kill data of ciprofloxacin and Escherichia coli to illustrate the potential of this type of approach to predict the time-course of bacterial killing at different sites of infection. The predicted unbound concentration-time profile in extracellular tissue was driving the bacterial killing in the PKPD model and the rate and extent of take-over of mutant bacteria in different tissues were explored. The bacterial killing was predicted to be most efficient in lung and kidney, which correspond well to ciprofloxacin's indications pneumonia and urinary tract infections. Furthermore, a function based on available information on bacterial killing by the immune system in vivo was incorporated. This work demonstrates the development and application of a WB-PBPK-PD model to compare killing of bacteria with different antibiotic susceptibility, of value for drug development and the optimal use of antibiotics .

Prior human polyomavirus and papillomavirus infection and incident lung cancer: a nested case-control study.

PubMed

Colombara, Danny V; Manhart, Lisa E; Carter, Joseph J; Hawes, Stephen E; Weiss, Noel S; Hughes, James P; Barnett, Matt J; Goodman, Gary E; Smith, Jennifer S; Qiao, You-Lin; Galloway, Denise A

2015-12-01

To test whether infection with select human polyomaviruses (HPyV) and human papillomaviruses (HPV) is associated with incident lung cancer. We performed a nested case-control study, testing serum from the carotene and retinol efficacy trial, conducted 1985-2005, for antibodies to Merkel cell (MCV), KI (KIV), and WU (WUV) HPyVs as well as to six high-risk and two low-risk HPV types. Incident lung cancer cases (n = 200) were frequency-matched with controls (n = 200) on age, enrollment and blood draw dates, intervention arm assignment, and the number of serum freeze/thaw cycles. Sera were tested using multiplex liquid bead microarray antibody assays. We used logistic regression to assess the association between HPyV and HPV antibodies and lung cancer. There was no evidence of a positive association between levels of MCV, KIV, or WUV antibodies and incident lung cancer (p corrected >0.10 for all trend tests; odds ratio (OR) range 0.72-1.09, p corrected >0.10 for all). There was also no evidence for a positive association between HPV 16 or 18 infection and incident lung cancer (p corrected ≥0.10 for all trend tests; OR range 0.25-2.54, p > 0.05 for all OR > 1), but the number of persons with serologic evidence of these infections was small. Prior infection with any of several types of HPyV or HPV was not associated with subsequent diagnosis of lung cancer. Infection with these viruses likely does not influence a person's risk of lung cancer in Western smoking populations.

Vaccine-elicited memory CD4+ T cell expansion is impaired in the lungs during tuberculosis.

PubMed

Carpenter, Stephen M; Yang, Jason D; Lee, Jinhee; Barreira-Silva, Palmira; Behar, Samuel M

2017-11-01

Immunological memory is the key biological process that makes vaccines possible. Although tuberculosis vaccines elicit protective immunity in animals, few provide durable protection. To understand why protection is transient, we evaluated the ability of memory CD4+ T cells to expand, differentiate, and control Mycobacterium tuberculosis. Both naïve and memory CD4+ T cells initially proliferated exponentially, and the accumulation of memory T cells in the lung correlated with early bacterial control. However, later during infection, memory CD4+ T cell proliferation was curtailed and no protection was observed. We show that memory CD4+ T cells are first activated in the LN and their recruitment to the lung attenuates bacterial growth. However, their interaction with Mtb-infected macrophages does not promote continued proliferation. We conclude that a lack of sustained expansion by memory-derived T cells in the lung limits the durability of their protection, linking their slower expansion with transient protection in vaccinated mice.

[Toll-like receptor in lung response to pathogens].

PubMed

Rivas-Santiago, Bruno; Juárez, Esmeralda

2007-01-01

Innate immunity plays a central role in antimicrobial defense. Advances in the understanding of pathogen recognition systems of innate cells have yielded the identification of Toll like receptors (TLR) as key elements of the lung defense mechanisms which is heavily exposed to a variety of stimuli. TLR recognition of several microbial compounds induces proinflammatory cytokines production whose contribution to the host may be either protective or detrimental. Human immune response diversity may explain the differences observed between patients facing bacterial, viral and fungal lung infections. New strategies designs that modify innate immune response may be useful to limit detrimental consequences of inflammatory processes in the lung.

Macrophage origin limits functional plasticity in helminth-bacterial co-infection

PubMed Central

Campbell, Sharon M.; Duncan, Sheelagh; Hewitson, James P.; Barr, Tom A.; Jackson-Jones, Lucy H.; Maizels, Rick M.

2017-01-01

Rapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents. However, in the setting of persistent, chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear. Here we show that resident peritoneal macrophages expanded by infection with the nematode Heligmosomoides polygyrus bakeri altered their activation phenotype in response to infection with Salmonella enterica ser. Typhimurium in vitro and in vivo. The nematode-expanded resident F4/80high macrophages efficiently upregulated bacterial induced effector molecules (e.g. MHC-II, NOS2) similarly to newly recruited monocyte-derived macrophages. Nonetheless, recruitment of blood monocyte-derived macrophages to Salmonella infection occurred with equal magnitude in co-infected animals and caused displacement of the nematode-expanded, tissue resident-derived macrophages from the peritoneal cavity. Global gene expression analysis revealed that although nematode-expanded resident F4/80high macrophages made an anti-bacterial response, this was muted as compared to newly recruited F4/80low macrophages. However, the F4/80high macrophages adopted unique functional characteristics that included enhanced neutrophil-stimulating chemokine production. Thus, our data provide important evidence that plastic adaptation of MΦ activation does occur in vivo, but that cellular plasticity is outweighed by functional capabilities specific to the tissue origin of the cell. PMID:28334040

The Rab-binding Profiles of Bacterial Virulence Factors during Infection.

PubMed

So, Ernest C; Schroeder, Gunnar N; Carson, Danielle; Mattheis, Corinna; Mousnier, Aurélie; Broncel, Malgorzata; Tate, Edward W; Frankel, Gad

2016-03-11

Legionella pneumophila, the causative agent of Legionnaire's disease, uses its type IV secretion system to translocate over 300 effector proteins into host cells. These effectors subvert host cell signaling pathways to ensure bacterial proliferation. Despite their importance for pathogenesis, the roles of most of the effectors are yet to be characterized. Key to understanding the function of effectors is the identification of host proteins they bind during infection. We previously developed a novel tandem-affinity purification (TAP) approach using hexahistidine and BirA-specific biotinylation tags for isolating translocated effector complexes from infected cells whose composition were subsequently deciphered by mass spectrometry. Here we further advanced the workflow for the TAP approach and determined the infection-dependent interactomes of the effectors SidM and LidA, which were previously reported to promiscuously bind multiple Rab GTPases in vitro. In this study we defined a stringent subset of Rab GTPases targeted by SidM and LidA during infection, comprising of Rab1A, 1B, 6, and 10; in addition, LidA targets Rab14 and 18. Taken together, this study illustrates the power of this approach to profile the intracellular interactomes of bacterial effectors during infection. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Bypassing bacterial infection in phage display by sequencing DNA released from phage particles.

PubMed

Villequey, Camille; Kong, Xu-Dong; Heinis, Christian

2017-11-01

Phage display relies on a bacterial infection step in which the phage particles are replicated to perform multiple affinity selection rounds and to enable the identification of isolated clones by DNA sequencing. While this process is efficient for wild-type phage, the bacterial infection rate of phage with mutant or chemically modified coat proteins can be low. For example, a phage mutant with a disulfide-free p3 coat protein, used for the selection of bicyclic peptides, has a more than 100-fold reduced infection rate compared to the wild-type. A potential strategy for bypassing the bacterial infection step is to directly sequence DNA extracted from phage particles after a single round of phage panning using high-throughput sequencing. In this work, we have quantified the fraction of phage clones that can be identified by directly sequencing DNA from phage particles. The results show that the DNA of essentially all of the phage particles can be 'decoded', and that the sequence coverage for mutants equals that of amplified DNA extracted from cells infected with wild-type phage. This procedure is particularly attractive for selections with phage that have a compromised infection capacity, and it may allow phage display to be performed with particles that are not infective at all. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Concomitant Mycobacterium tuberculosis infection promotes lung tumor growth through enhancing Treg development.

PubMed

Zhou, Yan; Hu, Zhangguo; Cao, Shuhui; Yan, Bo; Qian, Jialin; Zhong, Hua

2017-08-01

Lung cancer is the most common malignancy in humans. An increased population of CD4+Foxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. The exact role and the involved mechanisms of concomitant H37Rv infection in non-small cell lung cancer (NSCLC) development are still not clear. Here, we showed that H37Rv infection promoted NSCLC cell growth with a higher percentage of Tregs found in draining lymph nodes. We also determined in vitro that H37Rv infection induced macrophage maturation and PD-L1 expression, which promoted Treg proportion, with enhanced proliferation suppression function. Mechanism analysis revealed that AKT-mTORC1 signal was important for PD-L1 expression induced by H37Rv infection. Suppressing of AKT-mTORC1 signal by rapamycin or raptor deficiency showed decreased PD-L1 levels which further reduced Treg proportion in a co-culture system. Finally, tumor-bearing mice injected with H37Rv plus rapamycin enhance the immune response of lung cancer compared with injected with H37Rv alone. This study demonstrated that concomitant H37Rv infection promote NSCLC tumor immune eacape through enhancing Treg proportion.

Primary Severe Acute Respiratory Syndrome Coronavirus Infection Limits Replication but Not Lung Inflammation upon Homologous Rechallenge

PubMed Central

Clay, Candice; Donart, Nathan; Fomukong, Ndingsa; Knight, Jennifer B.; Lei, Wanli; Price, Lance; Hahn, Fletcher; Van Westrienen, Jesse

2012-01-01

Our knowledge regarding immune-protective and immunopathogenic events in severe acute respiratory syndrome coronavirus (SARS-CoV) infection is limited, and little is known about the dynamics of the immune response at the primary site of disease. Here, an African green monkey (AGM) model was used to elucidate immune mechanisms that facilitate viral clearance but may also contribute to persistent lung inflammation following SARS-CoV infection. During primary infection, SARS-CoV replicated in the AGM lung for up to 10 days. Interestingly, lung inflammation was more prevalent following viral clearance, as leukocyte numbers peaked at 14 days postinfection (dpi) and remained elevated at 28 dpi compared to those of mock-infected controls. Lung macrophages but not dendritic cells were rapidly activated, and both cell types had high activation marker expression at late infection time points. Lung proinflammatory cytokines were induced at 1 to 14 dpi, but most returned to baseline by 28 dpi except interleukin 12 (IL-12) and gamma interferon. In SARS-CoV homologous rechallenge studies, 11 of the 12 animals were free of replicating virus at day 5 after rechallenge. However, incidence and severity of lung inflammation was not reduced despite the limited viral replication upon rechallenge. Evaluating the role of antibodies in immune protection or potentiation revealed a progressive increase in anti-SARS-CoV antibodies in lung and serum that did not correlate temporally or spatially with enhanced viral replication. This study represents one of the first comprehensive analyses of lung immunity, including changes in leukocyte populations, lung-specific cytokines, and antibody responses following SARS-CoV rechallenge in AGMs. PMID:22345460

[Infections of the oral mucosa II. Bacterial, mycotic and viral infections].

