title: Human host factors required for influenza virus replication.
abstract: Influenza A virus is an RNA virus that encodes up to 11 proteins and this small coding capacity demands that the virus use the host cellular machinery for many aspects of its life cycle. Knowledge of these host cell requirements not only informs us of the molecular pathways exploited by the virus but also provides further targets that could be pursued for antiviral drug development. Here we use an integrative systems approach, based on genome-wide RNA interference screening, to identify 295 cellular cofactors required for early-stage influenza virus replication. Within this group, those involved in kinase-regulated signalling, ubiquitination and phosphatase activity are the most highly enriched, and 181 factors assemble into a highly significant host-pathogen interaction network. Moreover, 219 of the 295 factors were confirmed to be required for efficient wild-type influenza virus growth, and further analysis of a subset of genes showed 23 factors necessary for viral entry, including members of the vacuolar ATPase (vATPase) and COPI-protein families, fibroblast growth factor receptor (FGFR) proteins, and glycogen synthase kinase 3 (GSK3)-beta. Furthermore, 10 proteins were confirmed to be involved in post-entry steps of influenza virus replication. These include nuclear import components, proteases, and the calcium/calmodulin-dependent protein kinase (CaM kinase) IIbeta (CAMK2B). Notably, growth of swine-origin H1N1 influenza virus is also dependent on the identified host factors, and we show that small molecule inhibitors of several factors, including vATPase and CAMK2B, antagonize influenza virus replication.
authors.affiliation: Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research.
authors.forename: Renate
authors.initials: R
authors.lastname: König
authors.forename: Silke
authors.initials: S
authors.lastname: Stertz
authors.forename: Yingyao
authors.initials: Y
authors.lastname: Zhou
authors.forename: Atsushi
authors.initials: A
authors.lastname: Inoue
authors.forename: H-Heinrich
authors.initials: HH
authors.lastname: Hoffmann
authors.forename: Suchita
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Judith G
authors.initials: JG
authors.lastname: Alamares
authors.forename: Donna M
authors.initials: DM
authors.lastname: Tscherne
authors.forename: Mila B
authors.initials: MB
authors.lastname: Ortigoza
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liang
authors.forename: Qinshan
authors.initials: Q
authors.lastname: Gao
authors.forename: Shane E
authors.initials: SE
authors.lastname: Andrews
authors.forename: Sourav
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Paul
authors.initials: P
authors.lastname: De Jesus
authors.forename: Buu P
authors.initials: BP
authors.lastname: Tu
authors.forename: Lars
authors.initials: L
authors.lastname: Pache
authors.forename: Crystal
authors.initials: C
authors.lastname: Shih
authors.forename: Anthony
authors.initials: A
authors.lastname: Orth
authors.forename: Ghislain
authors.initials: G
authors.lastname: Bonamy
authors.forename: Loren
authors.initials: L
authors.lastname: Miraglia
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: John A T
authors.initials: JA
authors.lastname: Young
authors.forename: Peter
authors.initials: P
authors.lastname: Palese
authors.forename: Megan L
authors.initials: ML
authors.lastname: Shaw
authors.forename: Sumit K
authors.initials: SK
authors.lastname: Chanda
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D015723:Gene Library; D015894:Genome, Human / Q000235:genetics; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000502:physiology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000145:classification / Q000254:growth & development; D009980:Influenza A virus / Q000145:classification / Q000254:growth & development*; D007251:Influenza, Human / Q000235:genetics* / Q000821:virology*; D034622:RNA Interference; D014709:Vero Cells; D053586:Virus Internalization; D014779:Virus Replication / Q000502:physiology*
chemical_list: D001685:Biological Factors