The Nasal Symbiont Staphylococcus Epidermidis Restricts the Transcription of SARS-CoV-2 Entry Factors in Human Nasal Epithelium

Emerging evidence indicates that severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) targets the human nasal epithelium via the principal entry factors angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), which are highly expressed in the nasal epithelium. However, little is known about suppressive biologics against SARS-CoV-2 entry factors. Here, we show that the nasal commensal Staphylococcus epidermidis altered the host transcriptional response against SARS-CoV-2 by reducing ACE2 and TMPRSS2 gene expression in concert with an increase in serine protease inhibitors. Our data reveal that ACE2 was more abundantly expressed in nasal epithelial (NHNE) cells than bronchial epithelial cells, and inoculation with S. epidermidis reduced ACE2 transcription in NHNE cells. TMPRSS2 mRNA was significantly decreased in NHNE cells and S. epidermidis colony number in human nasal mucus was inversely correlated with ACE2 and TMPRSS2 gene expression in nasal mucosa. In addition, levels of the serine protease inhibitors SERPINE1 and SERPINE2 were significantly increased by S. epidermidis , and this accompanied reduction of TMPRSS2 transcription in nasal epithelial cells. These results characterize the S. epidermidis -regulated host transcriptional response restricting SARS-CoV-2 entry to the nasal epithelium via downregulation of cellular receptors and principal host protease of SARS-CoV-2 coupled with SERPINE1 and SERPINE2 induction.Funding: This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2016R1D1A1B01014116 and 2019M3C9A6091945 to HJK). This research was also supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare of the Republic of Korea (HI20C0546 to HJK).Declaration of Interest: The authors declare that the research was conducted in the absence of anycommercial or financial relationships that could be construed as potential conflicts ofinterest.Ethical Approval: Participation was voluntary, with written informed consent obtained from all subjects.This study was approved by the Institutional Review Board (IRB) of the SeoulNational University College of Medicine (no. 1709-049-883).