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. 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

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

Computer Science

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	1104-1122.e9
Journal	Molecular Cell
Volume	80
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2020.11.028
State	Published - Dec 17 2020

Keywords

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

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2020.11.028

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Hekman, R. M., Hume, A. J., Goel, R. K., Abo, K. M., Huang, J., Blum, B. C., Werder, R. B., Suder, E. L., Paul, I., Phanse, S., Youssef, A., Alysandratos, K. D., Padhorny, D., Ojha, S., Mora-Martin, A., Kretov, D., Ash, P., Varma, M., Zhao, J., ... Emili, A. (2020). Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2. Molecular Cell, 80(6), 1104-1122.e9. https://doi.org/10.1016/j.molcel.2020.11.028

Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2. / Hekman, Ryan M.; Hume, Adam J.; Goel, Raghuveera Kumar; Abo, Kristine M.; Huang, Jessie; Blum, Benjamin C.; Werder, Rhiannon Bree; Suder, Ellen L.; Paul, Indranil; Phanse, Sadhna; Youssef, Ahmed; Alysandratos, Kostantinos D.; Padhorny, Dzmitry; Ojha, Sandeep; Mora-Martin, Alexandra; Kretov, Dmitry; Ash, Peter; Varma, Mamta; Zhao, Jian; Patten, J. J.; Villacorta-Martin, Carlos; Bolzan, Dante; Perea-Resa, Carlos; Bullitt, Esther; Hinds, Anne; Tilston-Lunel, Andrew; Varelas, Xaralabos; Farhangmehr, Shaghayegh; Braunschweig, Ulrich; Kwan, Julian H.; McComb, Mark; Basu, Avik; Saeed, Mohsan; Perissi, Valentina; Burks, Eric J.; Layne, Matthew D.; Connor, John H.; Davey, Robert; Cheng, Ji Xin; Wolozin, Benjamin L.; Blencowe, Benjamin J.; Wuchty, Stefan; Lyons, Shawn M.; Kozakov, Dima; Cifuentes, Daniel; Blower, Michael; Kotton, Darrell N.; Wilson, Andrew A.; Mühlberger, Elke; Emili, Andrew.

In: Molecular Cell, Vol. 80, No. 6, 17.12.2020, p. 1104-1122.e9.

Research output: Contribution to journal › Article › peer-review

Hekman, RM, Hume, AJ, Goel, RK, Abo, KM, Huang, J, Blum, BC, Werder, RB, Suder, EL, Paul, I, Phanse, S, Youssef, A, Alysandratos, KD, Padhorny, D, Ojha, S, Mora-Martin, A, Kretov, D, Ash, P, Varma, M, Zhao, J, Patten, JJ, Villacorta-Martin, C, Bolzan, D, Perea-Resa, C, Bullitt, E, Hinds, A, Tilston-Lunel, A, Varelas, X, Farhangmehr, S, Braunschweig, U, Kwan, JH, McComb, M, Basu, A, Saeed, M, Perissi, V, Burks, EJ, Layne, MD, Connor, JH, Davey, R, Cheng, JX, Wolozin, BL, Blencowe, BJ, Wuchty, S, Lyons, SM, Kozakov, D, Cifuentes, D, Blower, M, Kotton, DN, Wilson, AA, Mühlberger, E & Emili, A 2020, 'Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2', Molecular Cell, vol. 80, no. 6, pp. 1104-1122.e9. https://doi.org/10.1016/j.molcel.2020.11.028

Hekman, Ryan M. ; Hume, Adam J. ; Goel, Raghuveera Kumar ; Abo, Kristine M. ; Huang, Jessie ; Blum, Benjamin C. ; Werder, Rhiannon Bree ; Suder, Ellen L. ; Paul, Indranil ; Phanse, Sadhna ; Youssef, Ahmed ; Alysandratos, Kostantinos D. ; Padhorny, Dzmitry ; Ojha, Sandeep ; Mora-Martin, Alexandra ; Kretov, Dmitry ; Ash, Peter ; Varma, Mamta ; Zhao, Jian ; Patten, J. J. ; Villacorta-Martin, Carlos ; Bolzan, Dante ; Perea-Resa, Carlos ; Bullitt, Esther ; Hinds, Anne ; Tilston-Lunel, Andrew ; Varelas, Xaralabos ; Farhangmehr, Shaghayegh ; Braunschweig, Ulrich ; Kwan, Julian H. ; McComb, Mark ; Basu, Avik ; Saeed, Mohsan ; Perissi, Valentina ; Burks, Eric J. ; Layne, Matthew D. ; Connor, John H. ; Davey, Robert ; Cheng, Ji Xin ; Wolozin, Benjamin L. ; Blencowe, Benjamin J. ; Wuchty, Stefan ; Lyons, Shawn M. ; Kozakov, Dima ; Cifuentes, Daniel ; Blower, Michael ; Kotton, Darrell N. ; Wilson, Andrew A. ; Mühlberger, Elke ; Emili, Andrew. / Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2. In: Molecular Cell. 2020 ; Vol. 80, No. 6. pp. 1104-1122.e9.

@article{351ea3dbc9364f63947e2b5d3408dafe,

title = "Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2",

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

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

note = "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: {\textcopyright} 2020 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2020",

month = dec,

day = "17",

doi = "10.1016/j.molcel.2020.11.028",

language = "English (US)",

volume = "80",

pages = "1104--1122.e9",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "6",

}

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. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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 - antivirals

KW - COVID-19

KW - infection

KW - mass spectrometry

KW - pathogenesis

KW - pathways

KW - phosphoproteomics

KW - pneumocytes

KW - SARS-CoV-2

KW - time course

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UR - http://www.scopus.com/inward/citedby.url?scp=85097080933&partnerID=8YFLogxK

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 -