JSON
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
Nat Commun 14 (1) 6030 [2023-09-27; online 2023-09-27]
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.
PubMed 37758692
DOI 10.1038/s41467-023-41442-z
Crossref 10.1038/s41467-023-41442-z
pmc: PMC10533562
pii: 10.1038/s41467-023-41442-z