Innate Immune Regulation of the Epithelium in Chronic Rhinosinusitis with Nasal Polyps

ABSTRACTThe ongoing outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acuterespiratory syndrome coronavirus 2 (SARS-CoV-2), has become a major threat to global health.The nasal passages are the key portal of entry for airway virus infections, and evidencesuggests that the nasal epithelium is a key reservoir for SARS-CoV-2 and a source of viralshedding that accounts for high transmissibility and elevated rates of COVID-19. We hypothesize that diminished interferon-induced innate immune responses in infected nasal epithelial cells is a primary mechanism allowing rapid viral replication without cytotoxicity. Theparent grant focuses on how human sinonasal epithelial cell populations participate in immunedefense and damage repair. In this supplement proposal, in response to NOT-AI-20-031, wewill extend these studies to research in depth the epithelial cell innate immune response toSARS-CoV-2. Specifically, delayed interferon signaling may prevent induction of nitric oxide,which has been previously shown to inhibit viral entry and replication. Nitric oxide can beinduced in nasal epithelial by stimuli other than interferon, including through activation of bittertaste receptors expressed on the cilia. There are a number of approved medications in clinicaluse that taste bitter and can bind to bitter taste receptors. Among these, certain anti-nausea and antihistamines are particularly strong bitter taste agonists. In this proposal, we will test the ability of these medications to inhibit SARS-CoV-2 infection of primary nasal epithelial cells invitro. We will then use pharmacologic modulators of the bitter taste signaling and nitric oxidepathways to establish the mechanism of action of drugs that decrease infection. We will also determine if these medications impact the interferon response to SARS-CoV-2 infection. Ifsuccessful, these studies may lay the foundation for novel therapeutic approaches to enhancethe initial epithelial cell innate immune defense against SARS-CoV-2 infection, limitingprogression of COVID-19 and decreasing transmissibility.