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Strain- and cell type-specific influenza A virus (IAV)-host protein-protein interaction (PPI) network identified by affinity purification-mass spectrometry (AP-MS)

ABSTRACT: Influenza A Virus (IAV) is a recurring respiratory virus with antiviral therapies of limited use. 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 with three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we mapped 332 IAV-human protein-protein interactions and identified 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza revealed several genes, including the structural scaffold protein AHNAK, with predicted loss-of-function variants that were also identified in our proteomic analyses. Of our identified host factors, 54 significantly altered IAV infection upon siRNA knockdown, and two factors, COPB1 and AHNAK, were also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppressed IAV replication, with three targeting ATP6V1A, 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. This project includes the AP-MS data; all global proteomic data (abundance and phosphorylation) has been submitted separately as its own dataset and has its own dataset identifier.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Monocyte, Epithelial Cell

DISEASE(S): Influenza,Avian Influenza

SUBMITTER: Robyn Kaake

LAB HEAD: Robyn Kaake

PROVIDER: PXD036077 | Pride | 2023-07-25

REPOSITORIES: Pride

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