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

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

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1104-1122.e9
JournalMolecular Cell
Volume80
Issue number6
DOIs
StatePublished - Dec 17 2020

Keywords

  • COVID-19
  • SARS-CoV-2
  • antivirals
  • infection
  • mass spectrometry
  • pathogenesis
  • pathways
  • phosphoproteomics
  • pneumocytes
  • time course

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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