Balancing epithelial cell resistance and resilience to respiratory viral infections

SUPPLEMENT PROJECT SUMMARY Single-cell studies of the nasal mucosa of COVID-19 and influenza patients have helped to identify epithelial cell subsets and states that are associated with disease severity. Our project's goal is to determine the roles of specific transcription factors in specifying the fates and functions of discrete nasal epithelial cell subsets. We have prioritized these epithelial subsets, which appear to emerge from the goblet cell lineage, based on our preliminary data that highlight how closely-related goblet cell subsets are significantly enriched or depleted as targets of viral infection. Our central hypothesis is that the combined activation of two transcription factors will specify goblet cells that are uniquely-protected from RNA viral infection. Aim 1 will determine the downstream targets and gene regulatory networks induced by these transcriptional regulators, and Aim 2 will investigate the role of these transcription factors in regulating antiviral immunity in goblet cells. Identifying the transcriptional regulators of these goblet cells will allow for the generation of better ex vivo models to study their function, and to potentially rebalance epithelial cells in vivo to better-protect the nasal mucosa from viral infection.