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

Autor: Carlos Villacorta-Martin, Shaghayegh Farhangmehr, Ryan M. Hekman, Mohsan Saeed, Carlos Perea-Resa, Robert A. Davey, Andrew Emili, Jian Zhao, Peter E.A. Ash, Raghuveera Kumar Goel, Benjamin C. Blum, Andrew A. Wilson, Benjamin J. Blencowe, Ulrich Braunschweig, Benjamin Wolozin, Andrew Tilston-Lunel, Darrell N. Kotton, Ji-Xin Cheng, Avik Basu, Alexandra Mora-Martin, Esther Bullitt, Rhiannon B. Werder, Mark E. McComb, Dmitry A. Kretov, Dzmitry Padhorny, Sandeep Ojha, Shawn M. Lyons, Konstantinos D. Alysandratos, Jessie Huang, Anne Hinds, Valentina Perissi, J. J. Patten, Ahmed Youssef, Xaralabos Varelas, John H Connor, Dima Kozakov, Mamta Verma, Dante Bolzan, Indranil Paul, Ellen L Suder, Eric J. Burks, Matthew D. Layne, Elke Mühlberger, Stefan Wuchty, Adam J. Hume, Daniel Cifuentes, Sadhna Phanse, Julian H. Kwan, Michael D. Blower, Kristine M. Abo
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Cell cycle checkpoint
Proteome
Cell
pathways
Drug Evaluation
Preclinical
0302 clinical medicine
antivirals
Cytopathogenic Effect
Viral
Chlorocebus aethiops
Induced pluripotent stem cell
Pathogen
Cytoskeleton
mass spectrometry
0303 health sciences
pathogenesis
Phosphoproteomics
phosphoproteomics
Translation (biology)
respiratory system
Protein Transport
medicine.anatomical_structure
Signal Transduction
Resource
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Induced Pluripotent Stem Cells
Lung injury
Biology
Antiviral Agents
Virus
03 medical and health sciences
medicine
Animals
Humans
Vero Cells
Molecular Biology
030304 developmental biology
time course
Innate immune system
Alveolar type
Host (biology)
SARS-CoV-2
Correction
COVID-19
pneumocytes
Cell Biology
Phosphoproteins
Virology
infection
COVID-19 Drug Treatment
Alveolar Epithelial Cells
030217 neurology & neurosurgery
Zdroj: Molecular Cell
ISSN: 1097-2765
DOI: 10.1016/j.molcel.2020.11.028
Popis: 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.
Graphical Abstract
Highlights • SARS-CoV-2 infection in induced lung cells is characterized by phosphoproteomics • Analysis of response reveals host cell signaling and protein expression profile • Comparison to studies in undifferentiated cell lines shows unique pathology in iAT2s • Systems-level predictions find druggable pathways that can impede viral life cycle
Hekman et al. describe how a layer of primary stem cells (iAT2s) recapitulating lung biology responds to infection with SARS-CoV-2. They compare their work to previous studies with immortalized cell lines. Their data predict what effect the virus has on a lung cell and which drugs may slow infection.
Databáze: OpenAIRE
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