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

Author:

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

Abstract

AbstractInfluenza 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.

Publisher

Springer Science and Business Media LLC

Subject

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

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