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.

项目概要 20世纪初抗生素的发现开辟了医学治疗的新时代。如果没有抗生素，当今很容易治疗的感染可能会造成致命的后果。近年来，由于选择压力，这些药物的过度使用一直受到关注。然而，抗生素的另一个不良后果是治疗可以改变体内的共生生物，我们现在知道它们具有重要的体内平衡作用事实上，许多生活在身体组织内的细菌、真菌和病毒生物体都可以调节。免疫系统和微生物群的改变（例如使用抗生素）可能会导致因此，我们的研究表明，给予预防性治疗。流感感染期间使用抗生素（常见的临床实践）会增加患流感的风险继发性细菌性肺炎，这是最初病毒性疾病发病和死亡的主要原因。尽管抗生素会直接影响细菌微生物组的丰度和多样性，新的生态位和减少的营养竞争为真菌的扩张提供了机会我们的数据表明，真菌失调是继发性细菌性肺炎恶化的一个驱动因素。此外，我们发现抗生素引起的真菌失调会增加肺部炎症。包括增加干扰素-γ 水平，这是一种细胞因子，可以清除导致后遗症的不健康影响。最后，我们发现嗜酸性粒细胞部分调节了加重的肺损伤，肠道酿酒酵母的增加与真菌失调引起的表型相关。研究结果支持我们的中心假设，即流感感染期间的抗生素治疗会导致真菌失调具有肺部免疫调节作用，从而增加宿主对细菌的易感性我们将通过以下目标检验这一假设：目标 1. 确定真菌失调是否会改变流感后肺炎的先天免疫功能。目标 2. 评估真菌失调如何导致肺部嗜酸性粒细胞增多，从而加剧肺部炎症。目标 3. 研究酿酒酵母在介导流感后 MRSA 肺炎肺损伤中的作用。