PubMed

Reichart, P A

1999-11-01

Non-specific infections of the oral mucosa are rare; however, they may present during HIV infection in the form of gingivo-periodontal lesions. In some of these Candida albicans may play a role in the pathogenesis. Sexually transmitted bacterial infections such as gonorrhoea and syphilis are frequently associated with HIV infection. Since penicillin resistance is frequent in gonorrhoea, the cephalosporines are mainly used for treatment. Syphilis increases the risk for transmission of HIV. Lues maligna with oral manifestations has been described. For this, penicillin G is the therapy of choice. Tuberculosis, characterized by multitherapy resistance, is associated with HIV infections world-wide; oral manifestations are rare. Oral candidiasis during HIV infection is often characterized by therapy resistance against fluconazole and a shift in species, with Candida glabrata and Candida krusei as the emerging species. The azoles are still the mainstay of therapy, particularly fluconazole. Herpes simplex (HSV) infections run an atypical course during HIV disease; resistance against acyclovir is a clinical problem. The association of HSV infection with erythema exudativum multiforme has been clearly shown. Oral hairy leukoplakia caused by Epstein Barr virus is a characteristic infection during immunosuppression. Cytomegalovirus infection is also observed in immunodeficient patients. Cases of ganciclovir resistance have been described. Human herpes virus 8 (HHV 8) is associated with Kaposi's sarcoma. Therapeutic trials have focussed on the inhibition of HHV 8 replication. Over 100 different genotypes of human papillomaviruses are known; some can cause infections of the oral mucosa. Characteristic lesions caused by different HPV genotypes are verruca vulgaris, condyloma acuminatum and focal epithelial hyperplasia.

Early life rhinovirus infection exacerbates house-dust-mite induced lung disease more severely in female mice.

PubMed

Phan, Jennifer A; Kicic, Anthony; Berry, Luke J; Sly, Peter D; Larcombe, Alexander N

2016-01-01

Recent studies have employed animal models to investigate links between rhinovirus infection and allergic airways disease, however, most do not involve early life infection, and none consider the effects of sex on responses. Here, we infected male and female mice with human rhinovirus 1B (or control) on day 7 of life. Mice were then subjected to 7 weeks of exposure to house-dust-mite prior to assessment of bronchoalveolar inflammation, serum antibodies, lung function, and responsiveness to methacholine. There were significant differences in responses between males and females in most outcomes. In males, chronic house-dust-mite exposure increased bronchoalveolar inflammation, house-dust-mite specific IgG1 and responsiveness of the lung parenchyma, however, there was no additional impact of rhinovirus infection. Conversely, in females, there were additive and synergistic effects of rhinovirus infection and house-dust-mite exposure on neutrophilia, airway resistance, and responsiveness of the lung parenchyma. We conclude that early life rhinovirus infection influences the development of house-dust-mite induced lung disease in female, but not male mice.

Update on bacterial pathogenesis in BRD.

PubMed

Confer, Anthony W

2009-12-01

Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, Mycoplasma bovis and Arcanobacterium pyogenes are all frequently implicated in bovine respiratory disease (BRD). M. haemolytica is considered the most important of the group. These bacteria are commensals in the nasopharynx and establish infection in the lungs of cattle that are subjected to a variety of stresses. Factors that permit adherence to and proliferation in the lungs and factors that cause tissue destruction and inflammation have been identified as having major roles in pathogenesis. These virulence factors include protein adhesins, capsular polysaccharide, outer membrane proteins, iron-binding proteins, lipopolysacharide or lipooligosaccharide, enzymes and toxins. These bacterial products function to evade the immune system, damage the immune system and induce a severe inflammatory response.

Serum sCD30: A promising biomarker for predicting the risk of bacterial infection after kidney transplantation.

PubMed

Fernández-Ruiz, Mario; Parra, Patricia; López-Medrano, Francisco; Ruiz-Merlo, Tamara; González, Esther; Polanco, Natalia; Origüen, Julia; San Juan, Rafael; Andrés, Amado; Aguado, José María

2017-04-01

The transmembrane glycoprotein CD30 contributes to regulate the balance between Th 1 and Th 2 responses. Previous studies have reported conflicting results on the utility of its soluble form (sCD30) to predict post-transplant infection. Serum sCD30 was measured by a commercial ELISA assay at baseline and post-transplant months 1, 3, and 6 in 100 kidney transplant (KT) recipients (279 monitoring points). The impact of sCD30 levels on the incidence of overall, bacterial and opportunistic infection during the first 12 months after transplantation was assessed by Cox regression. There were no differences in serum sCD30 according to the occurrence of overall or opportunistic infection. However, sCD30 levels were higher in patients with bacterial infection compared to those without at baseline (P=.038) and months 1 (P<.0001), 3 (P=.043), and 6 after transplantation (P=.006). Patients with baseline sCD30 levels ≥13.5 ng/mL had lower 12-month bacterial infection-free survival (35.0% vs 80.0%; P<.0001). After adjusting for potential confounders, baseline sCD30 levels ≥13.5 ng/mL remained as an independent risk factor for bacterial infection (adjusted hazard ratio [aHR]: 4.65; 95% confidence interval [CI]: 2.05-10.53; <.001). Analogously, sCD30 levels ≥6.0 ng/mL at month 1 acted as a risk factor for subsequent bacterial infection (aHR: 5.29; 95% CI: 1.11-25.14; P=.036). Higher serum sCD30 levels were associated with an increased risk of bacterial infection after KT. We hypothesize that this biomarker reflects a Th 2 -polarized T-cell response, which exerts a detrimental effect on the immunity against bacterial pathogens. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Ischaemia-modified albumin: a marker of bacterial infection in hospitalized patients with cirrhosis.

PubMed

Giannone, Ferdinando A; Domenicali, Marco; Baldassarre, Maurizio; Bartoletti, Michele; Naldi, Marina; Laggetta, Maristella; Bertucci, Carlo; Colecchia, Antonio; Viale, Pierluigi; Bernardi, Mauro; Caraceni, Paolo

2015-11-01

Patients with cirrhosis present structural changes of human serum albumin (HSA) affecting non-oncotic functions. Ischaemia-modified albumin (IMA), which reflects the capacity to bind cobalt, has been associated to patient mortality during acute-on-chronic liver failure. This study aimed to assess whether circulating IMA is elevated in advanced cirrhosis and its relationship with severity of cirrhosis and specific complications. A total of 127 cirrhotic patients hospitalized for an acute complication of the disease and 44 healthy controls were enrolled. Plasma IMA and IMA to albumin ratio (IMAr) were measured with a cobalt-binding assay. HSA isoforms carrying post-transcriptional molecular changes were assessed with HPLC-ESI-MS. The effect of endotoxemia on IMA was evaluated in rats with CCl4 -cirrhosis. IMA/IMAr is significantly higher in cirrhotic patients than in controls, but no correlations were found with prognostic scores. IMA did not correlate with the altered HSA isoforms. Ascites, renal impairment and hepatic encephalopathy did not influence IMA/IMAr levels. In contrast, IMA/IMAr is significantly higher in infected than non-infected patients. ROC curves showed that IMA/IMAr had similar discriminating performances for bacterial infection as C-reactive protein (CRP). Moreover, CRP and IMA were independently associated with bacterial infection. Consistently, endotoxin injection significantly increased IMA in cirrhotic, but not in healthy rats. IMA is elevated in patients with advanced cirrhosis. The IMA level does not correlate with disease severity scores, but it is specifically associated to bacterial infection, showing a discriminating performance similar to CRP. Further investigations to assess IMA as a novel diagnostic test for bacterial infection are advocated. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Detection of Intracellular Bacterial Communities in Human Urinary Tract Infection

PubMed Central

Rosen, David A; Hooton, Thomas M; Stamm, Walter E; Humphrey, Peter A; Hultgren, Scott J

2007-01-01

Background Urinary tract infections (UTIs) are one of the most common bacterial infections and are predominantly caused by uropathogenic Escherichia coli (UPEC). While UTIs are typically considered extracellular infections, it has been recently demonstrated that UPEC bind to, invade, and replicate within the murine bladder urothelium to form intracellular bacterial communities (IBCs). These IBCs dissociate and bacteria flux out of bladder facet cells, some with filamentous morphology, and ultimately establish quiescent intracellular reservoirs that can seed recurrent infection. This IBC pathogenic cycle has not yet been investigated in humans. In this study we sought to determine whether evidence of an IBC pathway could be found in urine specimens from women with acute UTI. Methods and Findings We collected midstream, clean-catch urine specimens from 80 young healthy women with acute uncomplicated cystitis and 20 asymptomatic women with a history of UTI. Investigators were blinded to culture results and clinical history. Samples were analyzed by light microscopy, immunofluorescence, and electron microscopy for evidence of exfoliated IBCs and filamentous bacteria. Evidence of IBCs was found in 14 of 80 (18%) urines from women with UTI. Filamentous bacteria were found in 33 of 80 (41%) urines from women with UTI. None of the 20 urines from the asymptomatic comparative group showed evidence of IBCs or filaments. Filamentous bacteria were present in all 14 of the urines with IBCs compared to 19 (29%) of 66 samples with no evidence of IBCs (p < 0.001). Of 65 urines from patients with E. coli infections, 14 (22%) had evidence of IBCs and 29 (45%) had filamentous bacteria, while none of the gram-positive infections had IBCs or filamentous bacteria. Conclusions The presence of exfoliated IBCs and filamentous bacteria in the urines of women with acute cystitis suggests that the IBC pathogenic pathway characterized in the murine model may occur in humans. The findings

Photodynamic antimicrobial chemotherapy using zinc phthalocyanine derivatives in treatment of bacterial skin infection

NASA Astrophysics Data System (ADS)

Chen, Zhuo; Zhang, Yaxin; Wang, Dong; Li, Linsen; Zhou, Shanyong; Huang, Joy H.; Chen, Jincan; Hu, Ping; Huang, Mingdong

2016-01-01

Photodynamic antimicrobial chemotherapy (PACT) is an effective method for killing bacterial cells in view of the increasing problem of multiantibiotic resistance. We herein reported the PACT effect on bacteria involved in skin infections using a zinc phthalocyanine derivative, pentalysine β-carbonylphthalocyanine zinc (ZnPc-Lys). Compared with its anionic ZnPc counterpart, ZnPc-Lys showed an enhanced antibacterial efficacy in vitro and in an animal model of localized infection. Meanwhile, ZnPc-Lys was observed to significantly reduce the wound skin blood flow during wound healing, indicating an anti-inflammation activity. This study provides new insight on the mechanisms of PACT in bacterial skin infection.

Effect of Advanced HIV Infection on the Respiratory Microbiome.

PubMed

Twigg, Homer L; Knox, Kenneth S; Zhou, Jin; Crothers, Kristina A; Nelson, David E; Toh, Evelyn; Day, Richard B; Lin, Huaiying; Gao, Xiang; Dong, Qunfeng; Mi, Deming; Katz, Barry P; Sodergren, Erica; Weinstock, George M

2016-07-15

Previous work found the lung microbiome in healthy subjects infected with HIV was similar to that in uninfected subjects. We hypothesized the lung microbiome from subjects infected with HIV with more advanced disease would differ from that of an uninfected control population. To measure the lung microbiome in an HIV-infected population with advanced disease. 16s RNA gene sequencing was performed on acellular bronchoalveolar lavage (BAL) fluid from 30 subjects infected with HIV with advanced disease (baseline mean CD4 count, 262 cells/mm(3)) before and up to 3 years after starting highly active antiretroviral therapy (HAART) and compared with 22 uninfected control subjects. The lung microbiome in subjects infected with HIV with advanced disease demonstrated decreased alpha diversity (richness and diversity) and greater beta diversity compared with uninfected BAL. Differences improved with HAART, but still persisted up to 3 years after starting therapy. Population dispersion in the group infected with HIV was significantly greater than in the uninfected cohort and declined after treatment. There were differences in the relative abundance of some bacteria between the two groups at baseline and after 1 year of therapy. After 1 year on HAART, HIV BAL contained an increased abundance of Prevotella and Veillonella, bacteria previously associated with lung inflammation. The lung microbiome in subjects infected with HIV with advanced disease is altered compared with an uninfected population both in diversity and bacterial composition. Differences remain up to 3 years after starting HAART. We speculate an altered lung microbiome in HIV infection may contribute to chronic inflammation and lung complications seen in the HAART era.

Microbiome in the pathogenesis of cystic fibrosis and lung transplant-related disease.

