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Fungal dysbiosis regulation of post-influenza bacterial pneumonia

流感后细菌性肺炎的真菌失调调节

基本信息

批准号：
10097806
负责人：
PETER CHEN
金额：
$ 59.71万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-16 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10097806
关键词：
Acute Adoptive Transfer Affect Allergic Alveolar Macrophages Antibiotic Therapy Antibiotics Bacteria Bacterial Pneumonia Cell Death Chronic Colitis Communities Data Development Disease Eosinophilia Epidemic Epithelial Epithelial Cells Feces Functional disorder Gastrointestinal tract structure Gnotobiotic Goals Grant Homeostasis Human Immune Immune system Immunity Immunocompetent Impairment In Vitro Infection Influenza Interferons Lead Lung Lung Inflammation Mediating Mediator of activation protein Medical Medicine Methods Modeling Morbidity - disease rate Mucous Membrane Mus Nutritional Organism Pathology Patients Phenotype Pneumonia Predisposition Preventive measure Publishing Pulmonary Pathology Recovery Regulation Risk Role Saccharomyces cerevisiae Sampling Serum Signal Transduction Staphylococcus aureus infection Testing Tissues Uric Acid Veins Viral Virus Diseases Work allergic response bacterial resistance bacteriome clinical practice commensal bacteria cytokine dysbiosis eosinophil fighting fungus gut microbiota helminth infection high risk immune function immunoregulation in vitro Model in vivo influenza infection influenza pneumonia influenzavirus innate immune function lung injury macrophage methicillin resistant Staphylococcus aureus microbiome alteration mortality mouse model mycobiome novel therapeutics pathogen pathogenic bacteria pressure prophylactic recruit regenerative cell response superinfection translational study

项目摘要

Project summary The discovery of antibiotics in the early 20th century opened up a new era of medical treatment. Indeed, many present-day infections that are easily treated could have had deadly consequences in the absence of antibiotics. The overuse of these medicines has been a concern in the recent years due to the selection pressures that have allowed resistant bacterial species to emerge. However, another untoward consequence of antibiotics is that treatment can alter the commensal organisms of the body, which we now understand has important homeostatic functions. Indeed, many bacterial, fungal, and viral organisms that live within tissues of the body can condition the immunologic system, and an altered microbiome, such as with antibiotic use, can contribute to the development of many acute and chronic pathologies. As such, our studies demonstrate that giving prophylactic antibiotics during influenza infection (a common clinical practice) increases the risk for development of a secondary bacterial pneumonia, which is major reason for the morbidity and mortality from the initial viral illness. Although antibiotics have direct effects on decreasing the abundance and diversity of the bacterial microbiome, the newly available niche with reduced nutritional competition provides an opportunity for expansion of fungal communities. Our data demonstrates that fungal dysbiosis is a driver of worsened secondary bacteria pneumonia after influenza infection. Moreover, we find that antibiotic-induced fungal dysbiosis increases lung inflammation including augmented interferon-γ levels, a cytokine that can clear detrimental effects that contribute to post- influenza bacterial pneumonia. Finally, we find that eosinophils partially modulate the augmented lung injury, and increased gut S. cerevisiae correlates with the phenotype induced by fungal dysbiosis. Altogether, these findings support our central hypothesis that antibiotic treatment during influenza infection causes fungal dysbiosis that has lung immunomodulatory effects, which in turn increases the host susceptibility to bacterial superinfection. We will test this hypothesis in the following aims: Aim 1. Determine if fungal dysbiosis alters innate immune functions in post-influenza pneumonia. Aim 2. Evaluate how fungal dysbiosis causes lung eosinophilia to augment lung inflammation. Aim 3. Investigate the role of S. cerevisiae in mediating lung injury from post-influenza MRSA pneumonia.

项目总结