title: Host modulators of H1N1 cytopathogenicity.
abstract: Influenza A virus infects 5-20% of the population annually, resulting in ~35,000 deaths and significant morbidity. Current treatments include vaccines and drugs that target viral proteins. However, both of these approaches have limitations, as vaccines require yearly development and the rapid evolution of viral proteins gives rise to drug resistance. In consequence additional intervention strategies, that target host factors required for the viral life cycle, are under investigation. Here we employed arrayed whole-genome siRNA screening strategies to identify cell-autonomous molecular components that are subverted to support H1N1 influenza A virus infection of human bronchial epithelial cells. Integration across relevant public data sets exposed druggable gene products required for epithelial cell infection or required for viral proteins to deflect host cell suicide checkpoint activation. Pharmacological inhibition of representative targets, RGGT and CHEK1, resulted in significant protection against infection of human epithelial cells by the A/WS/33 virus. In addition, chemical inhibition of RGGT partially protected against H5N1 and the 2009 H1N1 pandemic strain. The observations reported here thus contribute to an expanding body of studies directed at decoding vulnerabilities in the command and control networks specified by influenza virulence factors.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical School, Dallas, Texas, United States of America.
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Ward
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Kakajan
authors.initials: K
authors.lastname: Komurov
authors.forename: Saurabh
authors.initials: S
authors.lastname: Mendiratta
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Tsai
authors.forename: Mirco
authors.initials: M
authors.lastname: Schmolke
authors.forename: Neal
authors.initials: N
authors.lastname: Satterly
authors.forename: Balaji
authors.initials: B
authors.lastname: Manicassamy
authors.forename: Christian V
authors.initials: CV
authors.lastname: Forst
authors.forename: Michael G
authors.initials: MG
authors.lastname: Roth
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Blazewska
authors.forename: Charles E
authors.initials: CE
authors.lastname: McKenna
authors.forename: Beatriz M
authors.initials: BM
authors.lastname: Fontoura
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
mesh_terms: D000818:Animals; D002460:Cell Line; D016000:Cluster Analysis; D003588:Cytopathogenic Effect, Viral; D004847:Epithelial Cells / Q000821:virology; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000502:physiology*; D007773:Lactates / Q000494:pharmacology; D058977:Molecular Sequence Annotation; D063065:Organophosphonates / Q000494:pharmacology; D034622:RNA Interference; D020545:Respiratory Mucosa / Q000821:virology*; D014779:Virus Replication
chemical_list: C549922:2-hydroxy-3-imidazo(1,2-a)pyridin-3-yl-2-phosphonopropionic acid; D007773:Lactates; D063065:Organophosphonates