PubMed

Cribbs, Sushma K; Beck, James M

2017-01-01

Significant advances in culture-independent methods have expanded our knowledge about the diversity of the lung microbial environment. Complex microorganisms and microbial communities can now be identified in the distal airways in a variety of respiratory diseases, including cystic fibrosis (CF) and the posttransplantation lung. Although there are significant methodologic concerns about sampling the lung microbiome, several studies have now shown that the microbiome of the lower respiratory tract is distinct from the upper airway. CF is a disease characterized by chronic airway infections that lead to significant morbidity and mortality. Traditional culture-dependent methods have identified a select group of pathogens that cause exacerbations in CF, but studies using bacterial 16S rRNA gene-based microarrays have shown that the CF microbiome is an intricate and dynamic bacterial ecosystem, which influences both host immune health and disease pathogenesis. These microbial communities can shift with external influences, including antibiotic exposure. In addition, there have been a number of studies suggesting a link between the gut microbiome and respiratory health in CF. Compared with CF, there is significantly less knowledge about the microbiome of the transplanted lung. Risk factors for bronchiolitis obliterans syndrome, one of the leading causes of death, include microbial infections. Lung transplant patients have a unique lung microbiome that is different than the pretransplanted microbiome and changes with time. Understanding the host-pathogen interactions in these diseases may suggest targeted therapies and improve long-term survival in these patients. Published by Elsevier Inc.

Description of Bacterial Respiratory Infections among Department of Defense Beneficiaries, Utilizing Electronic Clinical Laboratory Data, October 2008-September 2013

DTIC Science & Technology

2014-08-01

i Description of bacterial respiratory infections among Department of Defense beneficiaries, utilizing electronic clinical laboratory...Description of Bacterial Respiratory Infections in the DOD, October 2008-September 2013 Prepared: 12 July 2014 EpiData Center Department ii...Description of Bacterial Respiratory Infections in the DOD, October 2008-September 2013 Prepared: 12 July 2014 EpiData Center Department Abstract

Lung granulomatous response induced by infection with the intestinal nematode Nippostrongylusbrasiliensis is suppressed in mast cell-deficient Ws/Ws rats

PubMed Central

ARIZONO, N; NISHIDA, M; UCHIKAWA, R; YAMADA, M; MATSUDA, S; TEGOSHI, T; KITAMURA, Y; SASABE, M

1996-01-01

Certain nematode infections induce eosinophil infiltration and granulomatous responses in the lungs. To examine the role of mast cells in the development of lung lesions, normal +/+ and genetically mast cell-deficient Ws/Ws rats were infected with the nematode Nippostrongylusbrasiliensis. In +/+ rats, numbers of eosinophils in bronchoalveolar lavage fluid (BALF) increased significantly 3–7 days after infection, and granulomatous responses composed of histiocytes/macrophages and multinucleate giant cells were triggered in the lungs 3–14 days after infection. Challenge infection, which was carried out on day 28 after primary infection, induced much higher levels of granulomatous response than after primary infection, suggesting that the response is mediated at least in part by an immunological mechanism. In Ws/Ws rats, both the eosinophil percentage in BALF and the size of the granulomas in the lungs were significantly smaller than in +/+ rats after primary as well as after challenge infection. The amount of rat mast cell protease (RMCP) II in +/+ rat BALF was increased 1 day after primary infection and more significantly after challenge infection, suggesting that lung mucosal mast cells were activated more markedly after the challenge infection. In Ws/Ws rats, RMCP II was undetectable throughout the observation period. The time course of nematode migration in the lungs did not differ in +/+ and Ws/Ws rats. These results suggest that mast cell activation might be relevant to eosinophil infiltration and granulomatous response in the lungs, although the responses do not affect lung migration of the nematode. PMID:8870698

PvdQ Quorum Quenching Acylase Attenuates Pseudomonas aeruginosa Virulence in a Mouse Model of Pulmonary Infection

PubMed Central

Utari, Putri D.; Setroikromo, Rita; Melgert, Barbro N.; Quax, Wim J.

2018-01-01

Pseudomonas aeruginosa is the predominant pathogen in pulmonary infections associated with cystic fibrosis. Quorum sensing (QS) systems regulate the production of virulence factors and play an important role in the establishment of successful P. aeruginosa infections. Inhibition of the QS system (termed quorum quenching) renders the bacteria avirulent thus serving as an alternative approach in the development of novel antibiotics. Quorum quenching in Gram negative bacteria can be achieved by preventing the accumulation of N-acyl homoserine lactone (AHL) signaling molecule via enzymatic degradation. Previous work by us has shown that PvdQ acylase hydrolyzes AHL signaling molecules irreversibly, thereby inhibiting QS in P. aeruginosa in vitro and in a Caenorhabditis elegans model of P. aeruginosa infection. The aim of the present study is to assess the therapeutic efficacy of intranasally instilled PvdQ acylase in a mouse model of pulmonary P. aeruginosa infection. First, we evaluated the deposition pattern of intranasally administered fluorochrome-tagged PvdQ (PvdQ-VT) in mice at different stages of pulmonary infection by in vivo imaging studies. Following intranasal instillation, PvdQ-VT could be traced in all lung lobes with 42 ± 7.5% of the delivered dose being deposited at 0 h post-bacterial-infection, and 34 ± 5.2% at 72 h post bacterial-infection. We then treated mice with PvdQ during lethal P. aeruginosa pulmonary infection and that resulted in a 5-fold reduction of lung bacterial load and a prolonged survival of the infected animals with the median survival time of 57 hin comparison to 42 h for the PBS-treated group. In a sublethal P. aeruginosa pulmonary infection, PvdQ treatment resulted in less lung inflammation as well as decrease of CXCL2 and TNF-α levels at 24 h post-bacterial-infection by 15 and 20%, respectively. In conclusion, our study has shown therapeutic efficacy of PvdQ acylase as a quorum quenching agent during P. aeruginosa infection. PMID

Epidemiology and aetiology of maternal bacterial and viral infections in low- and middle-income countries

PubMed Central

Velu, Prasad Palani; Gravett, Courtney A.; Roberts, Tom K.; Wagner, Thor A.; Zhang, Jian Shayne F.; Rubens, Craig E.; Gravett, Michael G.; Campbell, Harry; Rudan, Igor

2011-01-01

Background Maternal morbidity and mortality in low- and middle-income countries has remained exceedingly high. However, information on bacterial and viral maternal infections, which are important contributors to poor pregnancy outcomes, is sparse and poorly characterised. This review aims to describe the epidemiology and aetiology of bacterial and viral maternal infections in low- and middle-income countries. Methods A systematic search of published literature was conducted and data on aetiology and epidemiology of maternal infections was extracted from relevant studies for analysis. Searches were conducted in parallel by two reviewers (using OVID) in the following databases: Medline (1950 to 2010), EMBASE (1980 to 2010) and Global Health (1973 to 2010). Results Data from 158 relevant studies was used to characterise the epidemiology of the 10 most extensively reported maternal infections with the following median prevalence rates: Treponema pallidum (2.6%), Neisseria gonorrhoeae (1.5%), Chlamydia trachomatis (5.8%), Group B Streptococcus (8.6%), bacterial vaginosis (20.9%), hepatitis B virus (4.3%), hepatitis C virus (1.4%), Cytomegalovirus (95.7% past infection), Rubella (8.9% susceptible) and Herpes simplex (20.7%). Large variations in the prevalence of these infections between countries and regions were noted. Conclusion This review confirms the suspected high prevalence of maternal bacterial and viral infections and identifies particular diseases and regions requiring urgent attention in public health policy planning, setting research priorities and donor funding towards reducing maternal morbidity and mortality in low- and middle-income countries. PMID:23198117

Pulmonary infections and risk of lung cancer among persons with AIDS.

PubMed

Shebl, Fatma M; Engels, Eric A; Goedert, James J; Chaturvedi, Anil K

2010-11-01

Lung cancer risk is significantly increased among persons with AIDS (PWA), and increased smoking may not explain all of the elevated risk, suggesting a role for additional cofactors. We investigated whether AIDS-defining pulmonary infections (recurrent pneumonia, Pneumocystis jirovecii pneumonia, and pulmonary tuberculosis) affected the risk of subsequent lung cancer over 10 years after AIDS onset among 322,675 PWA, whose records were linked with cancer registries in 11 US regions. We assessed lung cancer hazard ratios (HRs) using Cox regression and indirectly adjusted HRs for confounding by smoking. Individuals with recurrent pneumonia (n = 5317) were at significantly higher lung cancer risk than those without [HR = 1.63, 95% confidence interval (CI) = 1.08 to 2.46, adjusted for age, race, sex, HIV acquisition mode, CD4 count, and AIDS diagnosis year]. This association was especially strong among young PWA (<50 years HR = 1.99 vs. ≥50 years HR = 1.10) and was significantly elevated during 5-10 years after recurrent pneumonia diagnosis (HR = 2.41; 95% CI = 1.07 to 5.47). Although attenuated, HRs for recurrent pneumonia remained nonsignificantly elevated after indirect adjustment for smoking. Lung cancer risk was unrelated to tuberculosis [(n = 13,878) HR = 1.12, 95% CI = 0.82 to 1.53] or Pneumocystis jirovecii pneumonia [(n = 69,771) HR = 0.97, 95% CI = 0.80 to 1.18]. The increased lung cancer risk associated with recurrent pneumonia supports the hypothesis that chronic pulmonary inflammation arising from infections contributes to lung carcinogenesis.

Lack of Accuracy of Body Temperature for Detecting Serious Bacterial Infection in Febrile Episodes.

PubMed

De, Sukanya; Williams, Gabrielle J; Teixeira-Pinto, Armando; Macaskill, Petra; McCaskill, Mary; Isaacs, David; Craig, Jonathan C

2015-09-01

Body temperature is a time-honored marker of serious bacterial infection, but there are few studies of its test performance. The aim of our study was to determine the accuracy of temperature measured on presentation to medical care for detecting serious bacterial infection. Febrile children 0-5 years of age presenting to the emergency department of a tertiary care pediatric hospital were sampled consecutively. The accuracy of the axillary temperature measured at presentation was evaluated using logistic regression models to generate receiver operating characteristic curves. Reference standard tests for serious bacterial infection were standard microbiologic/radiologic tests and clinical follow-up. Age, clinicians' impression of appearance of the child (well versus unwell) and duration of illness were assessed as possible effect modifiers. Of 15,781 illness episodes 1120 (7.1%) had serious bacterial infection. The area under the receiver operating characteristic curve for temperature was 0.60 [95% confidence intervals (CI): 0.58-0.62]. A threshold of ≥ 38°C had a sensitivity of 0.67 (95% CI: 0.64-0.70), specificity of 0.45 (95% CI: 0.44-0.46), positive likelihood ratio of 1.2 (95% CI: 1.2-1.3) and negative likelihood ratio of 0.7 (95% CI: 0.7-0.8). Age and illness duration had a small but significant effect on the accuracy of temperature increasing its "rule-in" potential. Measured temperature at presentation to hospital is not an accurate marker of serious bacterial infection in febrile children. Younger age and longer duration of illness increase the rule-in potential of temperature but without substantial overall change in its test accuracy.

Cytomegalovirus infections in lung and hematopoietic cell transplant recipients in the Organ Transplant Infection Prevention and Detection Study: A multi-year, multicenter prospective cohort study.

PubMed

Avery, Robin K; Silveira, Fernanda P; Benedict, Kaitlin; Cleveland, Angela A; Kauffman, Carol A; Schuster, Mindy G; Dubberke, Erik R; Husain, Shahid; Paterson, David L; Chiller, Tom; Pappas, Peter

2018-03-07

Most studies of post-transplant CMV infection have focused on either solid organ or hematopoietic cell transplant (HCT) recipients. A large prospective cohort study involving both lung and HCT recipients provided an opportunity to compare the epidemiology and outcomes of CMV infections in these 2 groups. Patients were followed up for 30 months in a 6-center prospective cohort study. Data on demographics, CMV infections, tissue-invasive disease, recurrences, rejection, and immunosuppression were recorded. The overall incidence of CMV infection was 83/293 (28.3%) in the lung transplant group and 154/444 (34.7%) in the HCT group (P = .0706). Tissue-invasive CMV disease occurred in 8/83 (9.6%) of lung and 6/154 (3.9%) of HCT recipients with CMV infection, respectively (P = .087). Median time to CMV infection was longer in the lung transplant group (236 vs 40 days, P < .0001), likely reflecting the effects of prophylaxis vs preemptive therapy. Total IgG levels of < 350 mg/dL in lung recipients and graft vs host disease (GvHD) in HCT recipients were associated with increased CMV risk. HCT recipients had a higher mean number of CMV episodes (P = .008), although duration of viremia was not significantly different between the 2 groups. CMV infection was not associated with reduced overall survival in either group. Current CMV prevention strategies have resulted in a low incidence of tissue-invasive disease in both lung transplant and HCT, although CMV viremia is still relatively common. Differences between the lung and HCT groups in terms of time to CMV and recurrences of CMV viremia likely reflect differences in underlying host immunobiology and in CMV prevention strategies in the modern era. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pseudomonas aeruginosa proteolytically alters the interleukin 22-dependent lung mucosal defense.

