The nasal microbiome modulates risk for SARS-CoV-2 infection

Background: The nasal microbiome may influence host risk for COVID-19 by modulating the expression of key proteins that facilitate SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2), which binds the virus, and transmembrane serine protease 2 (TMPRSS2), which activates viral entry into nasal epithelial cells. This study examined whether the expression levels of ACE2 and TMPRSS2 in the nasal cavity predict the risk of SARS-CoV-2 infection and whether the host nasal microbiome modulates their expression. Methods: Using 1548 self-collected nasal swabs from a population-based surveillance testing of community-dwelling adults in Washington D.C., we conducted two retrospective case–control studies (cross-sectional: n = 111 cases and 343 controls; longitudinal: n = 97 cases, 286 controls) and a nasal microbiome study (n = 428). Cases, defined as individuals with a positive SARS-CoV-2 test, were matched with controls based on age and test date. Pre-infection samples were analysed. We measured nasal ACE2/TMPRSS2 expression using RT-qPCR and characterized the nasal microbiome using 16S rRNA gene-based qPCR and sequencing. We used machine learning and regression analysis to determine if nasal ACE2/TMPRSS2 expression predicts SARS-CoV-2 infection and whether the nasal microbiome influences their expression. Findings: Elevated nasal ACE2/TMPRSS2 expression was associated with 3.6-fold increased risk of contracting COVID-19 (95% CI = 1.71–7.47) compared to those with no detectable levels of ACE2 or TMPRSS2. Before testing positive for SARS-CoV-2, cases also had significantly higher and more unstable ACE2/TMPRSS2 expression in their nasal cavity than controls. Having high densities of Staphylococcus aureus, Haemophilus influenzae, or Moraxella catarrhalis/nonliquefaciens was linked to increased nasal ACE2/TMPRSS2 expression. In contrast, having high densities of Dolosigranulum pigrum was associated with decreased nasal ACE2/TMPRSS2 expression. Interpretation: These results suggest that natural variation in the nasal microbiome significantly impacts ACE2/TMPRSS2 expression in the nasal cavity and the near-term risk of SARS-CoV-2 infection in adults. Modifying the nasal microbiome could potentially reduce COVID-19 risk. Funding: Research reported in this article was supported by the Milken Institute School of Public Health, the George Washington University and the National Institute of Allergy and Infectious Diseases, National Institutes of Health under award number R01AI168182. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.