The Oropharyngeal Microbiome in COVID-19

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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.