PubMed

Guillon, Antoine; Brea, Deborah; Morello, Eric; Tang, Aihua; Jouan, Youenn; Ramphal, Reuben; Korkmaz, Brice; Perez-Cruz, Magdiel; Trottein, Francois; O'Callaghan, Richard J; Gosset, Philippe; Si-Tahar, Mustapha

2017-08-18

The IL-22 signaling pathway is critical for regulating mucosal defense and limiting bacterial dissemination. IL-22 is unusual among interleukins because it does not directly regulate the function of conventional immune cells, but instead targets cells at outer body barriers, such as respiratory epithelial cells. Consequently, IL-22 signaling participates in the maintenance of the lung mucosal barrier by controlling cell proliferation and tissue repair, and enhancing the production of specific chemokines and anti-microbial peptides. Pseudomonas aeruginosa is a major pathogen of ventilator-associated pneumonia and causes considerable lung tissue damage. A feature underlying the pathogenicity of this bacterium is its capacity to persist and develop in the host, particularly in the clinical context of nosocomial lung infections. We aimed to investigate the ability of P. auruginosa to disrupt immune-epithelial cells cross-talk. We found that P. aeruginosa escapes the host mucosal defenses by degrading IL-22, leading to severe inhibition of IL-22-mediated immune responses. We demonstrated in vitro that, protease IV, a type 2 secretion system-dependent serine protease, is responsible for the degradation of IL-22 by P. aeruginosa. Moreover, the major anti-proteases molecules present in the lungs were unable to inhibit protease IV enzymatic activity. In addition, tracheal aspirates of patients infected by P. aeruginosa contain protease IV activity which further results in IL-22 degradation. This so far undescribed cleavage of IL-22 by a bacterial protease is likely to be an immune-evasion strategy that contributes to P. aeruginosa-triggered respiratory infections.

Myeloid-Derived Suppressor Cells in Bacterial Infections

PubMed Central

Ost, Michael; Singh, Anurag; Peschel, Andreas; Mehling, Roman; Rieber, Nikolaus; Hartl, Dominik

2016-01-01

Myeloid-derived suppressor cells (MDSCs) comprise monocytic and granulocytic innate immune cells with the capability of suppressing T- and NK-cell responses. While the role of MDSCs has been studied in depth in malignant diseases, the understanding of their regulation and function in infectious disease conditions has just begun to evolve. Here we summarize and discuss the current view how MDSCs participate in bacterial infections and how this knowledge could be exploited for potential future therapeutics. PMID:27066459

Bacterial infections of Chinook salmon, Oncorhynchus tshawytscha (Walbaum), returning to gamete collecting weirs in Michigan.

PubMed

Loch, T P; Scribner, K; Tempelman, R; Whelan, G; Faisal, M

2012-01-01

Herein, we describe the prevalence of bacterial infections in Chinook salmon, Oncorhynchus tshawytscha (Walbaum), returning to spawn in two tributaries within the Lake Michigan watershed. Ten bacterial genera, including Renibacterium, Aeromonas, Carnobacterium, Serratia, Proteus, Pseudomonas, Hafnia, Salmonella, Shewanella and Morganella, were detected in the kidneys of Chinook salmon (n = 480) using culture, serological and molecular analyses. Among these, Aeromonas salmonicida was detected at a prevalence of ∼15%. Analyses revealed significant interactions between location/time of collection and gender for these infections, whereby overall infection prevalence increased greatly later in the spawning run and was significantly higher in females. Renibacterium salmoninarum was detected in fish kidneys at an overall prevalence of >25%. Logistic regression analyses revealed that R. salmoninarum prevalence differed significantly by location/time of collection and gender, with a higher likelihood of infection later in the spawning season and in females vs. males. Chi-square analyses quantifying non-independence of infection by multiple pathogens revealed a significant association between R. salmoninarum and motile aeromonad infections. Additionally, greater numbers of fish were found to be co-infected by multiple bacterial species than would be expected by chance alone. The findings of this study suggest a potential synergism between bacteria infecting spawning Chinook salmon. © 2011 Blackwell Publishing Ltd.

Bacterial pneumonia, HIV therapy, and disease progression among HIV-infected women in the HIV epidemiologic research (HER) study.

PubMed

Kohli, Rakhi; Lo, Yungtai; Homel, Peter; Flanigan, Timothy P; Gardner, Lytt I; Howard, Andrea A; Rompalo, Anne M; Moskaleva, Galina; Schuman, Paula; Schoenbaum, Ellie E

2006-07-01

To determine the rate and predictors of community-acquired bacterial pneumonia and its effect on human immunodeficiency virus (HIV) disease progression in HIV-infected women, we performed a multiple-site, prospective study of HIV-infected women in 4 cities in the United States. During the period of 1993-2000, we observed 885 HIV-infected and 425 HIV-uninfected women with a history of injection drug use or high-risk sexual behavior. Participants underwent semiannual interviews, and CD4+ lymphocyte count and viral load were assessed in HIV-infected subjects. Data regarding episodes of bacterial pneumonia were ascertained from medical record reviews. The rate of bacterial pneumonia among 885 HIV-infected women was 8.5 cases per 100 person-years, compared with 0.7 cases per 100 person-years in 425 HIV-uninfected women (P < .001). In analyses limited to follow-up after 1 January 1996, highly active antiretroviral therapy (HAART) and trimethoprim-sulfamethoxazole (TMP-SMX) use were associated with a decreased risk of bacterial pneumonia. Among women who had used TMP-SMX for 12 months, each month of HAART decreased bacterial pneumonia risk by 8% (adjusted hazard ratio [HR(adj)], 0.92; 95% confidence interval [CI], 0.89-0.95). Increments of 50 CD4+ cells/mm3 decreased the risk (HR(adj), 0.88; 95% CI, 0.84-0.93), and smoking doubled the risk (HR(adj), 2.12; 95% CI, 1.26-3.55). Bacterial pneumonia increased mortality risk (HR(adj), 5.02; 95% CI, 2.12-11.87), with adjustment for CD4+ lymphocyte count and duration of HAART and TMP-SMX use. High rates of bacterial pneumonia persist among HIV-infected women. Although HAART and TMP-SMX treatment decreased the risk, bacterial pneumonia was associated with an accelerated progression to death. Interventions that improve HAART utilization and promote smoking cessation among HIV-infected women are warranted.

Antibiofilm and Anti-Infection of a Marine Bacterial Exopolysaccharide Against Pseudomonas aeruginosa

PubMed Central

Wu, Shimei; Liu, Ge; Jin, Weihua; Xiu, Pengyuan; Sun, Chaomin

2016-01-01

Pseudomonas aeruginosa is a well-known pathogenic bacterium that forms biofilms and produces virulence factors, thus leading to major problems in many fields, such as clinical infection, food contamination, and marine biofouling. In this study, we report the purification and characterization of an exopolysaccharide EPS273 from the culture supernatant of marine bacterium P. stutzeri 273. The exopolysaccharide EPS273 not only effectively inhibits biofilm formation but also disperses preformed biofilm of P. aeruginosa PAO1. High performance liquid chromatography traces of the hydrolyzed polysaccharides shows that EPS273 primarily consists of glucosamine, rhamnose, glucose and mannose. Further investigation demonstrates that EPS273 reduces the production of the virulence factors pyocyanin, exoprotease, and rhamnolipid, and the virulence of P. aeruginosa PAO1 to human lung cells A549 and zebrafish embryos is also obviously attenuated by EPS273. In addition, EPS273 also greatly reduces the production of hydrogen peroxide (H2O2) and extracellular DNA (eDNA), which are important factors for biofilm formation. Furthermore, EPS273 exhibits strong antioxidant potential by quenching hydroxyl and superoxide anion radicals. Notably, the antibiofouling activity of EPS273 is observed in the marine environment up to 2 weeks according to the amounts of bacteria and diatoms in the glass slides submerged in the ocean. Taken together, the properties of EPS273 indicate that it has a promising prospect in combating bacterial biofilm-associated infection, food-processing contamination and marine biofouling. PMID:26903981

Immunological and infectious risk factors for lung cancer in US veterans with HIV: a longitudinal cohort study.

PubMed

Sigel, Keith; Wisnivesky, Juan; Crothers, Kristina; Gordon, Kirsha; Brown, Sheldon T; Rimland, David; Rodriguez-Barradas, Maria C; Gibert, Cynthia; Goetz, Matthew Bidwell; Bedimo, Roger; Park, Lesley S; Dubrow, Robert

2017-02-01

HIV infection is independently associated with risk of lung cancer, but few data exist for the relation between longitudinal measurements of immune function and lung-cancer risk in people living with HIV. We followed up participants with HIV from the Veterans Aging Cohort Study for a minimum of 3 years between Jan 1, 1998, and Dec 31, 2012, and used cancer registry data to identify incident cases of lung cancer. The index date for each patient was the later of the date HIV care began or Jan 1, 1998. We excluded patients with less than 3 years' follow-up, prevalent diagnoses of lung cancer, or incomplete laboratory data. We used Cox regression models to investigate the relation between different time-updated lagged and cumulative exposures (CD4 cell count, CD8 cell count, CD4/CD8 ratio, HIV RNA, and bacterial pneumonia) and risk of lung cancer. Models were adjusted for age, race or ethnicity, smoking, hepatitis C virus infection, alcohol use disorders, drug use disorders, and history of chronic obstructive pulmonary disease and occupational lung disease. We identified 277 cases of incident lung cancer in 21 666 participants with HIV. In separate models for each time-updated 12 month lagged, 24 month simple moving average cumulative exposure, increased risk of lung cancer was associated with low CD4 cell count (p trend=0·001), low CD4/CD8 ratio (p trend=0·0001), high HIV RNA concentration (p=0·004), and more cumulative bacterial pneumonia episodes (12 month lag only; p trend=0·0004). In a mutually adjusted model including these factors, CD4/CD8 ratio and cumulative bacterial pneumonia episodes remained significant (p trends 0·003 and 0·004, respectively). In our large HIV cohort in the antiretroviral therapy era, we found evidence that dysfunctional immune activation and chronic inflammation contribute to the development of lung cancer in the setting of HIV infection. These findings could be used to target lung-cancer prevention measures to high-risk groups

Rapid detection of Mannheimia haemolytica in lung tissues of sheep and from bacterial culture.

