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 () and Nevan J. Krogan ()
Additional contact information
Kelsey M. Haas: J. David Gladstone Institutes
Michael J. McGregor: J. David Gladstone Institutes
Mehdi Bouhaddou: J. David Gladstone Institutes
Benjamin J. Polacco: University of California San Francisco
Eun-Young Kim: Northwestern University Feinberg School of Medicine
Thong T. Nguyen: J. David Gladstone Institutes
Billy W. Newton: University of California San Francisco
Matthew Urbanowski: Icahn School of Medicine at Mount Sinai
Heejin Kim: Northwestern University Feinberg School of Medicine
Michael A. P. Williams: Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG)
Veronica V. Rezelj: Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG)
Alexandra Hardy: Viral Populations and Pathogenesis Unit
Andrea Fossati: J. David Gladstone Institutes
Erica J. Stevenson: J. David Gladstone Institutes
Ellie Sukerman: Oregon Health & Science University
Tiffany Kim: Northwestern University Feinberg School of Medicine
Sudhir Penugonda: Northwestern University Feinberg School of Medicine
Elena Moreno: Icahn School of Medicine at Mount Sinai
Hannes Braberg: University of California San Francisco
Yuan Zhou: J. David Gladstone Institutes
Giorgi Metreveli: Icahn School of Medicine at Mount Sinai
Bhavya Harjai: J. David Gladstone Institutes
Tia A. Tummino: University of California San Francisco
James E. Melnyk: University of California San Francisco
Margaret Soucheray: J. David Gladstone Institutes
Jyoti Batra: J. David Gladstone Institutes
Lars Pache: Sanford Burnham Prebys Medical Discovery Institute
Laura Martin-Sancho: The Scripps Research Institute
Jared Carlson-Stevermer: Synthego Corporation
Alexander S. Jureka: Centers for Disease Control & Prevention
Christopher F. Basler: Icahn School of Medicine at Mount Sinai
Kevan M. Shokat: University of California San Francisco
Brian K. Shoichet: University of California San Francisco
Leah P. Shriver: Washington University in St. Louis
Jeffrey R. Johnson: J. David Gladstone Institutes
Megan L. Shaw: Icahn School of Medicine at Mount Sinai
Sumit K. Chanda: The Scripps Research Institute
Dan M. Roden: Vanderbilt University Medical Center
Tonia C. Carter: Marshfield Clinic Research Institute
Leah C. Kottyan: Cincinnati Children’s Hospital Medical Center
Rex L. Chisholm: Northwestern University
Jennifer A. Pacheco: Northwestern University
Maureen E. Smith: Northwestern University
Steven J. Schrodi: University of Wisconsin Madison
Randy A. Albrecht: Icahn School of Medicine at Mount Sinai
Marco Vignuzzi: Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG)
Lorena Zuliani-Alvarez: J. David Gladstone Institutes
Danielle L. Swaney: J. David Gladstone Institutes
Manon Eckhardt: J. David Gladstone Institutes
Steven M. Wolinsky: Northwestern University Feinberg School of Medicine
Kris M. White: Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG)
Judd F. Hultquist: Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG)
Robyn M. Kaake: J. David Gladstone Institutes
Adolfo García-Sastre: Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG)
Nevan J. Krogan: J. David Gladstone Institutes

Nature Communications, 2023, vol. 14, issue 1, 1-27

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41442-z

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