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（摘要） SARS-COV-2首先感染了口咽和上呼吸道，在该区域保持局部，并且是 清除或传播到下呼吸道，在那里它可以发展为肺炎和呼吸衰竭。 几个患者因素与199年的covid严重程度的增加相关，包括年龄较大，肥胖和糖尿病， 但是，将这些因素与Covid-19发病机理联系起来的机制尚不完全理解。什么 确定SARS-COV-2上呼吸道（URT）复制的程度 因此，局部或传播下呼吸道（LRT）是一个关键的知识差距。 使用其他呼吸道病毒（RSV，流感）的研究表明，局部URT微生物组可以调节 免疫反应和影响感染的肺后果。另外，SARS-COV-2受体ACE2 是干扰素刺激的基因，表明它可以由局部菌群调节。因此，微生物组 可以通过机制在局部SARS-COV-2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，我们和其他人表明 口咽微生物组是肺微生物群的主要来源，它是从URT得出的 微型诱惑，以及影响口咽微生物群的因素也可能影响肺微生物组 有类似的效果。 我们研究了住院的Covid-19患者，发现口咽（OP）微生物组有所不同 明显来自健康的受试者，也来自住院的其他疾病患者。 OP微生物组 早期抽样点与住院过程中最大疾病严重程度相关。 OP 微生物组也与血液中的全身免疫参数相关。这些发现增加了 口咽和上呼吸区的微生物组可能会影响COVID-19的严重程度。然而， 在组和合并症中对OP微生物组的知识有限（糖尿病，肥胖，老年人） 与可能是这种关系的基础的严重共同疾病有关。 我们的假设是，口咽微生物组在调节SARS-的后果中起关键作用 通过调节ACE2表达和/或免疫力来确定感染是否为 局部包含在URT中或传播LRT参与以引起严重疾病。这种机制可能 在LRT上局部起作用在URT内，还通过URT-LRT微生物组串扰。我们的目标是： （1）定义具有轻度与严重covid-19的风险的个体的口咽微生物组，关系 表达ACE2和相关粘膜基因，以及早期看到的微生物组群落 Covid-19患者。 （2）确定在A中引入的人源性口咽微生物组群落的影响 新颖的鼠模型，在ACE2和口咽和下部气道上皮细胞中的ACE2和免疫基因上。