PubMed

Kumar, Jyoti; Dixit, Shivendra Kumar; Kumar, Rajiv

2015-09-01

This study was aimed to detect Mannheimia haemolytica in lung tissues of sheep and from a bacterial culture. M. haemolytica is one of the most important and well-established etiological agents of pneumonia in sheep and other ruminants throughout the world. Accurate diagnosis of M. haemolytica primarily relies on bacteriological examination, biochemical characteristics and, biotyping and serotyping of the isolates. In an effort to facilitate rapid M. haemolytica detection, polymerase chain reaction assay targeting Pasteurella haemolytica serotype-1 specific antigens (PHSSA), Rpt2 and 12S ribosomal RNA (rRNA) genes were used to detect M. haemolytica directly from lung tissues and from bacterial culture. A total of 12 archived lung tissues from sheep that died of pneumonia on an organized farm were used. A multiplex polymerase chain reaction (mPCR) based on two-amplicons targeted PHSSA and Rpt2 genes of M. haemolytica were used for identification of M. haemolytica isolates in culture from the lung samples. All the 12 lung tissue samples were tested for the presence M. haemolytica by PHSSA and Rpt2 genes based PCR and its confirmation by sequencing of the amplicons. All the 12 lung tissue samples tested for the presence of PHSSA and Rpt2 genes of M. haemolytica by mPCR were found to be positive. Amplification of 12S rRNA gene fragment as internal amplification control was obtained with each mPCR reaction performed from DNA extracted directly from lung tissue samples. All the M. haemolytica were also positive for mPCR. No amplified DNA bands were observed for negative control reactions. All the three nucleotide sequences were deposited in NCBI GenBank (Accession No. KJ534629, KJ534630 and KJ534631). Sequencing of the amplified products revealed the identity of 99-100%, with published sequence of PHSSA and Rpt2 genes of M. haemolytica available in the NCBI database. Sheep specific mitochondrial 12S rRNA gene sequence also revealed the identity of 98% with published

Common bacterial urinary tract infections in women.

PubMed

Cimino, J E

1976-09-01

Unfortunately, there is no general consensus as to how long patients with bacteriuria or urinary tract infections should be monitored and certainly there is no agreement on how long recurrent episodes should be treated beyond ten days to two weeks. The most important points to remember are: 1. Culture the urine both at the time of therapy and during follow-up. The patient should be examined periodically for the presence of bacteruria. If bacteria cannot be eradicated, at least the physician is aware of the organism most likely causing the patient's symptoms. 2. Do not subject the patient with frequent recurrent (chronic) and complicated infections to continual antibacterial therapy, but rather, manage the acute episodes. 3. Use prophylaxis, particularly single bed-time doses for dysuria and frequency symptoms. 4. Screen for bacteriuria during pregnancy. 5. Avoid the use of catheters except where absolutely necessary. 6. Avoid systemic prophylaxis of infection in patients with catheters; rather, use closed-system drainage with antibacteri-irrigation. It is to be hoped within the next few years, studies now underway will allow specific recommendations regarding the management of asymptomatic bacteruria, the duration of therapy for recurrent infections, the prevention and treatment of L-form bacterial infections, and indications for urologic procedures.

Transcriptome profile of lung dendritic cells after in vitro porcine reproductive and respiratory syndrome virus (PRRSV) infection

PubMed Central

Pröll, Maren Julia; Neuhoff, Christiane; Schellander, Karl; Uddin, Muhammad Jasim; Cinar, Mehmet Ulas; Sahadevan, Sudeep; Qu, Xueqi; Islam, Md. Aminul; Poirier, Mikhael; Müller, Marcel A.; Drosten, Christian; Tesfaye, Dawit; Tholen, Ernst; Große-Brinkhaus, Christine

2017-01-01

The porcine reproductive and respiratory syndrome (PRRS) is an infectious disease that leads to high financial and production losses in the global swine industry. The pathogenesis of this disease is dependent on a multitude of factors, and its control remains problematic. The immune system generally defends against infectious diseases, especially dendritic cells (DCs), which play a crucial role in the activation of the immune response after viral infections. However, the understanding of the immune response and the genetic impact on the immune response to PRRS virus (PRRSV) remains incomplete. In light of this, we investigated the regulation of the host immune response to PRRSV in porcine lung DCs using RNA-sequencing (RNA-Seq). Lung DCs from two different pig breeds (Pietrain and Duroc) were collected before (0 hours) and during various periods of infection (3, 6, 9, 12, and 24 hours post infection (hpi)). RNA-Seq analysis revealed a total of 20,396 predicted porcine genes, which included breed-specific differentially expressed immune genes. Pietrain and Duroc infected lung DCs showed opposite gene expression courses during the first time points post infection. Duroc lung DCs reacted more strongly and distinctly than Pietrain lung DCs during these periods (3, 6, 9, 12 hpi). Additionally, cluster analysis revealed time-dependent co-expressed groups of genes that were involved in immune-relevant pathways. Key clusters and pathways were identified, which help to explain the biological and functional background of lung DCs post PRRSV infection and suggest IL-1β1 as an important candidate gene. RNA-Seq was also used to characterize the viral replication of PRRSV for each breed. PRRSV was able to infect and to replicate differently in lung DCs between the two mentioned breeds. These results could be useful in investigations on immunity traits in pig breeding and enhancing the health of pigs. PMID:29140992

Profile of cytokines in the lungs of BALB/c mice after intra-nasal infection with Histoplasma capsulatum mycelial propagules.

PubMed

Sahaza, Jorge Humberto; Suárez-Alvarez, Roberto; Estrada-Bárcenas, Daniel Alfonso; Pérez-Torres, Armando; Taylor, Maria Lucia

2015-08-01

The host pulmonary response to the fungus Histoplasma capsulatum was evaluated, through the profile of cytokines detected by the MagPix magnetic beads platform in lung homogenates and by lung-granulomas formation, from mice intra-nasally infected with mycelial propagules (M-phase) of two virulent H. capsulatum strains, EH-46 and G-217B. Results highlight that mice lung inflammatory response depends on the H. capsulatum strain used, during the first step of the fungal infection. IL-1β and TNF-α increased their concentrations in mice infected with both strains. The highest levels of IL-6, IL-17, and IL-23 were found in EH-46-infected mice, whereas levels of IL-22 were variable at all post-infection times for both strains. Significant increases of IL-12, IFN-γ, IL-4, and IL-10 were associated to EH-46-infected mice. Histological lung findings from EH-46-infected mice revealed incipient and numerous well-developed granulomas, distributed in lung-lobes at the 14th and the 21st days after infection, according to cytokine profiles. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cyclic AMP-Elevating Capacity of Adenylate Cyclase Toxin-Hemolysin Is Sufficient for Lung Infection but Not for Full Virulence of Bordetella pertussis

PubMed Central

Skopova, Karolina; Tomalova, Barbora; Kanchev, Ivan; Rossmann, Pavel; Svedova, Martina; Adkins, Irena; Bibova, Ilona; Tomala, Jakub; Masin, Jiri; Guiso, Nicole; Osicka, Radim; Sedlacek, Radislav; Kovar, Marek

2017-01-01

ABSTRACT The adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) of Bordetella pertussis targets phagocytic cells expressing the complement receptor 3 (CR3, Mac-1, αMβ2 integrin, or CD11b/CD18). CyaA delivers into cells an N-terminal adenylyl cyclase (AC) enzyme domain that is activated by cytosolic calmodulin and catalyzes unregulated conversion of cellular ATP into cyclic AMP (cAMP), a key second messenger subverting bactericidal activities of phagocytes. In parallel, the hemolysin (Hly) moiety of CyaA forms cation-selective hemolytic pores that permeabilize target cell membranes. We constructed the first B. pertussis mutant secreting a CyaA toxin having an intact capacity to deliver the AC enzyme into CD11b-expressing (CD11b+) host phagocytes but impaired in formation of cell-permeabilizing pores and defective in cAMP elevation in CD11b− cells. The nonhemolytic AC+ Hly− bacteria inhibited the antigen-presenting capacities of coincubated mouse dendritic cells in vitro and skewed their Toll-like receptor (TLR)-triggered maturation toward a tolerogenic phenotype. The AC+ Hly− mutant also infected mouse lungs as efficiently as the parental AC+ Hly+ strain. Hence, elevation of cAMP in CD11b− cells and/or the pore-forming capacity of CyaA were not required for infection of mouse airways. The latter activities were, however, involved in bacterial penetration across the epithelial layer, enhanced neutrophil influx into lung parenchyma during sublethal infections, and the exacerbated lung pathology and lethality of B. pertussis infections at higher inoculation doses (>107 CFU/mouse). The pore-forming activity of CyaA further synergized with the cAMP-elevating activity in downregulation of major histocompatibility complex class II (MHC-II) molecules on infiltrating myeloid cells, likely contributing to immune subversion of host defenses by the whooping cough agent. PMID:28396322

[Bacterial drug resistance and etiology of non-complicated urinary tract infections].

PubMed

Chávez-Valencia, Venice; Gallegos-Nava, Selma; Arce-Salinas, C Alejandro

2010-01-01

Bacterial resistance to antibiotics is associated with morbidity, mortality, and an increase in cost. Our objective was to assess bacterial resistance from cultures of patients with non-complicated urinary tract infection (UTI). We analyzed antibiotic resistance using the VITEK-II system among patients attending the internal medicine unit with non-complicated UTI. 1,479 urine cultures were performed; we excluded: 98 due to contamination, 924 had no bacterial growth, and 57 had missing data. Among the 404 samples that were positive, 240 were found among out patients and 164 among hospitalized patients. E coli were the most frequent pathogen, followed by Enterococcus, and K pneumonia, in out patients; E coli, P aeruginosa, and fungal infections (23% of cases) in hospitalized patients. Samples with E coli among out patients displayed resistance of 50% to fluoroquinolones and 55% to sulfas. Among hospitalized patients, resistance was observed in 71 and 66% respectively. Resistance to P aeruginosa was 38% for amynoglucosides and carbapenems and 100% for piperacillin; Enterococcus had 50% for fluoroquinolones. E. coli is the most common pathogen among UTI patients. We must adapt guidelines to recommend antibiotics and design a comprehensive control program to reduce the high levels of bacterial antibiotic resistance among our population.

Benefits and harms of lung cancer screening in HIV-infected individuals with CD4+ ≥ 500: a simulation study.

PubMed

Kong, Chung Yin; Sigel, Keith; Criss, Steven D; Sheehan, Deirdre F; Triplette, Matthew; Silverberg, Michael J; Henschke, Claudia I; Justice, Amy; Braithwaite, R Scott; Wisnivesky, Juan; Crothers, Kristina

2018-04-19

Lung cancer is the leading cause of non-AIDS-defining cancer deaths among HIV-infected individuals. Although lung cancer screening with low-dose computed tomography (LDCT) is endorsed by multiple national organizations, whether HIV-infected individuals would have similar benefit as uninfected individuals from lung cancer screening is unknown. Our objective was to determine the benefits and harms of lung cancer screening among HIV-infected individuals. We modified an existing simulation model, the Lung Cancer Policy Model, for HIV-infected patients. Veterans Aging Cohort Study, Kaiser Permanente Northern California HIV Cohort, and medical literature. Target population: HIV-infected current and former smokers. Lifetime. Population. Annual LDCT screening from ages 45, 50, or 55 until ages 72 or 77 years. Benefits assessed included lung cancer mortality reduction and life-years gained; harms assessed included numbers of LDCT examinations, false-positive results, and overdiagnosed cases. For HIV-infected patients with CD4 at least 500 and 100% antiretroviral therapy adherence, screening using the Centers for Medicare & Medicaid Services criteria (age 55-77, 30 pack-years of smoking, current smoker or quit within 15 years of screening) would reduce lung cancer mortality by 18.9%, similar to the mortality reduction of uninfected individuals. Alternative screening strategies utilizing lower screening age and/or pack-years criteria increase mortality reduction, but require more LDCT examinations. Strategies assumed 100% screening adherence. Lung cancer screening reduces mortality in HIV-infected patients with CD4 at least l500, with a number of efficient strategies for eligibility, including the current Centers for Medicare & Medicaid Services criteria.

