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

Mol Cell. 2020 Dec 17;80(6):1104-1122.e9. doi: 10.1016/j.molcel.2020.11.028. Epub 2020 Nov 19.


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.

Keywords: COVID-19; SARS-CoV-2; antivirals; infection; mass spectrometry; pathogenesis; pathways; phosphoproteomics; pneumocytes; time course.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alveolar Epithelial Cells / metabolism*
  • Alveolar Epithelial Cells / pathology
  • Alveolar Epithelial Cells / virology
  • Animals
  • Antiviral Agents
  • COVID-19 / genetics
  • COVID-19 / metabolism*
  • COVID-19 / pathology
  • COVID-19 Drug Treatment
  • Chlorocebus aethiops
  • Cytopathogenic Effect, Viral
  • Cytoskeleton
  • Drug Evaluation, Preclinical
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology
  • Induced Pluripotent Stem Cells / virology
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Transport
  • Proteome / genetics
  • Proteome / metabolism*
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / metabolism*
  • Signal Transduction
  • Vero Cells


  • Antiviral Agents
  • Phosphoproteins
  • Proteome