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 journalArticlepeer-review

3 Scopus citations


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 languageEnglish (US)
Article number6030
JournalNature communications
Issue number1
StatePublished - Dec 2023

ASJC Scopus subject areas

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


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