Prophylactic Administration of Bacterially Derived Immunomodulators Improves the Outcome of Influenza Virus Infection in a Murine Model▿

PubMed Central

Norton, Elizabeth B.; Clements, John D.; Voss, Thomas G.; Cárdenas-Freytag, Lucia

2010-01-01

Prophylactic or therapeutic immunomodulation is an antigen-independent strategy that induces nonspecific immune system activation, thereby enhancing host defense to disease. In this study, we investigated the effect of prophylactic immunomodulation on the outcome of influenza virus infection using three bacterially derived immune-enhancing agents known for promoting distinct immunological profiles. BALB/c mice were treated nasally with either cholera toxin (CT), a mutant form of the CT-related Escherichia coli heat-labile enterotoxin designated LT(R192G), or CpG oligodeoxynucleotide. Mice were subsequently challenged with a lethal dose of influenza A/PR/8/34 virus 24 h after the last immunomodulation treatment and either monitored for survival or sacrificed postchallenge for viral and immunological analysis. Treatment with the three immunomodulators prevented or delayed mortality and weight loss, but only CT and LT(R192G) significantly reduced initial lung viral loads as measured by plaque assay. Analysis performed 4 days postinfection indicated that prophylactic treatments with CT, LT(R192G), or CpG resulted in significantly increased numbers of CD4 T cells, B cells, and dendritic cells and altered costimulatory marker expression in the airways of infected mice, coinciding with reduced expression of pulmonary chemokines and the appearance of inducible bronchus-associated lymphoid tissue-like structures in the lungs. Collectively, these results suggest that, despite different immunomodulatory mechanisms, CT, LT(R192G), and CpG induce an initial inflammatory process and enhance the immune response to primary influenza virus challenge while preventing potentially damaging chemokine expression. These studies provide insight into the immunological parameters and immune modulation strategies that have the potential to enhance the nonspecific host response to influenza virus infection. PMID:20053748

78 FR 63220 - Guidance for Industry on Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-23

...] Guidance for Industry on Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment... Administration (FDA) is announcing the availability of a guidance for industry entitled ``Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment.'' The purpose of this guidance is to...

Stimulation of Lung Innate Immunity Protects against Lethal Pneumococcal Pneumonia in Mice

PubMed Central

Clement, Cecilia G.; Evans, Scott E.; Evans, Christopher M.; Hawke, David; Kobayashi, Ryuji; Reynolds, Paul R.; Moghaddam, Seyed J.; Scott, Brenton L.; Melicoff, Ernestina; Adachi, Roberto; Dickey, Burton F.; Tuvim, Michael J.

2008-01-01

Rationale: The lungs are a common site of serious infection in both healthy and immunocompromised subjects, and the most likely route of delivery of a bioterror agent. Since the airway epithelium shows great structural plasticity in response to inflammatory stimuli, we hypothesized it might also show functional plasticity. Objectives: To test the inducibility of lung defenses against bacterial challenge. Methods: Mice were treated with an aerosolized lysate of ultraviolet-killed nontypeable (unencapsulated) Haemophilus influenzae (NTHi), then challenged with a lethal dose of live Streptococcus pneumoniae (Spn) delivered by aerosol. Measurements and Main Results: Treatment with the NTHi lysate induced complete protection against challenge with a lethal dose of Spn if treatment preceded challenge by 4 to 24 hours. Lesser levels of protection occurred at shorter (83% at 2 h) and longer (83% at 48–72 h) intervals between treatment and challenge. There was also some protection when treatment was given 2 hours after challenge (survival increased from 14 to 57%), but not 24 hours after challenge. Protection did not depend on recruited neutrophils or resident mast cells and alveolar macrophages. Protection was specific to the airway route of infection, correlated in magnitude and time with rapid bacterial killing within the lungs, and was associated with increases of multiple antimicrobial polypeptides in lung lining fluid. Conclusions: We infer that protection derives from stimulation of local innate immune mechanisms, and that activated lung epithelium is the most likely cellular effector of this response. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value. PMID:18388354

Validating and updating a prediction rule for serious bacterial infection in patients with fever without source.

PubMed

Bleeker, S E; Derksen-Lubsen, G; Grobbee, D E; Donders, A R T; Moons, K G M; Moll, H A

2007-01-01

To externally validate and update a previously developed rule for predicting the presence of serious bacterial infections in children with fever without apparent source. Patients, 1-36 mo, presenting with fever without source, were prospectively enrolled. Serious bacterial infection included bacterial meningitis, sepsis, bacteraemia, pneumonia, urinary tract infection, bacterial gastroenteritis, osteomyelitis/ethmoiditis. The generalizability of the original rule was determined. Subsequently, the prediction rule was updated using all available data of the patients with fever without source (1996-1998 and 2000-2001, n = 381) using multivariable logistic regression. the generalizability of the rule appeared insufficient in the new patients (n = 150). In the updated rule, independent predictors from history and examination were duration of fever, vomiting, ill clinical appearance, chest-wall retractions and poor peripheral circulation (ROC area (95%CI): 0.69 (0.63-0.75)). Additional independent predictors from laboratory were serum white blood cell count and C-reactive protein, and in urinalysis > or = 70 white bloods (ROC area (95%CI): 0.83 (0.78-0.88). A previously developed prediction rule for predicting the presence of serious bacterial infection in children with fever without apparent source was updated. Its clinical score can be used as a first screening tool. Additional laboratory testing may specify the individual risk estimate (range: 4-54%) further.

Klebsiella pneumoniae Siderophores Induce Inflammation, Bacterial Dissemination, and HIF-1α Stabilization during Pneumonia.

PubMed

Holden, Victoria I; Breen, Paul; Houle, Sébastien; Dozois, Charles M; Bachman, Michael A

2016-09-13

iron from its host by secreting siderophores, small iron-chelating molecules. Classically, siderophores are thought to worsen infections by promoting bacterial growth. In this study, we determined that siderophore-secreting K. pneumoniae causes lung inflammation and bacterial dissemination to the bloodstream independently of bacterial growth. Furthermore, we determined that siderophore-secreting K. pneumoniae activates a host protein, hypoxia inducible factor (HIF)-1α, and requires it for siderophore-dependent bacterial dissemination. Although HIF-1α can protect against some infections, it appears to worsen infection with K. pneumoniae Together, these results indicate that bacterial siderophores directly alter the host response to pneumonia in addition to providing iron for bacterial growth. Therapies that disrupt production of siderophores could provide a two-pronged attack against K. pneumoniae infection by preventing bacterial growth and preventing bacterial dissemination to the blood. Copyright © 2016 Holden et al.

Cystic fibrosis lung transplantation.

PubMed

Braun, Andrew T; Merlo, Christian A

2011-11-01

This review summarizes recently published investigations on issues pertaining to cystic fibrosis (CF) lung transplantation. We specifically focus on indications and candidate selection as well as infectious and noninfectious issues specific to CF lung transplant recipients. Recent studies have focused on candidate adequacy in high-risk CF patients. We review the current literature on individuals who develop respiratory failure requiring mechanical ventilation and those patients with a pretransplant diagnosis of pulmonary hypertension. Furthermore, the management of peri-operative infectious issues is reviewed including recurrent infections with multidrug-resistant bacterial, mycobacterial, and fungal organisms. Other CF-specific issues addressed include common comorbidities such as CF-related diabetes, gastroesophageal reflux, CF liver disease, and bone metabolism. Lung transplantation is a limited, but potentially life-saving therapeutic option for patients with CF. Optimal candidate selection and awareness of CF-specific issues in the pretransplant and posttransplant setting may lead to better long-term outcomes. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

Concomitant pulmonary infection with Nocardia transvalensis and Aspergillus ustus in lung transplantation.

PubMed

Cabada, Miguel M; Nishi, Shawn P; Lea, Alfred S; Schnadig, Vicki; Lombard, Gisele A; Lick, Scott D; Valentine, Vincent G

2010-08-01

Lung infections with Nocardia and Aspergillus spp in lung transplant recipients (LTRs) create diagnostic and therapeutic challenges. The present case illustrates the difficulties in identifying these pathogens in LTRs. A high degree of clinical suspicion and aggressive early management are required to ensure good outcomes. Although prospective data on treating these conditions are scarce, the empiric use of combination broad-spectrum anti-microbials initially seems prudent. Copyright (c) 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Effect of Enteral Nutrition and Synbiotics on Bacterial Infection Rates After Pylorus-preserving Pancreatoduodenectomy

PubMed Central

Rayes, Nada; Seehofer, Daniel; Theruvath, Tom; Mogl, Martina; Langrehr, Jan M.; Nüssler, Natascha C.; Bengmark, Stig; Neuhaus, Peter

2007-01-01

Objective: Patients undergoing pancreas resection carry several risk factors for nosocomial bacterial infections. Pre- and probiotics (synbiotics) are potentially useful for prevention of these infections. Summary Background Data: First trials in patients following major abdominal surgery including liver transplantation using one Lactobacillus (LAB) and one fiber showed significant reduction of infection rates and reduced length of antibiotic therapy compared with a control group. The present study was designed to analyze whether a combination of different LAB and fibers would further improve outcome. Methods: A prospective randomized monocentric double-blind trial was undertaken in 80 patients following pylorus-preserving pancreatoduodenectomy (PPPD). All patients received enteral nutrition immediately postoperatively. One group (A) received a composition of 4 LAB and 4 fibers, and another group (B) received placebo (fibers only) starting the day before surgery and continuing for 8 days. Thirty-day infection rate, length of hospital stay, duration of antibiotic therapy, noninfectious complications, and side effects were recorded. Results: The incidence of postoperative bacterial infections was significantly lower with LAB and fibers (12.5%) than with fibers only (40%). In addition, the duration of antibiotic therapy was significantly shorter in the latter group. Fibers and LAB were well tolerated. Conclusion: Early enteral nutrition supplemented with a mixture of LAB and fibers reduces bacterial infection rates and antibiotic therapy following PPPD. PMID:17592288

Inflammatory Monocyte Recruitment Is Regulated by Interleukin-23 during Systemic Bacterial Infection

PubMed Central

Indramohan, Mohanalaxmi; Sieve, Amy N.; Break, Timothy J.

2012-01-01

Listeria monocytogenes is a Gram-positive intracellular pathogen that causes meningitis and septicemia in immunocompromised individuals and spontaneous abortion in pregnant women. The innate immune response against L. monocytogenes is primarily mediated by neutrophils and monocytes. Interleukin-23 (IL-23) is an important proinflammatory cytokine well known for its role in neutrophil recruitment in various infectious and autoimmune diseases. We have previously shown that IL-23 is required for host resistance against L. monocytogenes and for neutrophil recruitment to the liver, but not the spleen, during infection. Despite efficient neutrophil recruitment to the spleen, IL-23p19 knockout (KO) mice have an increased bacterial burden in this organ, suggesting that IL-23 may regulate the recruitment/function of another cell type to the spleen. In this study, we show that specific depletion of neutrophils abrogated the differences in bacterial burdens in the livers but not the spleens of C57BL/6 (B6) and IL-23p19 KO mice. Interestingly, L. monocytogenes-infected IL-23p19 KO mice had fewer monocytes in the spleen than B6 mice, as well as a reduction in the monocyte-recruiting chemokines CCL2 and CCL7. Additionally, the overall concentrations of tumor necrosis factor alpha (TNF-α) and nitric oxide (NO•), as well as the percentages and total numbers of monocytes producing TNF-α and NO•, were reduced in IL-23p19 KO mice compared to levels in B6 mice, leading to increased bacterial burdens in the spleens of L. monocytogenes-infected IL-23p19 KO mice. Collectively, our data establish that IL-23 is required for the optimal recruitment of TNF-α- and NO•-producing inflammatory monocytes, thus revealing a novel mechanism by which this proinflammatory cytokine provides protection against bacterial infection. PMID:22966045

Innate lymphoid cells: the role in respiratory infections and lung tissue damage.

PubMed

Głobińska, Anna; Kowalski, Marek L

2017-10-01

Innate lymphoid cells (ILCs) represent a diverse family of cells of the innate immune system, which play an important role in regulation of tissue homeostasis, immunity and inflammation. Emerging evidence has highlighted the importance of ILCs in both protective immunity to respiratory infections and their pathological roles in the lungs. Therefore, the aim of this review is to summarize the current knowledge, interpret and integrate it into broader perspective, enabling greater insight into the role of ILCs in respiratory diseases. Areas covered: In this review we highlighted the role of ILCs in the lungs, citing the most recent studies in this area. PubMed searches (2004- July 2017) were conducted using the term 'innate lymphoid cells respiratory viral infections' in combination with other relevant terms including various respiratory viruses. Expert commentary: Since studies of ILCs have opened new areas of investigation, understanding the role of ILCs in respiratory infections may help to clarify the mechanisms underlying viral-induced exacerbations of lung diseases, providing the basis for novel therapeutic strategies. Potential therapeutic targets have already been identified. So far, the most promising strategy is cytokine-targeting, although further clinical trials are needed to verify its effectiveness.

