Human host factors required for influenza virus replication.

TitleHuman host factors required for influenza virus replication.
Publication TypeJournal Article
Year of Publication2010
AuthorsKönig R, Stertz S, Zhou Y, Inoue A, Hoffmann H-H, Bhattacharyya S, Alamares JG, Tscherne DM, Ortigoza MB, Liang Y, Gao Q, Andrews SE, Bandyopadhyay S, De Jesus P, Tu BP, Pache L, Shih C, Orth A, Bonamy G, Miraglia L, Ideker T, García-Sastre A, Young JAT, Palese P, Shaw ML, Chanda SK
JournalNature
Volume463
Issue7282
Pagination813-7
Date Published2010 Feb 11
ISSN1476-4687
KeywordsAnimals, Biological Factors, Cell Line, Cercopithecus aethiops, Gene Library, Genome, Human, Host-Pathogen Interactions, Humans, Influenza A virus, Influenza A Virus, H1N1 Subtype, Influenza, Human, RNA Interference, Vero Cells, Virus Internalization, 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.

DOI10.1038/nature08699
PubMed URLhttp://www.ncbi.nlm.nih.gov/pubmed/20027183?dopt=Abstract
PMCPMC2862546
Alternate JournalNature
PubMed ID20027183