Understanding the Molecular Genetic Mechanisms of Asthma Risk Loci: IL33, IL1RL1, and GSDMB - COVID 19 Supplement

This is an administrative supplement to the parent R01 "Understanding the Molecular Genetic Mechanisms ofAsthma Risk Loci: IL33, IL1RL1, and GSDMB," which focuses on understanding how genetic polymorphismsalter 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 acritical 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 toconstrain the virus to the upper airway and prevent lower airway infection. The proposal allows our laboratoryto use genetically altered cell lines that we generated as part of the parent grant to quickly study the balance ofinterferon and IL-1 responses of the airway epithelium to SARS-CoV-2 infection and test commerciallyavailable drugs that block caspases or IL-1 signaling to inhibit viral replication. This proposal seeks to rapidlytranslate our current understanding of airway epithelial cell biology to address a critical need for therapeuticsagainst the SARS-CoV-2 virus which has currently infected more than a million people worldwide and killedover 60,000 in less than 4 months.