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Journal of Virology, January 2008, p. 609-616, Vol. 82, No. 2
0022-538X/08/$08.00+0     doi:10.1128/JVI.01305-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Establishment and Maintenance of the Innate Antiviral Response to West Nile Virus Involves both RIG-I and MDA5 Signaling through IPS-1{triangledown} ,{dagger}

Brenda L. Fredericksen,1* Brian C. Keller,2,{ddagger} Jamie Fornek,3,{ddagger} Michael G. Katze,3 and Michael Gale Jr.2,4

Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland,1 Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas,2 Department of Microbiology,3 Department of Immunology, University of Washington School of Medicine, Seattle, Washington4

Received 14 June 2007/ Accepted 12 October 2007

RIG-I and MDA5, two related pathogen recognition receptors (PRRs), are known to be required for sensing various RNA viruses. Here we investigated the roles that RIG-I and MDA5 play in eliciting the antiviral response to West Nile virus (WNV). Functional genomics analysis of WNV-infected fibroblasts from wild-type mice and RIG-I null mice revealed that the normal antiviral response to this virus occurs in two distinct waves. The initial response to WNV resulted in the expression of interferon (IFN) regulatory factor 3 target genes and IFN-stimulated genes, including several subtypes of alpha IFN. Subsequently, a second phase of IFN-dependent antiviral gene expression occurred very late in infection. In cells lacking RIG-I, both the initial and the secondary responses to WNV were delayed, indicating that RIG-I plays a critical role in initiating innate immunity against WNV. However, another PRR(s) was able to trigger a response to WNV in the absence of RIG-I. Disruption of both MDA5 and RIG-I pathways abrogated activation of the antiviral response to WNV, suggesting that MDA5 is involved in the host's defense against WNV infection. In addition, ablation of the function of IPS-1, an essential RIG-I and MDA5 adaptor molecule, completely disabled the innate antiviral response to WNV. Our data indicate that RIG-I and MDA5 are responsible for triggering downstream gene expression in response to WNV infection by signaling through IPS-1. We propose a model in which RIG-I and MDA5 operate cooperatively to establish an antiviral state and mediate an IFN amplification loop that supports immune effector gene expression during WNV infection.

* Corresponding author. Mailing address: 2101 Microbiology, College Park, MD 20742. Phone: (301) 405-1251. Fax: (301) 314-9489. E-mail: bfreder{at}umd.edu

{triangledown} Published ahead of print on 31 October 2007.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} B. C. Keller and J. Fornek contributed equally to this study.

Journal of Virology, January 2008, p. 609-616, Vol. 82, No. 2
0022-538X/08/$08.00+0     doi:10.1128/JVI.01305-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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