Empiric Antibiotic Use and Susceptibility in Infants With Bacterial Infections: A Multicenter Retrospective Cohort Study.

PubMed

Feldman, Elana A; McCulloh, Russell J; Myers, Angela L; Aronson, Paul L; Neuman, Mark I; Bradford, Miranda C; Alpern, Elizabeth R; Balamuth, Frances; Blackstone, Mercedes M; Browning, Whitney L; Hayes, Katie; Korman, Rosalynne; Leazer, Rianna C; Nigrovic, Lise E; Marble, Richard; Roben, Emily; Williams, Derek J; Tieder, Joel S

2017-07-20

To assess hospital differences in empirical antibiotic use, bacterial epidemiology, and antimicrobial susceptibility for common antibiotic regimens among young infants with urinary tract infection (UTI), bacteremia, or bacterial meningitis. We reviewed medical records from infants <90 days old presenting to 8 US children's hospitals with UTI, bacteremia, or meningitis. We used the Pediatric Health Information System database to identify cases and empirical antibiotic use and medical record review to determine infection, pathogen, and antimicrobial susceptibility patterns. We compared hospital-level differences in antimicrobial use, pathogen, infection site, and antimicrobial susceptibility. We identified 470 infants with bacterial infections: 362 (77%) with UTI alone and 108 (23%) with meningitis or bacteremia. Infection type did not differ across hospitals ( P = .85). Empirical antibiotic use varied across hospitals ( P < .01), although antimicrobial susceptibility patterns for common empirical regimens were similar. A third-generation cephalosporin would have empirically treated 90% of all ages, 89% in 7- to 28-day-olds, and 91% in 29- to 89-day-olds. The addition of ampicillin would have improved coverage in only 4 cases of bacteremia and meningitis. Ampicillin plus gentamicin would have treated 95%, 89%, and 97% in these age groups, respectively. Empirical antibiotic use differed across regionally diverse US children's hospitals in infants <90 days old with UTI, bacteremia, or meningitis. Antimicrobial susceptibility to common antibiotic regimens was similar across hospitals, and adding ampicillin to a third-generation cephalosporin minimally improves coverage. Our findings support incorporating empirical antibiotic recommendations into national guidelines for infants with suspected bacterial infection. Copyright © 2017 by the American Academy of Pediatrics.

Transcriptional response of honey bee larvae infected with the bacterial pathogen Paenibacillus larvae

USDA-ARS?s Scientific Manuscript database

American foulbrood disease of honey bees is caused by the bacterium Paenibacillus larvae. Infection occurs per os in larvae and systemic infection requires a breaching of the host peritrophic matrix and midgut epithelium. Genetic variation exists for both bacterial virulence and host resistance, and...

Diallylthiosulfinate (Allicin), a Volatile Antimicrobial from Garlic (Allium sativum), Kills Human Lung Pathogenic Bacteria, Including MDR Strains, as a Vapor.

PubMed

Reiter, Jana; Levina, Natalja; van der Linden, Mark; Gruhlke, Martin; Martin, Christian; Slusarenko, Alan J

2017-10-12

Garlic ( Allium sativum ) has potent antimicrobial activity due to allicin (diallylthiosulfinate) synthesized by enzyme catalysis in damaged garlic tissues. Allicin gives crushed garlic its characteristic odor and its volatility makes it potentially useful for combating lung infections. Allicin was synthesized (>98% pure) by oxidation of diallyl disulfide by H₂O₂ using formic acid as a catalyst and the growth inhibitory effect of allicin vapor and allicin in solution to clinical isolates of lung pathogenic bacteria from the genera Pseudomonas , Streptococcus , and Staphylococcus , including multi-drug resistant (MDR) strains, was demonstrated. Minimal inhibitory (MIC) and minimal bactericidal concentrations (MBC) were determined and compared to clinical antibiotics using standard European Committee on Antimicrobial Susceptibility Testing (EUCAST) procedures. The cytotoxicity of allicin to human lung and colon epithelial and murine fibroblast cells was tested in vitro and shown to be ameliorated by glutathione (GSH). Similarly, the sensitivity of rat precision-cut lung slices (PCLS) to allicin was decreased by raising the [GSH] to the approximate blood plasma level of 1 mM. Because allicin inhibited bacterial growth as a vapor, it could be used to combat bacterial lung infections via direct inhalation. Since there are no volatile antibiotics available to treat pulmonary infections, allicin, particularly at sublethal doses in combination with oral antibiotics, could make a valuable addition to currently available treatments.

Downregulation of Aquaporins (AQP1 and AQP5) and Na,K-ATPase in Porcine Reproductive and Respiratory Syndrome Virus-Infected Pig Lungs.

PubMed

Zhang, Jianping; Yan, Meiping; Gu, Wei; Chen, Ao; Liu, Jie; Li, Lexing; Zhang, Songlin; Liu, Guoquan

2018-06-01

Aquaporins (AQPs) and Na,K-ATPase control water transport across the air space-capillary barrier in the distal lung and play an important role in the formation and resolution of lung edema. Porcine reproductive and respiratory syndrome virus (PRRSV) infection usually causes pulmonary inflammation and edema in the infected pig lungs. To investigate the possibility that PRRSV infection may cause altered expression of AQPs and Na,K-ATPase messenger RNA (mRNA) levels and protein expression of AQP1, AQP5, and Na,K-ATPase in the PRRSV-infected pig lungs were detected. Quantitative real-time PCR (qRT-PCR) analysis showed markedly decreased mRNA levels of AQP1 and AQP5 and Na,K-ATPase in the PRRSV-infected pig lungs compared to those of uninfected pig lungs. Western blot studies also revealed significantly reduced levels of AQP1, AQP5, and Na,K-ATPase proteins in the PRRSV-infected pig lungs. In addition, immunohistochemical (IHC) analysis showed decreased protein expression of AQP1 and AQP5 in the endothelial cells of the capillaries and venules and secretory cells of terminal bronchiole and the alveolar type I cells, respectively. The expression of Na,K-ATPase in the basolateral membrane of alveolar type II cells presented great reduction in the PRRSV-infected pig lungs. To further understand the reduction of these proteins, the ubiquitination of AQP1 and Na,K-ATPase was examined in uninfected and PRRSV-infected pig lungs. The results showed that there is no difference of ubiquitination for these proteins. Thus, our results suggest that PRRSV infection may induce downregulation of these proteins and cause impairment of edema resolution by failed water clearance in the infected pig lungs.

The influence of Actinobacillus pleuropneumoniae infection on tulathromycin pharmacokinetics and lung tissue disposition in pigs.

PubMed

Gajda, A; Bladek, T; Jablonski, A; Posyniak, A

2016-04-01

A tulathromycin concentration and pharmacokinetic parameters in plasma and lung tissue from healthy pigs and Actinobacillus pleuropneumoniae (App)-infected pigs were compared. Tulathromycin was administered intramuscularly (i.m.) to all pigs at a single dose of 2.5 mg/kg. Blood and lung tissue samples were collected during 33 days postdrug application. Tulathromycin concentration in plasma and lung was determined by high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. The mean maximum plasma concentration (Cmax ) in healthy pigs was 586 ± 71 ng/mL, reached by 0.5 h, while the mean value for Cmax of tulathromycin in infected pigs was 386 ± 97 ng/mL after 0.5 h. The mean maximum tulathromycin concentration in lung of healthy group was calculated as 3412 ± 748 ng/g, detected at 12 h, while in pigs with App, the highest concentration in lung was 3337 ± 937 ng/g, determined at 48 h postdosing. The higher plasma and lung concentrations in pigs with no pulmonary inflammation were observed at the first time points sampling after tulathromycin administration, but slower elimination with elimination half-life t1/2el  = 126 h in plasma and t1/2el  = 165 h in lung, as well as longer drug persistent in infected pigs, was found. © 2015 John Wiley & Sons Ltd.

Serial Histopathological Examination of the Lungs of Mice Infected with Influenza A Virus PR8 Strain

PubMed Central

Fukushi, Masaya; Ito, Tateki; Oka, Teruaki; Kitazawa, Toshio; Miyoshi-Akiyama, Tohru; Kirikae, Teruo; Yamashita, Makoto; Kudo, Koichiro

2011-01-01

Avian influenza H5N1 and pandemic (H1N1) 2009 viruses are known to induce viral pneumonia and subsequent acute respiratory distress syndrome (ARDS) with diffuse alveolar damage (DAD). The mortality rate of ARDS/DAD is extremely high, at approximately 60%, and no effective treatment for ARDS/DAD has been established. We examined serial pathological changes in the lungs of mice infected with influenza virus to determine the progress from viral pneumonia to ARDS/DAD. Mice were intranasally infected with influenza A/Puerto Rico/8/34 (PR8) virus, and their lungs were examined both macro- and micro-pathologically every 2 days. We also evaluated general condition, survival rate, body weight, viral loads in lung, and surfactant proteins in serum. As a result, all infected mice died within 9 days postinfection. At 2 days postinfection, inflammation in alveolar septa, i.e., interstitial pneumonia, was observed around bronchioles. From 4 to 6 days postinfection, interstitial pneumonia with alveolar collapse expanded throughout the lungs. From 6 to 9 days postinfection, DAD with severe alveolar collapse was observed in the lungs of all of dying and dead mice. In contrast, DAD was not observed in the live infected-mice from 2 to 6 days postinfection, despite their poor general condition. In addition, histopathological analysis was performed in mice infected with a dose of PR8 virus which was 50% of the lethal dose for mice in the 20-day observation period. DAD with alveolar collapse was observed in all dead mice. However, in the surviving mice, instead of DAD, glandular metaplasia was broadly observed in their lungs. The present study indicates that DAD with severe alveolar collapse is associated with death in this mouse infection model of influenza virus. Inhibition of the development of DAD with alveolar collapse may decrease the mortality rate in severe viral pneumonia caused by influenza virus infection. PMID:21701593

Mycobacterium tuberculosis Infection and Innate Responses in a New Model of Lung Alveolar Macrophages.

PubMed

Woo, Minjeong; Wood, Connor; Kwon, Doyoon; Park, Kyu-Ho Paul; Fejer, György; Delorme, Vincent

2018-01-01

Lung alveolar macrophages (AMs) are in the first line of immune defense against respiratory pathogens and play key roles in the pathogenesis of Mycobacterium tuberculosis ( Mtb ) in humans. Nevertheless, AMs are available only in limited amounts for in vitro studies, which hamper the detailed molecular understanding of host- Mtb interactions in these macrophages. The recent establishment of the self-renewing and primary Max Planck Institute (MPI) cells, functionally very close to lung AMs, opens unique opportunities for in vitro studies of host-pathogen interactions in respiratory diseases. Here, we investigated the suitability of MPI cells as a host cell system for Mtb infection. Bacterial, cellular, and innate immune features of MPI cells infected with Mtb were characterized. Live bacteria were readily internalized and efficiently replicated in MPI cells, similarly to primary murine macrophages and other cell lines. MPI cells were also suitable for the determination of anti-tuberculosis (TB) drug activity. The primary innate immune response of MPI cells to live Mtb showed significantly higher and earlier induction of the pro-inflammatory cytokines TNFα, interleukin 6 (IL-6), IL-1α, and IL-1β, as compared to stimulation with heat-killed (HK) bacteria. MPI cells previously showed a lack of induction of the anti-inflammatory cytokine IL-10 to a wide range of stimuli, including HK Mtb . By contrast, we show here that live Mtb is able to induce significant amounts of IL-10 in MPI cells. Autophagy experiments using light chain 3B immunostaining, as well as LysoTracker labeling of acidic vacuoles, demonstrated that MPI cells efficiently control killed Mtb by elimination through phagolysosomes. MPI cells were also able to accumulate lipid droplets in their cytoplasm following exposure to lipoproteins. Collectively, this study establishes the MPI cells as a relevant, versatile host cell model for TB research, allowing a deeper understanding of AMs functions in this

