Fungal dysbiosis regulation of post-influenza bacterial pneumonia

流感后细菌性肺炎的真菌失调调节

• 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
• 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

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 20世纪初抗生素的发现开启了医疗的新纪元。事实上，有很多人 当今容易治疗的感染在没有抗生素的情况下可能会产生致命的后果。 近年来，由于选择压力，这些药物的过度使用一直是一个令人担忧的问题 使得抗药性细菌种类得以出现。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体，我们现在知道它们具有重要的动态平衡。 功能。事实上，许多生活在身体组织中的细菌、真菌和病毒生物可能会 免疫系统和改变的微生物群，如抗生素的使用，可以促进 许多急慢性疾病的发展。因此，我们的研究表明，给予避孕药 在流感感染期间使用抗生素(一种常见的临床做法)会增加患上 继发性细菌性肺炎，是最初病毒性疾病发病率和死亡率的主要原因。 虽然抗生素对降低细菌微生物群的丰度和多样性有直接作用， 营养竞争减少的新利基市场为真菌的扩展提供了机会 社区。我们的数据表明，真菌菌群失调是继发性细菌性肺炎恶化的驱动因素。 在感染流感之后。此外，我们发现，抗生素诱导的真菌生物失调会增加肺部炎症。 包括增强的干扰素-γ水平，这是一种细胞因子，可以清除导致后遗症的有害影响 流行性感冒细菌性肺炎。最后，我们发现嗜酸性粒细胞部分调节了加重的肺损伤， 而肠道中酿酒葡萄球菌的增加与真菌失调所诱导的表型相关。总而言之，这些 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生态失调 这对肺部有免疫调节作用，进而增加宿主对细菌的易感性。 双重感染。我们将在以下目标中检验这一假设： 目的1.确定流感后肺炎中真菌的失调是否会改变先天免疫功能。 目的2.评价真菌菌群失调如何引起肺嗜酸性粒细胞增多症以增加肺部炎症。 目的3.探讨酿酒酵母在流感后耐甲氧西林金黄色葡萄球菌肺炎肺损伤中的作用。