The Oropharyngeal Microbiome in COVID-19

COVID-19 中的口咽微生物组

• 批准号: 10592682
• 负责人: Ronald G Collman
• 金额: $ 20.31万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592682
• 关键词: 2019-nCoV; ACE2; Address; Affect; Age; Animal Model; Bacteria; Blood; Body Surface; Body mass index; COVID-19; COVID-19 pathogenesis; COVID-19 patient; COVID-19 risk; COVID-19 severity; Cells; Clinical; Communities; Data; Diabetes Mellitus; Disease; Disease susceptibility; Economics; Elderly; Environment; Epithelial Cells; Exhibits; Future; Gender; Genes; Genetic; Goals; Hand; Heterogeneity; Hospitalization; Human; Human body; Immune; Immune response; Immunity; Individual; Infection; Inflammation; Influenza; Innate Immune Response; Interferons; Knowledge; Link; Lower respiratory tract structure; Lung; Lymphocyte; Modeling; Modification; Mononuclear; Morbidity - disease rate; Mucous Membrane; Mus; Nasopharynx; Natural Immunity; Obesity; Oropharyngeal; Outcome; Patients; Persons; Phase; Play; Pneumonia; Resolution; Respiratory Failure; Risk; SARS-CoV-2 infection; Sampling; Severities; Severity of illness; Shapes; Source; Specimen; Therapeutic Intervention; Upper respiratory tract; Viral; Virus Receptors; Work; advanced disease; airway epithelium; antimicrobial; aspirate; cohort; comorbidity; coronavirus disease; diabetic; dysbiosis; endotracheal; gene function; human old age (65+); immune function; immunoregulation; innovation; insight; lung microbiome; lung microbiota; microbial; microbiome; microbiota; microorganism; mortality; mouse model; neutrophil; novel; prototype; receptor; receptor expression; respiratory; respiratory infection virus; respiratory microbiome; respiratory virus; response; severe COVID-19; social

The Oropharyngeal Microbiome in COVID-19 Summary (Abstract) SARS-CoV-2 first infects the oropharynx and upper respiratory tract, where it either remains localized and is cleared, or propagates to the lower respiratory tract where it can progress to pneumonia and respiratory failure. Several patient factors correlate with increased COVID-19 severity, including older age, obesity and diabetes, but the mechanisms linking these factors to COVID-19 pathogenesis are incompletely understood. What determines the extent of SARS-CoV-2 upper respiratory tract (URT) replication and whether infection remains localized or propagates to the lower respiratory tract (LRT) is therefore a critical knowledge gap. Studies with other respiratory viruses (RSV, influenza) suggest that the local URT microbiome can regulate immune responses and influence lung consequences of infection. In addition, the SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene, suggesting that it could be modulated by local microbiota. Thus, the microbiome could play a key role in local SARS-CoV-2 replication and consequences of infection through mechanisms involving both immune modulation and viral receptor expression. Furthermore, we and others have shown that the oropharyngeal microbiome is the principal source of lung microbiota, which are derived from the URT by microaspiration, and so factors that affect the oropharyngeal microbiota likely also impact the lung microbiome with similar effects. We investigated hospitalized COVID-19 patients and found that the oropharyngeal (OP) microbiome differed markedly from healthy subjects and also from hospitalized patients with other illnesses. The OP microbiome at early sampling points correlated with maximum disease severity over the course of hospitalization. The OP microbiome also correlated with systemic immune parameters in blood. These findings raise the possibility that the microbiome in the oropharynx and upper respiratory region may influence severity of COVID-19. However, there is limited knowledge on the OP microbiome in groups and comorbidities (diabetes, obesity, elderly) associated with severe COVID-19 disease that might underlie this relationship. Our hypothesis is that the oropharyngeal microbiome plays a key role in regulating consequences of SARS- CoV-2 infection through modulation of ACE2 expression and/or immunity that determine whether infection is locally contained in the URT or propagates to LRT involvement to cause severe disease. This mechanism may act locally within the URT and also, by URT-LRT microbiome crosstalk, on the LRT. Our aims are to: (1) Define the oropharyngeal microbiome of individuals at risk of mild vs severe COVID-19, relationship to expression of ACE2 and relevant mucosal genes, and to microbiome communities seen in early COVID-19 patients. (2) Determine the effect of human-derived oropharyngeal microbiome communities, introduced in a novel murine model, on ACE2 and immune genes in oropharyngeal and lower airway epithelial cells.

COVID-19中的口咽微生物组 摘要（Abstract） SARS-CoV-2首先感染口咽和上呼吸道，在那里它要么保持局部， 清除，或传播到下呼吸道，在那里它可以进展为肺炎和呼吸衰竭。 几个患者因素与COVID-19严重程度增加相关，包括年龄较大、肥胖和糖尿病， 但将这些因素与COVID-19发病机制联系起来的机制尚不完全清楚。什么 确定SARS-CoV-2上呼吸道（URT）复制的程度以及感染是否仍然存在 因此，局部化或传播到下呼吸道（LRT）是一个关键的知识缺口。 对其他呼吸道病毒（RSV、流感）的研究表明，当地URT微生物组可以调节 免疫反应和影响肺部感染后果。此外，SARS-CoV-2受体ACE 2 是一种干扰素刺激的基因，这表明它可能受到当地微生物群的调节。因此，微生物组 可能通过机制在SARS-CoV-2的局部复制和感染后果中发挥关键作用 涉及免疫调节和病毒受体表达。此外，我们和其他人已经表明， 口咽部微生物组是肺部微生物组的主要来源，肺部微生物组通过以下途径来源于URT： 因此，影响口咽微生物群的因素也可能影响肺部微生物群。 具有相似的效果。 我们调查了住院的COVID-19患者，发现口咽（OP）微生物组不同， 明显来自健康受试者，也来自患有其他疾病的住院患者。OP微生物组在 早期采样点与住院期间的最大疾病严重程度相关。运算 微生物组还与血液中的全身免疫参数相关。这些发现提出了一种可能性， 口咽部和上呼吸道区域的微生物组可能影响COVID-19的严重程度。然而，在这方面， 对OP微生物组和合并症（糖尿病、肥胖症、老年人）的了解有限 与严重的COVID-19疾病相关，这可能是这种关系的基础。 我们的假设是，口咽微生物组在调节SARS后果中起着关键作用- CoV-2感染通过调节ACE 2表达和/或免疫来确定感染是否是 局部包含在URT中或传播到LRT参与引起严重疾病。该机制可以 在URT内局部作用，并且还通过URT-LRT微生物组串扰作用于LRT。我们的目标是： (1)定义轻度与重度COVID-19风险个体的口咽微生物组，关系 ACE 2和相关粘膜基因的表达，以及早期发现的微生物群落， 新冠肺炎患者。 (2)确定人源性口咽微生物群落的影响， 新的小鼠模型，在口咽和下气道上皮细胞中的ACE 2和免疫基因。