Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2

Hekman, Ryan M.; Hume, Adam J.; Goel, Raghuveera K.; Abo, Kristine M.; Huang, Jessie; Blum, Benjamin C.; Werder, Rhiannon B.; Suder, Ellen L.; Paul, Indranil; Phanse, Sadhna; Youssef, Ahmed; Alysandratos, Konstantinos D.; Padhorny, Dzmitry; Ojha, Sandeep; Mora-Martin, Alexandra; Kretov, Dmitry; Ash, Peter; Verma, Mamta; Zhao, Jian; Patten, J. J.; Villacorta-Martin, Carlos; Bolzan, Dante; Perea-Resa, Carlos; Bullitt, Esther; Hinds, Anne; Braunschweig, Ulrich; Farhangmehr, Shaghayegh; Tilston-Lunel, Andrew; Varelas, Xaralabos; Kwan, Julian H.; McComb, Mark; Basu, Avik; Saeed, Mohsan; Perissi, Valentina; Burks, Eric J.; Layne, Matthew D.; Connor, John H.; Davey, Robert; Cheng, Ji-Xin; Wolozin, Benjamin L.; Blencowe, Benjamin J.; Wuchty, Stefan; Lyons, Shawn M.; Kozakov, Dima; Cifuentes, Daniel; Blower, Michael; Kotton, Darrell N.; Wilson, Andrew A.; Mühlberger, Elke; Emili, Andrew

Human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative pathogen of the COVID-19 pandemic, exerts a massive health and socioeconomic crisis. The virus infects alveolar epithelial type 2 cells (AT2s), leading to lung injury and impaired gas exchange, but the mechanisms driving infection and pathology are unclear. We performed a quantitative phosphoproteomic survey of induced pluripotent stem cell-derived AT2s (iAT2s) infected with SARS-CoV-2 at air-liquid interface (ALI). Time course analysis revealed rapid remodeling of diverse host systems, including signaling, RNA processing, translation, metabolism, nuclear integrity, protein trafficking, and cytoskeletal-microtubule organization, leading to cell cycle arrest, genotoxic stress, and innate immunity. Comparison to analogous data from transformed cell lines revealed respiratory-specific processes hijacked by SARS-CoV-2, highlighting potential novel therapeutic avenues which were validated by a high hit rate in a targeted small molecule screen in our iAT2 ALI system.