Nanosized Selenium: A Novel Platform Technology to Prevent Bacterial Infections

NASA Astrophysics Data System (ADS)

Wang, Qi

As an important category of bacterial infections, healthcare-associated infections (HAIs) are considered an increasing threat to the safety and health of patients worldwide. HAIs lead to extended hospital stays, contribute to increased medical costs, and are a significant cause of morbidity and mortality. In the United States, infections encountered in the hospital or a health care facility affect more than 1.7 million patients, cost 35.7 billion to 45 billion, and contribute to 88,000 deaths in hospitals annually. The most conventional and widely accepted method to fight against bacterial infections is using antibiotics. However, because of the widespread and sometimes inappropriate use of antibiotics, many strains of bacteria have rapidly developed antibiotic resistance. Those new, stronger bacteria pose serious, worldwide threats to public health and welfare. In 2014, the World Health Organization (WHO) reported antibiotic resistance as a global serious threat that is no longer a prediction for the future but is now reality. It has the potential to affect anyone, of any age, in any country. The most effective strategy to prevent antibiotic resistance is minimizing the use of antibiotics. In recent years, nanomaterials have been investigated as one of the potential substitutes of antibiotics. As a result of their vastly increased ratio of surface area to volume, nanomaterials will likely exert a stronger interaction with bacteria which may affect bacterial growth and propagation. A major concern of most existing antibacterial nanomaterials, like silver nanoparticles, is their potential toxicity. But selenium is a non-metallic material and a required nutrition for the human body, which is recommended by the FDA at a 53 to 60 μg daily intake. Nanosized selenium is considered to be healthier and less toxic compared with many metal-based nanomaterials due to the generation of reactive oxygen species from metals, especially heavy metals. Therefore, the objectives of

Dendritic cells modulate lung response to Pseudomonas aeruginosa in a murine model of sepsis-induced immune dysfunction.

PubMed

Pène, Frédéric; Zuber, Benjamin; Courtine, Emilie; Rousseau, Christophe; Ouaaz, Fatah; Toubiana, Julie; Tazi, Asmaa; Mira, Jean-Paul; Chiche, Jean-Daniel

2008-12-15

Host infection by pathogens triggers an innate immune response leading to a systemic inflammatory response, often followed by an immune dysfunction which can favor the emergence of secondary infections. Dendritic cells (DCs) link innate and adaptive immunity and may be centrally involved in the regulation of sepsis-induced immune dysfunction. We assessed the contribution of DCs to lung defense in a murine model of sublethal polymicrobial sepsis (cecal ligature and puncture, CLP). In this model, bone marrow-derived DCs (BMDCs) retained an immature phenotype, associated with decreased capacity of IL-12p70 release and impaired priming of T cell lymphocytes. Eight days after CLP surgery, we induced a secondary pulmonary infection through intratracheal instillation of 5 x 10(6) CFUs of Pseudomonas aeruginosa. Whereas all sham-operated mice survived, 80% of post-CLP mice died after secondary pneumonia. Post-CLP mice exhibited marked lung damage with early recruitment of neutrophils, cytokine imbalance with decreased IL-12p70 production, and increased IL-10 release, but no defective bacterial lung clearance, while systemic bacterial dissemination was almost constant. Concomitant intrapulmonary administration of exogenous BMDCs into post-CLP mice challenged with P. aeruginosa dramatically improved survival. BMDCs did not improve bacterial lung clearance, but delayed neutrophil recruitment, strongly attenuated the early peak of TNF-alpha and restored an adequate Il-12p70/IL-10 balance in post-CLP mice. Thus, adoptive transfer of BMDCs reversed sepsis-induced immune dysfunction in a relevant model of secondary P. aeruginosa pneumonia. Unexpectedly, the mechanism of action of BMDCs did not involve enhanced antibacterial activity, but occurred by dampening the pulmonary inflammatory response.

Ultrastructure of Bacterial Cells Infected with Bacteriophage PM2, a Lipid-containing Bacterial Virus

PubMed Central

Cota-Robles, Eugene; Espejo, Romilio Torres; Haywood, Patricia Williams

1968-01-01

The cytological pattern of infection of a host pseudomonad with PM2, a lipid-containing bacterial virus, was investigated by electron microscopy. Normal and infected cells frequently contain a myelin figure, which is found in the nucleoid region or at the periphery of the cell. The most striking finding in this investigation was that completed virions are found in the cell adjacent to or in association with the cytoplasmic membrane. This localization is precise; virions are not found elsewhere in infected cells. The completed virions occasionally appear to be attached to the cytoplasmic membrane. The virus contains a darkly staining core surrounded by a tripartite envelope of a thickness of approximately 70 A, which is identical to the thickness of the cytoplasmic membrane. Lysing cells appear to undergo extensive damage of the cytoplasmic membrane prior to rupture of the L layer of the cell wall. Images PMID:5742028

Statistical signal processing technique for identification of different infected sites of the diseased lungs.

PubMed

Abbas, Ali

2012-06-01

Accurate Diagnosis of lung disease depends on understanding the sounds emanating from lung and its location. Lung sounds are of significance as they supply precise and important information on the health of the respiratory system. In addition, correct interpretation of breath sounds depends on a systematic approach to auscultation; it also requires the ability to describe the location of abnormal finding in relation to bony structures and anatomic landmark lines. Lungs consist of number of lobes; each lung lobe is further subdivided into smaller segments. These segments are attached to each other. Knowledge of the position of the lung segments is useful and important during the auscultation and diagnosis of the lung diseases. Usually the medical doctors give the location of the infection a segmental position reference. Breath sounds are auscultated over the anterior chest wall surface, the lateral chest wall surfaces, and posterior chest wall surface. Adventitious sounds from different location can be detected. It is common to seek confirmation of the sound detection and its location using invasive and potentially harmful imaging diagnosis techniques like x-rays. To overcome this limitation and for fast, reliable, accurate, and inexpensive diagnose a technique is developed in this research for identifying the location of infection through a computerized auscultation system.

Role of neutrophil to lymphocyte and monocyte to lymphocyte ratios in the diagnosis of bacterial infection in patients with fever.

PubMed

Naess, Are; Nilssen, Siri Saervold; Mo, Reidun; Eide, Geir Egil; Sjursen, Haakon

2017-06-01

To study the role of the neutrophil:lymphocyte ratio (NLR) and monocyte:lymphocyte ratio (MLR) in discriminating between different patient groups hospitalized for fever due to infection and those without infection. For 299 patients admitted to hospital for fever with unknown cause, a number of characteristics including NLR and MLR were recorded. These characteristics were used in a multiple multinomial regression analysis to estimate the probability of a final diagnostic group of bacterial, viral, clinically confirmed, or no infection. Both NLR and MLR significantly predicted final diagnostic group. Being highly correlated, however, both variables could not be retained in the same model. Both variables also interacted significantly with duration of fever. Generally, higher values of NLR and MLR indicated larger probabilities for bacterial infection and low probabilities for viral infection. Patients with septicemia had significantly higher NLR compared to patients with other bacterial infections with fever for less than one week. White blood cell counts, neutrophil counts, and C-reactive proteins did not differ significantly between septicemia and the other bacterial infection groups. NLR is a more useful diagnostic tool to identify patients with septicemia than other more commonly used diagnostic blood tests. NLR and MLR may be useful in the diagnosis of bacterial infection among patients hospitalized for fever.

A case of IgG4-related lung disease complicated by asymptomatic chronic Epstein-Barr virus infection.

PubMed

Kotetsu, Yasuaki; Ikegame, Satoshi; Takebe-Akazawa, Keiko; Koga, Takaomi; Okabayashi, Kan; Takata, Shohei

2017-11-01

IgG4-related disease is characterized by IgG4-positive plasmacyte infiltration into various organs, but its etiology is not unknown. To elucidate the etiology of IgG4-related disease. We experienced an interesting case of IgG4-related lung disease complicated by chronic EB virus infection. A 70-year-old male visited our hospital due to failure of pneumonia treatment. Chest computed tomography (CT) showed consolidation in the right middle field and slight mediastinal lymphadenopathy in the subcarinal region. Lung consolidation improved with antibiotics; subcarinal lymphadenopathy progressed after 4 months. Malignant lymphoma was suspected given elevated sIL2-R levels (1862 U/mL). Patchy ground glass opacities appeared in the bilateral lung field just before surgical biopsy. He was diagnosed with IgG4-related lung disease after inspection of a pathological specimen obtained from the right upper lung and right hilar lymph node. EB virus-infected cells were also detected in the lymph node. Blood examination revealed EB virus viremia, but the patient did not present with symptoms or organ involvement. This led to a diagnosis of asymptomatic chronic EB virus infection. Recent studies have suggested an association between EB virus infection and IgG4-related diseases in the pathological exploration of surgically resected lymph nodes. Our case is the first case of IgG4-related lung disease in which EB virus infection was both pathologically and clinically proved. The present case is of particular interest in view of this newly reported association, and may serve as a fundamental report for future studies connecting EB virus infection with IgG4-related diseases. © 2016 John Wiley & Sons Ltd.

Digging through the Obstruction: Insight into the Epithelial Cell Response to Respiratory Virus Infection in Patients with Cystic Fibrosis.

PubMed

Hendricks, Matthew R; Bomberger, Jennifer M

2016-05-01

Respiratory virus infections are common but generally self-limiting infections in healthy individuals. Although early clinical studies reported low detection rates, the development of molecular diagnostic techniques by PCR has led to an increased recognition that respiratory virus infections are associated with morbidity and acute exacerbations of chronic lung diseases, such as cystic fibrosis (CF). The airway epithelium is the first barrier encountered by respiratory viruses following inhalation and the primary site of respiratory viral replication. Here, we describe how the airway epithelial response to respiratory viral infections contributes to disease progression in patients with CF and other chronic lung diseases, including the role respiratory viral infections play in bacterial acquisition in the CF patient lung. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Antibiotic use and bacterial complications following upper respiratory tract infections: a population-based study

PubMed Central

Cars, Thomas; Eriksson, Irene; Granath, Anna; Wettermark, Björn; Hellman, Jenny; Norman, Christer; Ternhag, Anders

2017-01-01

Objectives To investigate if use of antibiotics was associated with bacterial complications following upper respiratory tract infections (URTIs). Design Ecological time-trend analysis and a prospective cohort study. Setting Primary, outpatient specialist and inpatient care in Stockholm County, Sweden. All analyses were based on administrative healthcare data on consultations, diagnoses and dispensed antibiotics from January 2006 to January 2016. Main outcome measures Ecological time-trend analysis: 10-year trend analyses of the incidence of URTIs, bacterial infections/complications and respiratory antibiotic use. Prospective cohort study: Incidence of bacterial complications following URTIs in antibiotic-exposed and non-exposed patients. Results The utilisation of respiratory tract antibiotics decreased by 22% from 2006 to 2015, but no increased trend for mastoiditis (p=0.0933), peritonsillar abscess (p=0.0544), invasive group A streptococcal disease (p=0.3991), orbital abscess (p=0.9637), extradural and subdural abscesses (p=0.4790) and pansinusitis (p=0.3971) was observed. For meningitis and acute ethmoidal sinusitis, a decrease in the numbers of infections from 2006 to 2015 was observed (p=0.0038 and p=0.0003, respectively), and for retropharyngeal and parapharyngeal abscesses, an increase was observed (p=0.0214). Bacterial complications following URTIs were uncommon in both antibiotic-exposed (less than 1.5 per 10 000 episodes) and non-exposed patients (less than 1.3 per 10 000 episodes) with the exception of peritonsillar abscess after tonsillitis (risk per 10 000 tonsillitis episodes: 32.4 and 41.1 in patients with no antibiotic treatment and patients treated with antibiotics, respectively). Conclusions Bacterial complications following URTIs are rare, and antibiotics may lack protective effect in preventing bacterial complications. Analyses of routinely collected administrative healthcare data can provide valuable information on the number of URTIs