Human host factors required for influenza virus replication.
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.
König
Renate
R
Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research.
Stertz
Silke
S
Zhou
Yingyao
Y
Inoue
Atsushi
A
Hoffmann
H-Heinrich
HH
Bhattacharyya
Suchita
S
Alamares
Judith G
JG
Tscherne
Donna M
DM
Ortigoza
Mila B
MB
Liang
Yuhong
Y
Gao
Qinshan
Q
Andrews
Shane E
SE
Bandyopadhyay
Sourav
S
De Jesus
Paul
P
Tu
Buu P
BP
Pache
Lars
L
Shih
Crystal
C
Orth
Anthony
A
Bonamy
Ghislain
G
Miraglia
Loren
L
Ideker
Trey
T
García-Sastre
Adolfo
A
Young
John A T
JA
Palese
Peter
P
Shaw
Megan L
ML
Chanda
Sumit K
SK
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*
D001685:Biological Factors