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: 10654630
• 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/10654630
• 关键词: Acute; Adoptive Transfer; Affect; Allergic; Alveolar Macrophages; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Pneumonia; Cessation of life; Chronic; Colitis; Communities; Data; Development; Disease; Eosinophilia; Epidemic; Epithelial Cells; Epithelium; Feces; Functional disorder; Gastrointestinal tract structure; Gnotobiotic; Goals; Grant; Helminths; Homeostasis; Human; Immune; Immune system; Immunity; Immunocompetent; Impairment; In Vitro; Infection; Inflammatory; Inflammatory Response; Influenza; Interferon Type II; Lung; Macrophage; Mediating; Mediator; Medical; Medicine; Methods; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Nutritional; Organism; Pathology; Patients; Phenotype; Pneumonia; Predisposition; Preventive measure; Publishing; Pulmonary Inflammation; 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; high risk; immune function; immunoregulation; in vitro Model; in vivo; influenza infection; influenza pneumonia; influenzavirus; innate immune function; lung injury; methicillin resistant Staphylococcus aureus; microbiome alteration; mortality; mouse model; mycobiome; novel therapeutics; pathogen; pathogenic bacteria; pressure; programs; prophylactic; recruit; regenerative cell; 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.

项目摘要 世纪初抗生素的发现开辟了医学治疗的新纪元。事实上许多 如果没有抗生素，当今容易治疗的感染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， 使耐药细菌得以出现。然而，抗生素的另一个不利后果是， 治疗可以改变身体的神经组织，我们现在知道它对体内平衡有重要作用。 功能协调发展的事实上，许多生活在身体组织内的细菌、真菌和病毒有机体可以调节 免疫系统和微生物组的改变，如抗生素的使用，可能有助于 许多急性和慢性疾病的发展。因此，我们的研究表明， 在流感感染期间使用抗生素（常见的临床实践）会增加发生 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。 虽然抗生素对减少细菌微生物组的丰度和多样性有直接影响， 营养竞争减少的新生态位为真菌的扩张提供了机会， 社区.我们的数据表明，真菌生态失调是继发性细菌性肺炎恶化的驱动因素 流感感染后。此外，我们发现，寄生虫引起的真菌生态失调会增加肺部炎症 包括增强的干扰素-γ水平，一种可以清除有害作用的细胞因子， 流感细菌性肺炎。最后，我们发现嗜酸性粒细胞部分调节肺损伤的加重， 和增加的肠道S。酿酒酵母与真菌生态失调诱导的表型相关。总之，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导致真菌生态失调 具有肺免疫调节作用，这反过来又增加了宿主对细菌的易感性， 重复感染我们将在以下目标中检验这一假设： 目标1.确定真菌生态失调是否改变流感后肺炎的先天免疫功能。 目标2.评估真菌生态失调如何导致肺嗜酸性粒细胞增多，以增加肺部炎症。 目标3.探讨了S.酿酒酵母介导流感后MRSA肺炎的肺损伤。

项目成果

Comparison of clinical characteristics and outcomes of critically ill adults with SARS-CoV-2 infection during Delta and Omicron variant predominance periods: a single-hospital retrospective cohort study.

Delta 和 Omicron 变异优势期 SARS-CoV-2 感染危重成人的临床特征和结果比较：单医院回顾性队列研究。

• DOI: 10.1136/bmjresp-2022-001274
• 发表时间: 2023-02
• 期刊: BMJ open respiratory research
• 影响因子: 4.1

Reciprocal interactions between alveolar progenitor dysfunction and aging promote lung fibrosis.

• DOI: 10.7554/elife.85415
• 发表时间: 2023-06-14
• 期刊: eLife
• 影响因子: 7.7
• 作者: Liang J;Huang G;Liu X;Liu N;Taghavifar F;Dai K;Yao C;Deng N;Wang Y;Chen P;Hogaboam C;Stripp BR;Parks WC;Noble PW;Jiang D
• 通讯作者: Jiang D

Endogenous Antibody Responses to SARS-CoV-2 in Patients With Mild or Moderate COVID-19 Who Received Bamlanivimab Alone or Bamlanivimab and Etesevimab Together.

• DOI: 10.3389/fimmu.2021.790469
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Zhang L;Poorbaugh J;Dougan M;Chen P;Gottlieb RL;Huhn G;Beasley S;Daniels M;Ngoc Vy Trinh T;Crisp M;Freitas JJ;Vaillancourt P;Patel DR;Nirula A;Kallewaard NL;Higgs RE;Benschop RJ
• 通讯作者: Benschop RJ

First-in-Human Study of Bamlanivimab in a Randomized Trial of Hospitalized Patients With COVID-19.

• DOI: 10.1002/cpt.2405
• 发表时间: 2021-12
• 期刊: Clinical pharmacology and therapeutics
• 影响因子: 6.7
• 作者: Chen P;Datta G;Grace Li Y;Chien J;Price K;Chigutsa E;Brown-Augsburger P;Poorbaugh J;Fill J;Benschop RJ;Rouphael N;Kay A;Mulligan MJ;Saxena A;Fischer WA;Dougan M;Klekotka P;Nirula A;Benson C
• 通讯作者: Benson C

Protein biomarkers of disease progression in patients with systemic sclerosis associated interstitial lung disease.

• DOI: 10.1038/s41598-023-35840-y
• 发表时间: 2023-05-27
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Cerro-Chiang, Giuliana;Ayres, Matthew;Rivas, Alejandro;Romero, Tahmineh;Parker, Sarah J.;Mastali, Mitra;Elashoff, David;Chen, Peter;Van Eyk, Jennifer E.;Wolters, Paul J.;Boin, Francesco;Zaman, Tanzira
• 通讯作者: Zaman, Tanzira