SARS-CoV-2 Disrupts Proximal Elements in the JAK-STAT Pathway
Da‐Yuan Chen, Nazimuddin Khan, Brianna J. Close, Raghuveera Kumar Goel, Benjamin C. Blum, Alexander H. Tavares, Devin Kenney, Hasahn L. Conway, Jourdan K. Ewoldt, Vipul C. Chitalia, Nicholas A. Crossland, Christopher S. Chen, Darrell N. Kotton, Susan C. Baker, Serge Y. Fuchs, John H. Connor, Florian Douam, Andrew Emili, Mohsan Saeed
Abstract
SARS-CoV-2 can infect various organs in the human body, but the molecular interface between the virus and these organs remains unexplored. In this study, we generated a panel of highly infectible human cell lines originating from various body organs and employed these cells to identify cellular processes commonly or distinctly disrupted by SARS-CoV-2 in different cell types. One among the universally impaired processes was interferon signaling. Systematic analysis of this pathway in diverse culture systems showed that SARS-CoV-2 targets the proximal JAK-STAT pathway components, destabilizes the type I interferon receptor though ubiquitination, and consequently renders the infected cells resistant to type I interferon. These findings illuminate how SARS-CoV-2 can continue to propagate in different tissues even in the presence of a disseminated innate immune response.