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 B Werder; Ellen L Suder; Indranil Paul; Sadhna Phanse; Ahmed Youssef; Konstantinos D Alysandratos; Dzmitry Padhorny; Sandeep Ojha; Alexandra Mora-Martin; Dmitry Kretov; Peter E A Ash; Mamta Verma; Jian Zhao; J J Patten; Carlos 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

doi:10.1016/j.molcel.2020.11.028

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.

Authors

Ryan M Hekman¹, Adam J Hume², Raghuveera Kumar Goel¹, Kristine M Abo³, Jessie Huang³, Benjamin C Blum¹, Rhiannon B Werder³, Ellen L Suder², Indranil Paul¹, Sadhna Phanse⁴, Ahmed Youssef⁵, Konstantinos D Alysandratos³, Dzmitry Padhorny⁶, Sandeep Ojha⁷, Alexandra Mora-Martin⁷, Dmitry Kretov⁷, Peter E A Ash⁸, Mamta Verma⁸, Jian Zhao⁹, J J Patten², Carlos Villacorta-Martin¹⁰, Dante Bolzan¹¹, Carlos Perea-Resa¹², Esther Bullitt¹³, Anne Hinds¹⁴, Andrew Tilston-Lunel⁷, Xaralabos Varelas⁷, Shaghayegh Farhangmehr¹⁵, Ulrich Braunschweig¹⁶, Julian H Kwan¹, Mark McComb¹⁷, Avik Basu¹, Mohsan Saeed¹⁸, Valentina Perissi⁷, Eric J Burks¹⁹, Matthew D Layne⁷, John H Connor², Robert Davey², Ji-Xin Cheng²⁰, Benjamin L Wolozin⁸, Benjamin J Blencowe¹⁵, Stefan Wuchty²¹, Shawn M Lyons⁷, Dima Kozakov⁶, Daniel Cifuentes⁷, Michael Blower²², Darrell N Kotton²³, Andrew A Wilson²⁴, Elke Mühlberger²⁵, Andrew Emili²⁶

Affiliations

¹ Center for Network Systems Biology, Boston University, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
² Department of Microbiology, Boston University School of Medicine, Boston, MA, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA.
³ Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA; The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
⁴ Center for Network Systems Biology, Boston University, Boston, MA, USA.
⁵ Center for Network Systems Biology, Boston University, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA; Bioinformatics Program, Boston University, Boston, MA, USA.
⁶ Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, USA.
⁷ Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
⁸ Department of Pharmacology, Boston University School of Medicine, Boston, MA, USA.
⁹ Department of Electrical and Computer Engineering, Boston University, Boston, MA, USA.
¹⁰ Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA.
¹¹ Department of Computer Science, University of Miami, Miami, FL, USA.
¹² Department of Molecular Biology, Harvard Medical School, Boston, MA, USA.
¹³ Department of Physiology and Biophysics, Boston University, Boston, MA, USA.
¹⁴ The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
¹⁵ Donnelly Centre, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁶ Donnelly Centre, University of Toronto, Toronto, ON, Canada.
¹⁷ Center for Network Systems Biology, Boston University, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA; Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, MA, USA.
¹⁸ Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA.
¹⁹ Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
²⁰ Department of Biomedical Engineering, Boston University, Boston, MA, USA.
²¹ Department of Computer Science, University of Miami, Miami, FL, USA; Department of Biology, University of Miami, Miami, FL, USA; Miami Institute of Data Science and Computing, Miami, FL, USA.
²² Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA; Department of Molecular Biology, Harvard Medical School, Boston, MA, USA.
²³ Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA; The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. Electronic address: dkotton@bu.edu.
²⁴ Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA; The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. Electronic address: awilson@bu.edu.
²⁵ Department of Microbiology, Boston University School of Medicine, Boston, MA, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA. Electronic address: muehlber@bu.edu.
²⁶ Center for Network Systems Biology, Boston University, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA; Department of Biology, Boston University, Boston, MA, USA. Electronic address: aemili@bu.edu.

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.

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

Substances

Antiviral Agents
Phosphoproteins
Proteome

Abstract

Publication types

MeSH terms

Substances

Grants and funding