1. Section of Infectious Diseases,
2. Section of Rheumatology, Department of Internal Medicine,
3. Section for Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticutt 06520-8031, USA
4. Center for Computational and Integrative Biology, and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
5. Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555, USA
6. Department of Systems Biology,
7. Department of Genetics, Center for Genetics and Genomics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
8. Department of Neurobiology, Weizmann Institute of Science, Israel
9. L2 Diagnostics, 300 George Street, New Haven, Connecticutt 06511, USA
10. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA
11. These authors contributed equally to this work.

Correspondence to: Erol Fikrig^1,10,11 Correspondence and requests for materials should be addressed to E.F. (Email: erol.fikrig@yale.edu).

Abstract

West Nile virus (WNV), and related flaviviruses such as tick-borne encephalitis, Japanese encephalitis, yellow fever and dengue viruses, constitute a significant global human health problem¹. However, our understanding of the molecular interaction of such flaviviruses with mammalian host cells is limited¹. WNV encodes only 10 proteins, implying that it may use many cellular proteins for infection¹. WNV enters the cytoplasm through pH-dependent endocytosis, undergoes cycles of translation and replication, assembles progeny virions in association with endoplasmic reticulum, and exits along the secretory pathway^{1, 2, 3}. RNA interference (RNAi) presents a powerful forward genetics approach to dissect virus–host cell interactions^{4, 5, 6}. Here we report the identification of 305 host proteins that affect WNV infection, using a human-genome-wide RNAi screen. Functional clustering of the genes revealed a complex dependence of this virus on host cell physiology, requiring a wide variety of molecules and cellular pathways for successful infection. We further demonstrate a requirement for the ubiquitin ligase CBLL1 in WNV internalization, a post-entry role for the endoplasmic-reticulum-associated degradation pathway in viral infection, and the monocarboxylic acid transporter MCT4 as a viral replication resistance factor. By extending this study to dengue virus, we show that flaviviruses have both overlapping and unique interaction strategies with host cells. This study provides a comprehensive molecular portrait of WNV–human cell interactions that forms a model for understanding single plus-stranded RNA virus infection, and reveals potential antiviral targets.

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