The Respiratory Microbiome in COVID-19: Associations with Severity, Risk Factors, and Host Pathways

COVID-19 中的呼吸道微生物组：与严重程度、风险因素和宿主途径的关联

• 批准号: 10750387
• 负责人: Carter Merenstein
• 金额: $ 4.77万
• 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: 2023-09-30 至 2026-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750387
• 关键词: 2019-nCoV; ACE2; Acceleration; Actinomyces; Address; Affect; Age; Animal Model; Antibiotics; Bacteria; COVID-19; COVID-19 impact; COVID-19 patient; COVID-19 risk; COVID-19 severity; Cessation of life; Clinical; Data; Databases; Development; Diabetes Mellitus; Disease; Disease Outcome; Enrollment; Etiology; Experimental Animal Model; Experimental Designs; Future; Gene Expression; Genes; Graph; Hand; Hemophilus; Heterogeneity; Hospitalization; Immune; Immune response; In Vitro; Individual; Infection; Interferon Type II; Life; Link; Literature; Lung diseases; Lung infections; Machine Learning; Manuals; Mediating; Methods; Microbe; Neisseria; Obesity; Oropharyngeal; Outcome; Pathway interactions; Patients; Phenotype; Prevotella; Publishing; Respiratory Disease; Respiratory Failure; Respiratory System; Respiratory Tract Infections; Risk; Risk Factors; SARS-CoV-2 infection; Sampling; Severities; Severity of illness; Shapes; Specificity; Specimen; Stratification; Symptoms; Taxonomy; Techniques; Uncertainty; Upper respiratory tract; Validation; Viral; Virus; Virus Diseases; Work; cell type; clinical phenotype; cohort; comorbidity; coronavirus disease; cytokine; cytokine release syndrome; dysbiosis; experimental study; follow-up; high risk; host microbiome; host-associated microbial communities; host-microbe interactions; human old age (65+); immunoregulation; knowledge graph; metagenomic sequencing; microbiome; microbiome alteration; microbiome composition; microbiome research; morphogens; multiple data types; oral commensal; pathogen; protein protein interaction; public database; respiratory microbiome; severe COVID-19; superinfection; supplemental oxygen; synergism; tool; transcriptome sequencing

COVID-19 has caused unprecedented loss of life and global disruption since its emergence in 2019. Caused by the SARS CoV-2 virus, this infection shows extreme heterogeneity, ranging from completely asymptomatic to deadly. One factor that has been linked to COVID-19 severity is the microbiome of the upper respiratory tract, specifically the oropharynx. Lower relative abundance of oral commensal taxa, such as Haemophilus, Neisseria, Prevotella, and Actinomyces, and lower alpha diversity are seen in severe COVID-19 patients compared to individuals with more moderate disease. The mechanism of this association is still unknown, and it is unclear in which direction causation occurs. We propose to further examine the association between the respiratory microbiome and COVID-19 by 1) increasing specificity of these associations to the species, strain, and gene level, 2) identifying how comorbidities shape the respiratory microbiome prior to SARS CoV-2 infection, and 3) identifying host pathways that may be involved in these associations. For this first aim, we will leverage a cohort of over 200 hospitalized COVID-19 patients (previously enrolled and specimens already in hand), using deep metagenomic sequencing for taxonomic and functional annotation. The increased specificity provided by this aim will pave the way for in vitro or animal model experiments, which require species or strain level associations for proper experimental design. The second aim will focus on respiratory tract microbiome profiles in individuals with obesity, diabetes, or old age (who do not and have not had COVID-19), three conditions that are strongly associated with elevated risk of severe COVID-19. The effect that these have on the respiratory microbiome is unknown, but one still untested possibility is that the microbiome mediates some of the effects of these conditions on disease severity. By studying microbiome alterations in these diseases prior to SARS CoV-2 infection we could identify a potential high risk microbiome that precedes severe COVID- 19. Finally, the third aim pulls data from a diverse set of databases to create a knowledge graph of microbe- disease-gene associations. Using knowledge graph completion, we will predict host genes that both associate with COVID-19 severity, and interact with bacteria in the upper airway. With this data, we can propose possible host mechanisms that mediate microbiome-COVID-19 associations, allowing for in vitro follow-up to move from correlation to causation. Ultimately, this work is a bridge between existing high level associations between COVID-19 and the upper respiratory microbiome, and future work targeting specific mechanisms and causal links. Having recently published a review on all studies of the airway microbiome in COVID-19, we believe that these aims address the most critical gaps in understanding currently in the literature.

自2019年出现以来，Covid-19造成了前所未有的生命和全球破坏。 通过SARS COV-2病毒，这种感染显示出极端的异质性，范围从完全无症状 致命。与COVID-19的严重程度有关的一个因素是上呼吸道的微生物组 区域，特别是口咽。较低的口腔共生类群的相对丰度，例如嗜血杆菌， 在严重的Covid-19患者中，可见奈瑟氏菌，prevotella和放线菌以及较低的α多样性 与患有更为中度疾病的个体相比。该关联的机制仍然未知，并且 目前尚不清楚发生哪个方向发生。我们建议进一步研究 呼吸微生物组和covid-19 by 1）提高这些关联对物种的特异性，应变， 和基因水平，2）确定合并症如何在SARS COV-2之前塑造呼吸微生物组 感染和3）识别可能与这些关联有关的宿主途径。对于第一个目标，我们将 利用200多名住院Covid-199患者组成的队列（以前入学和标本已经进入 手），使用深核测序进行分类和功能注释。提高的特异性 该目标提供的目标将为体外或动物模型实验铺平道路，这些实验需要物种或应变 适当实验设计的水平关联。第二个目标将集中于呼吸道微生物组 患有肥胖，糖尿病或老年人的人（没有且没有共同的人），三个，三个 与严重的共同风险升高有关的条件与19号。这些对 呼吸微生物组尚不清楚，但仍未测试的可能性是微生物组介导了一些 这些疾病对疾病严重程度的影响。通过研究这些疾病的微生物组改变 在SARS COV-2感染之前，我们可以确定一个潜在的高风险微生物组，该微生物组在严重的covid- 19.最后，第三个目标从各种数据库中提取数据，以创建微生物的知识图 疾病 - 基因协会。使用知识图完成，我们将预测既关联的宿主基因 与19号的严重程度，并与上呼吸道的细菌相互作用。有了这些数据，我们可以提出可能 介导微生物组cOVID-19关联的宿主机制，可以在体外随访从 与因果关系的相关性。最终，这项工作是现有高级关联之间的桥梁 Covid-19和上呼吸道微生物组以及针对特定机制和因果的未来工作 链接。最近发表了有关Covid-19的气道微生物组所有研究的评论，我们相信 这些目的解决了文献中当前理解中最关键的差距。