Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets

Kelsey M. Haas; Michael J. McGregor; Mehdi Bouhaddou; Benjamin J. Polacco; Eun Young Kim; Thong T. Nguyen; Billy W. Newton; Matthew Urbanowski; Heejin Kim; Michael A.P. Williams; Veronica V. Rezelj; Alexandra Hardy; Andrea Fossati; Erica J. Stevenson; Ellie Sukerman; Tiffany Kim; Sudhir Penugonda; Elena Moreno; Hannes Braberg; Yuan Zhou; Giorgi Metreveli; Bhavya Harjai; Tia A. Tummino; James E. Melnyk; Margaret Soucheray; Jyoti Batra; Lars Pache; Laura Martin-Sancho; Jared Carlson-Stevermer; Alexander S. Jureka; Christopher F. Basler; Kevan M. Shokat; Brian K. Shoichet; Leah P. Shriver; Jeffrey R. Johnson; Megan L. Shaw; Sumit K. Chanda; Dan M. Roden; Tonia C. Carter; Leah C. Kottyan; Rex L. Chisholm; Jennifer A. Pacheco; Maureen E. Smith; Steven J. Schrodi; Randy A. Albrecht; Marco Vignuzzi; Lorena Zuliani-Alvarez; Danielle L. Swaney; Manon Eckhardt; Steven M. Wolinsky; Kris M. White; Judd F. Hultquist; Robyn M. Kaake; Adolfo García-Sastre; Nevan J. Krogan

doi:10.1038/s41467-023-41442-z

Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets

Kelsey M. Haas, Michael J. McGregor, Mehdi Bouhaddou, Benjamin J. Polacco, Eun Young Kim, Thong T. Nguyen, Billy W. Newton, Matthew Urbanowski, Heejin Kim, Michael A.P. Williams, Veronica V. Rezelj, Alexandra Hardy, Andrea Fossati, Erica J. Stevenson, Ellie Sukerman, Tiffany Kim, Sudhir Penugonda, Elena Moreno, Hannes Braberg, Yuan ZhouGiorgi Metreveli, Bhavya Harjai, Tia A. Tummino, James E. Melnyk, Margaret Soucheray, Jyoti Batra, Lars Pache, Laura Martin-Sancho, Jared Carlson-Stevermer, Alexander S. Jureka, Christopher F. Basler, Kevan M. Shokat, Brian K. Shoichet, Leah P. Shriver, Jeffrey R. Johnson, Megan L. Shaw, Sumit K. Chanda, Dan M. Roden, Tonia C. Carter, Leah C. Kottyan, Rex L. Chisholm, Jennifer A. Pacheco, Maureen E. Smith, Steven J. Schrodi, Randy A. Albrecht, Marco Vignuzzi, Lorena Zuliani-Alvarez, Danielle L. Swaney, Manon Eckhardt, Steven M. Wolinsky, Kris M. White, Judd F. Hultquist^*, Robyn M. Kaake^*, Adolfo García-Sastre^*, Nevan J. Krogan^*

^*Corresponding author for this work

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

14 Scopus citations

Abstract

Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

Original language	English (US)
Article number	6030
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-41442-z
State	Published - Dec 2023

Funding

The Krogan Laboratory has received research support from Vir Biotechnology, F. Hoffmann-La Roche, and Rezo Therapeutics. N.J.K. has previously held financially compensated consulting agreements with the Icahn School of Medicine at Mount Sinai, New York and Twist Bioscience Corp. He currently has financially compensated consulting agreements with Maze Therapeutics, Interline Therapeutics, Rezo Therapeutics, and GEn1E Lifesciences, Inc. He is on the Board of Directors of Rezo Therapeutics and is a shareholder in Tenaya Therapeutics, Maze Therapeutics, Rezo Therapeutics, and Interline Therapeutics. The García-Sastre laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories and Merck, outside of the reported work. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, Paratus, CureLab Oncology, CureLab Veterinary, Synairgen and Pfizer, outside of the reported work. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott and Astrazeneca. A.G.-S. is an inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. The Hultquist laboratory has received prior funding support from Gilead Sciences, and J.F.H. has a financially compensated consulting agreement with Merck. D.L.S. has a consulting agreement with Maze Therapeutics. M.B. is a financially compensated scientific advisor for GEn1E Life Sciences. K.M.S. has consulting agreements for the following companies involving cash and/or stock compensation: Black Diamond Therapeutics, BridGene Biosciences, Denali Therapeutics, Dice Molecules, eFFECTOR Therapeutics, Erasca, Genentech/Roche, Kumquat Biosciences, Kura Oncology, Merck, Mitokinin, Petra Pharma, Rezo Therapeutics, Revolution Medicines, Type6 Therapeutics, Vevo, Vicinitas and Wellspring Biosciences (Araxes Pharma). J.C.-S. is a former employee and stockholder of Synthego. While not directly relevant to this study, C.F.B. is a scientific advisor for Axion BioSystems, M.L.S. has a financially compensated consulting agreement with Calibr, and S.P. is employed by Roivant Sciences, Inc. S.P. also holds stock compensation from Roivant Sciences and AbbVie. The remaining authors declare no competing interests.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Haas, K. M., McGregor, M. J., Bouhaddou, M., Polacco, B. J., Kim, E. Y., Nguyen, T. T., Newton, B. W., Urbanowski, M., Kim, H., Williams, M. A. P., Rezelj, V. V., Hardy, A., Fossati, A., Stevenson, E. J., Sukerman, E., Kim, T., Penugonda, S., Moreno, E., Braberg, H., ... Krogan, N. J. (2023). Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets. Nature communications, 14(1), Article 6030. https://doi.org/10.1038/s41467-023-41442-z

