Journal Article

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

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

2023

Overview

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. Using a multi-OMICS approach, Haas et al identify 54 human genes and 16 host-targeting chemical compounds that regulate influenza A virus infection in lung epithelial cells, including AHNAK and COBP1 which are also essential for SARS-CoV-2 infection.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/89 / 38/109 / 38/43 / 631/326/596/1578 / 631/326/596/2557 / 631/553 / 82/58 / 82/80 / 82/83 / 96/106 / 96/31 / Antiviral activity / Antiviral agents / Antiviral Agents - metabolism / Antiviral drugs / Chemical compounds / Coronaviruses / COVID-19 / Epithelial cells / Epithelium / Genes / Genetic analysis / Host-Pathogen Interactions - genetics / Humanities and Social Sciences / Humans / Infections / Influenza / Influenza A / Influenza A virus - genetics / Influenza A Virus, H3N2 Subtype - metabolism / Influenza A Virus, H5N1 Subtype - genetics / Influenza, Human - genetics / Kinases / Mass spectrometry / Mass spectroscopy / multidisciplinary / Protein interaction / Protein purification / Proteins / Proteomics / SARS-CoV-2 / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / siRNA / Target recognition / Viral diseases / Virus Replication - genetics / Viruses