Nasal Symbiont <i>Staphylococcus Epidermidis</i> Promotes the Cellular Environment Lacking Airway Proteases to Restrict the Cellular Entry of Influenza a Virus in the Nasal Epithelium

Abstract

Background: Our recent study presented that human nasal commensal Staphylococcus Epidermidis could potentiate antiviral immunity in the nasal mucosa through interferon-related innate responses. Here, we found that human nasal commensal S. epidermidis promoted protease–protease inhibitor balance in favor of the host and prevented influenza A virus (IAV) replication in the nasal mucosa and lungs. Methods: We examined the contribution of intranasal administration of human nasal S. epidermidis in controlling IAV infection using murine model and culture nasal epithelial cells. IAV mRNA, viral titer, nucleoprotein levels, and histopathologic findings were evaluated. The induction of S. epidermidis-regulated serine protease inhibitors and correlation of serine proteases were also determined. Findings: A relatively higher induction of Serpine1 exhibited in S. epidermidis-inoculated nasal epithelium and S. epidermidis-induced Serpine1 significantly decreased the expression of serine proteases. Furthermore, the transcription of urokinase plasminogen activator (uPA) and Serpine1 was biologically relevant in S. epidermidis-inoculated nasal epithelium, and the induction of uPA might be related with the sequential increase of Serpine1 in human nasal epithelium. Interpretation: Our findings reveal that human nasal commensal S. epidermidismanipulates the cellular environment lacking serine proteases in the nasal epithelium through Serpine1 induction and disturbs IAV spread to the lungs at the level of the nasal mucosa. 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, 2019M3C9A6091945, 2017M3A9F3041233) and was also supported by a grant from the Korean Health Technology R&D Project through the Korean Health Industry Development Institute, funded by the Ministry of Health & Welfare of the Republic of Korea (HI20C0546). Declaration of Interest: None to declare. Ethical Approval: The institutional review board (IRB) of the Seoul National University College of Medicine approved the protocol for this study (IRB #C2012248 [943]). In vivo experiments with C57BL/6J mice were carried out according to guidelines approved by the IRB of the Seoul National University College of Medicine (IACUC #2016-0093).