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title = "Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets",

abstract = "Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.",

author = "Haas, {Kelsey M.} and McGregor, {Michael J.} and Mehdi Bouhaddou and Polacco, {Benjamin J.} and Kim, {Eun Young} and Nguyen, {Thong T.} and Newton, {Billy W.} and Matthew Urbanowski and Heejin Kim and Williams, {Michael A.P.} and Rezelj, {Veronica V.} and Alexandra Hardy and Andrea Fossati and Stevenson, {Erica J.} and Ellie Sukerman and Tiffany Kim and Sudhir Penugonda and Elena Moreno and Hannes Braberg and Yuan Zhou and Giorgi Metreveli and Bhavya Harjai and Tummino, {Tia A.} and Melnyk, {James E.} and Margaret Soucheray and Jyoti Batra and Lars Pache and Laura Martin-Sancho and Jared Carlson-Stevermer and Jureka, {Alexander S.} and Basler, {Christopher F.} and Shokat, {Kevan M.} and Shoichet, {Brian K.} and Shriver, {Leah P.} and Johnson, {Jeffrey R.} and Shaw, {Megan L.} and Chanda, {Sumit K.} and Roden, {Dan M.} and Carter, {Tonia C.} and Kottyan, {Leah C.} and Chisholm, {Rex L.} and Pacheco, {Jennifer A.} and Smith, {Maureen E.} and Schrodi, {Steven J.} and Albrecht, {Randy A.} and Marco Vignuzzi and Lorena Zuliani-Alvarez and Swaney, {Danielle L.} and Manon Eckhardt and Wolinsky, {Steven M.} and White, {Kris M.} and Hultquist, {Judd F.} and Kaake, {Robyn M.} and Adolfo Garc{\'i}a-Sastre and Krogan, {Nevan J.}",

note = "Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-41442-z",

language = "English (US)",

volume = "14",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Haas, KM, McGregor, MJ, Bouhaddou, M, Polacco, BJ, Kim, EY, Nguyen, TT, Newton, BW, Urbanowski, M, Kim, H, Williams, MAP, Rezelj, VV, Hardy, A, Fossati, A, Stevenson, EJ, Sukerman, E, Kim, T, Penugonda, S, Moreno, E, Braberg, H, Zhou, Y, Metreveli, G, Harjai, B, Tummino, TA, Melnyk, JE, Soucheray, M, Batra, J, Pache, L, Martin-Sancho, L, Carlson-Stevermer, J, Jureka, AS, Basler, CF, Shokat, KM, Shoichet, BK, Shriver, LP, Johnson, JR, Shaw, ML, Chanda, SK, Roden, DM, Carter, TC, Kottyan, LC, Chisholm, RL, Pacheco, JA, Smith, ME, Schrodi, SJ, Albrecht, RA, Vignuzzi, M, Zuliani-Alvarez, L, Swaney, DL, Eckhardt, M, Wolinsky, SM, White, KM, Hultquist, JF, Kaake, RM, García-Sastre, A & Krogan, NJ 2023, 'Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets', Nature communications, vol. 14, no. 1, 6030. https://doi.org/10.1038/s41467-023-41442-z

TY - JOUR

T1 - Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets

AU - Haas, Kelsey M.

AU - McGregor, Michael J.

AU - Bouhaddou, Mehdi

AU - Polacco, Benjamin J.

AU - Kim, Eun Young

AU - Nguyen, Thong T.

AU - Newton, Billy W.

AU - Urbanowski, Matthew

AU - Kim, Heejin

AU - Williams, Michael A.P.

AU - Rezelj, Veronica V.

AU - Hardy, Alexandra

AU - Fossati, Andrea

AU - Stevenson, Erica J.

AU - Sukerman, Ellie

AU - Kim, Tiffany

AU - Penugonda, Sudhir

AU - Moreno, Elena

AU - Braberg, Hannes

AU - Zhou, Yuan

AU - Metreveli, Giorgi

AU - Harjai, Bhavya

AU - Tummino, Tia A.

AU - Melnyk, James E.

AU - Soucheray, Margaret

AU - Batra, Jyoti

AU - Pache, Lars

AU - Martin-Sancho, Laura

AU - Carlson-Stevermer, Jared

AU - Jureka, Alexander S.

AU - Basler, Christopher F.

AU - Shokat, Kevan M.

AU - Shoichet, Brian K.

AU - Shriver, Leah P.

AU - Johnson, Jeffrey R.

AU - Shaw, Megan L.

AU - Chanda, Sumit K.

AU - Roden, Dan M.

AU - Carter, Tonia C.

AU - Kottyan, Leah C.

AU - Chisholm, Rex L.

AU - Pacheco, Jennifer A.

AU - Smith, Maureen E.

AU - Schrodi, Steven J.

AU - Albrecht, Randy A.

AU - Vignuzzi, Marco

AU - Zuliani-Alvarez, Lorena

AU - Swaney, Danielle L.

AU - Eckhardt, Manon

AU - Wolinsky, Steven M.

AU - White, Kris M.

AU - Hultquist, Judd F.

AU - Kaake, Robyn M.

AU - García-Sastre, Adolfo

AU - Krogan, Nevan J.

PY - 2023/12

Y1 - 2023/12

N2 - Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

AB - Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

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UR - http://www.scopus.com/inward/citedby.url?scp=85173073553&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-41442-z

DO - 10.1038/s41467-023-41442-z

M3 - Article

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AN - SCOPUS:85173073553

SN - 2041-1723

VL - 14

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 6030

ER -

Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets

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