Nature 463, 813-817 (11 February 2010) | doi:10.1038/nature08699; Received 24 September 2009; Accepted 24 November 2009; Published online 21 December 2009

Human host factors required for influenza virus replicationnear-final version

Renate König1,9, Silke Stertz4,9, Yingyao Zhou7, Atsushi Inoue1, H. -Heinrich Hoffmann4, Suchita Bhattacharyya2, Judith G. Alamares4, Donna M. Tscherne4, Mila B. Ortigoza4, Yuhong Liang4, Qinshan Gao4, Shane E. Andrews3, Sourav Bandyopadhyay8, Paul De Jesus1, Buu P. Tu7, Lars Pache1, Crystal Shih1, Anthony Orth7, Ghislain Bonamy7, Loren Miraglia7, Trey Ideker8, Adolfo García-Sastre4,5,6, John A. T. Young2, Peter Palese4,5, Megan L. Shaw4,9 & Sumit K. Chanda1,9

  1. Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road,
  2. Nomis Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road,
  3. Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
  4. Department of Microbiology,
  5. Department of Medicine, Division of Infectious Diseases,
  6. Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA
  7. Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, California 92121, USA
  8. Departments of Medicine and Bioengineering, University of California, San Diego, Pharmaceutical Sciences Building, 9500 Gilman Drive, La Jolla, California 92093, USA
  9. These authors contributed equally to this work.

Correspondence to: Megan L. Shaw4,9Sumit K. Chanda1,9 Correspondence and requests for materials should be addressed to S.K.C. (Email: schanda@burnham.org) or M.L.S. (Email: megan.shaw@mssm.edu).

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 cycle1. 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)-β. 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) IIβ (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.


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