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

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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 mech...

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Detalles Bibliográficos
Autores principales: Hekman, Ryan M., Hume, Adam J., Goel, Raghuveera Kumar, 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 E.A., Verma, Mamta, Zhao, Jian, Patten, J.J., Villacorta-Martin, Carlos, Bolzan, Dante, Perea-Resa, Carlos, Bullitt, Esther, Hinds, Anne, Tilston-Lunel, Andrew, Varelas, Xaralabos, Farhangmehr, Shaghayegh, Braunschweig, Ulrich, 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Inc. 2020
Materias:
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674017/
https://www.ncbi.nlm.nih.gov/pubmed/33259812
http://dx.doi.org/10.1016/j.molcel.2020.11.028
Descripción
Sumario: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 that were validated by a high hit rate in a targeted small molecule screen in our iAT2 ALI system.

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