TY - JOUR
T1 - Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2
AU - Hekman, Ryan M.
AU - Hume, Adam J.
AU - Goel, Raghuveera Kumar
AU - Abo, Kristine M.
AU - Huang, Jessie
AU - Blum, Benjamin C.
AU - Werder, Rhiannon Bree
AU - Suder, Ellen L.
AU - Paul, Indranil
AU - Phanse, Sadhna
AU - Youssef, Ahmed
AU - Alysandratos, Kostantinos D.
AU - Padhorny, Dzmitry
AU - Ojha, Sandeep
AU - Mora-Martin, Alexandra
AU - Kretov, Dmitry
AU - Ash, Peter
AU - Varma, Mamta
AU - Zhao, Jian
AU - Patten, J. J.
AU - Villacorta-Martin, Carlos
AU - Bolzan, Dante
AU - Perea-Resa, Carlos
AU - Bullitt, Esther
AU - Hinds, Anne
AU - Tilston-Lunel, Andrew
AU - Varelas, Xaralabos
AU - Farhangmehr, Shaghayegh
AU - Braunschweig, Ulrich
AU - Kwan, Julian H.
AU - McComb, Mark
AU - Basu, Avik
AU - Saeed, Mohsan
AU - Perissi, Valentina
AU - Burks, Eric J.
AU - Layne, Matthew D.
AU - Connor, John H.
AU - Davey, Robert
AU - Cheng, Ji Xin
AU - Wolozin, Benjamin L.
AU - Blencowe, Benjamin J.
AU - Wuchty, Stefan
AU - Lyons, Shawn M.
AU - Kozakov, Dima
AU - Cifuentes, Daniel
AU - Blower, Michael
AU - Kotton, Darrell N.
AU - Wilson, Andrew A.
AU - Mühlberger, Elke
AU - Emili, Andrew
N1 - Funding Information:
We thank team members for expert support. We acknowledge the following sources of funding: NIH F30HL147426 to K.M.A.; CJ Martin Fellowship from the Australian NHMRC to R.B.W.; IM Rosenzweig Award, Pulmonary Fibrosis Foundation to K.D.A.; NIH AG056318 , AG064932 , AG061706 , and AG050471 to B.L.W.; NIH RM1 GM135136 and R21GM127952 and NSF AF1816314 to D. Kozakov; Evergrande MassCPR , C3.ai Digital Transformation Institute Award , and NIH R01HL128172 , R01HL095993 , R01HL122442 , U01HL134745 , and U01HL134766 to D.N.K.; CIHR , COVID-19 Action Initiative to B.J.B.; NIH HL007035T32 to E.L.S.; NIH R01AI125453 , P01AI120943 , and R01AI128364 and Massachusetts Consortium on Pathogen Readiness to J.J.P. and R.D.; NIH U01TR001810 , UL1TR001430 , R01DK101501 , and R01DK117940 to A.A.W.; Fast Grants , Evergrande MassCPR , and NIH R01AI133486 , R21AI135912 , R21AI137793 , and R21AI147285 to E.M.; and NIH 1UL1TR001430 , RO1AG064932 , and RO1AG061706 to A.E.
Funding Information:
We thank team members for expert support. We acknowledge the following sources of funding: NIH F30HL147426 to K.M.A.; CJ Martin Fellowship from the Australian NHMRC to R.B.W.; IM Rosenzweig Award, Pulmonary Fibrosis Foundation to K.D.A.; NIH AG056318, AG064932, AG061706, and AG050471 to B.L.W.; NIH RM1 GM135136 and R21GM127952 and NSF AF1816314 to D. Kozakov; Evergrande MassCPR, C3.ai Digital Transformation Institute Award, and NIH R01HL128172, R01HL095993, R01HL122442, U01HL134745, and U01HL134766 to D.N.K.; CIHR, COVID-19 Action Initiative to B.J.B.; NIH HL007035T32 to E.L.S.; NIH R01AI125453, P01AI120943, and R01AI128364 and Massachusetts Consortium on Pathogen Readiness to J.J.P. and R.D.; NIH U01TR001810, UL1TR001430, R01DK101501, and R01DK117940 to A.A.W.; Fast Grants, Evergrande MassCPR, and NIH R01AI133486, R21AI135912, R21AI137793, and R21AI147285 to E.M.; and NIH 1UL1TR001430, RO1AG064932, and RO1AG061706 to A.E. We thank Greg Miller and Marianne James (CReM Laboratory and iPSC Core Managers), Mitchell White and Baylee Heiden (technical support M?hlberger lab), and Joseph Corbett (Controls Manager NEIDL). Bulk RNA-seq library preparation, sequencing, and data analysis was performed by the Molecular Biology Core Facility at Dana-Farber Cancer Institute. Conceptualization: E.M. D.N.K. A.E.; Experiments: R.M.H. A.J.H. R.K.G. R.B.W. E.L.S. E.B. A.H. U.B. J.H. S.D.; Methodology/Advice: A.A.W. K.D.A. J.H.C. B.C.B. M.S. R.D. M.M. S.W. K.M.A. R.B.W. J.H.; Analysis: A.Y. R.K.G. I.P. B.C.B. E.L.S. A.J.H. D.B. C.V.-M. S.P. D.P. M.D.L. V.P. B.L.W. D. Kozakov, D. Kretov, D.C. R.M.H. E.M. A.J.H. S.W. A.B. C.P.-R.; Validation: A.J.H. E.J.B. A.M.-M. D.C. M.B. P.A. J.Z. S.O. S.M.L. J.J.P. M.V. A.T.-L. X.V. K.M.A. R.B.W. J.X.-C. J.H. S.F. J.H.K. R.D. R.K.G. B.J.B.; Manuscript: R.K.G. S.P. M.B. I.P. B.C.B. R.B.W. K.M.A. J.H. A.A.W. D.N.K. D.C. J.H.C. S.W. A.J.H. E.L.S. E.M. A.E.; Resources: C.V.-M. B.C.B. I.P. S.P. B.L.W. declares a position as CSO of Aquinnah Pharmaceuticals. A.E. and D.N.K. declare industry funding from Johnson & Johnson, Merck, and Novartis.
Funding Information:
B.L.W. declares a position as CSO of Aquinnah Pharmaceuticals. A.E. and D.N.K. declare industry funding from Johnson & Johnson, Merck, and Novartis.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/12/17
Y1 - 2020/12/17
N2 - 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.
AB - 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.
KW - COVID-19
KW - SARS-CoV-2
KW - antivirals
KW - infection
KW - mass spectrometry
KW - pathogenesis
KW - pathways
KW - phosphoproteomics
KW - pneumocytes
KW - time course
UR - http://www.scopus.com/inward/record.url?scp=85097080933&partnerID=8YFLogxK
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U2 - 10.1016/j.molcel.2020.11.028
DO - 10.1016/j.molcel.2020.11.028
M3 - Article
C2 - 33259812
AN - SCOPUS:85097080933
VL - 80
SP - 1104-1122.e9
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 6
ER -