PROJECT SUMMARY: This is an administrative supplement to the parent R01 “Understanding the Molecular Genetic Mechanisms of Asthma Risk Loci: IL33, IL1RL1, and GSDMB,” which focuses on understanding how genetic polymorphisms alter epithelial secretion of the IL-1 family cytokine, IL-33. This supplement entitled “Clash of Titans: Understanding the Airway Epithelial Interferon and IL-1 Response to SARS-CoV-2 Infection,” addresses a critical need during a global pandemic. Our hypothesis is that a key virulence factor in the SAR-CoV-2 virus, the E protein, triggers IL-1B secretion from epithelial cells in a gasdermin and caspase dependent manner. That IL-1 secretion acts in an autocrine fashion, to inhibit critical interferon responses that are required to constrain the virus to the upper airway and prevent lower airway infection. The proposal allows our laboratory to use genetically altered cell lines that we generated as part of the parent grant to quickly study the balance of interferon and IL-1 responses of the airway epithelium to SARS-CoV-2 infection and test commercially available drugs that block caspases or IL-1 signaling to inhibit viral replication. This proposal seeks to rapidly translate our current understanding of airway epithelial cell biology to address a critical need for therapeutics against the SARS-CoV-2 virus which has currently infected more than a million people worldwide and killed over 60,000 in less than 4 months.