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

基本信息

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
项目类别：
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

项目摘要

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损失和全球破坏。这种感染是由 SARS CoV-2 病毒引起的，表现出极大的异质性，从完全无症状到至致命。与 COVID-19 严重程度相关的因素之一是上呼吸道微生物组道，特别是口咽部。口腔共生类群的相对丰度较低，例如嗜血杆菌，在重症 COVID-19 患者中观察到奈瑟氏菌、普雷沃氏菌和放线菌以及较低的 α 多样性与患有较轻疾病的个体相比。这种关联的机制尚不清楚，并且目前尚不清楚因果关系发生在哪个方向。我们建议进一步研究两者之间的关联呼吸道微生物组和 COVID-19 通过 1) 增加这些关联与物种、菌株、和基因水平，2) 确定合并症如何在 SARS CoV-2 之前塑造呼吸道微生物组感染，3) 确定可能参与这些关联的宿主途径。为了这第一个目标，我们将利用 200 多名住院的 COVID-19 患者组成的队列（之前已入组且样本已在手），使用深度宏基因组测序进行分类和功能注释。增加的特异性这一目标所提供的将为体外或动物模型实验铺平道路，这需要物种或菌株适当实验设计的水平关联。第二个目标将重点关注呼吸道微生物组患有肥胖症、糖尿病或老年（没有感染过也没有感染过 COVID-19）的个体的概况，三与严重 COVID-19 风险升高密切相关的疾病。这些所带来的影响呼吸道微生物组尚不清楚，但一种尚未测试的可能性是微生物组介导了一些这些条件对疾病严重程度的影响。通过研究这些疾病中微生物组的变化在 SARS CoV-2 感染之前，我们可以在严重的 COVID-1 之前识别出潜在的高风险微生物组 19. 最后，第三个目标是从不同的数据库中提取数据，创建微生物知识图谱。疾病-基因关联。使用知识图补全，我们将预测两者关联的宿主基因与 COVID-19 的严重程度有关，并与上呼吸道细菌相互作用。有了这些数据，我们可以提出可能的建议介导微生物组-COVID-19关联的宿主机制，允许体外随访从相关性与因果关系。最终，这项工作是现有高层协会之间的一座桥梁 COVID-19 和上呼吸道微生物组，以及针对特定机制和因果关系的未来工作链接。最近发表了一篇关于 COVID-19 气道微生物组所有研究的综述，我们认为这些目标解决了目前文献中最关键的理解差距。