JVI Accepts, published online ahead of print on 20 August 2008

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J. Virol. doi:10.1128/JVI.00935-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Toll-like receptor-3 has a protective role against West Nile virus infection

Stephane Daffis, Melanie A. Samuel, Mehul S. Suthar, Michael Gale Jr., and Michael S. Diamond^*

Departments of Medicine, Molecular Microbiology, and Pathology & Immunology, Washington University School of Medicine, St Louis. MO 63110; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195-7650

^* To whom correspondence should be addressed. Email: diamond{at}borcim.wustl.edu.

Protection against West Nile virus (WNV) infection requires rapid viral sensing and the generation of an interferon (IFN) response. Mice lacking interferon regulatory factor (IRF)-3 show increased vulnerability to WNV infection with enhanced viral replication and blunted IFN-stimulated gene (ISG) responses. IRF-3 functions downstream of several viral sensors including TLR3, RIG-I, and MDA5. Cell culture studies suggest that host recognizes WNV in part, through the cytoplasmic helicase RIG-I and to a lesser extent, MDA5, both of which activate ISG expression through IRF-3. However, the role of TLR3 in vivo in recognizing viral RNA and activating antiviral defense pathways has remained controversial. Here, we show that an absence of TLR3 enhances WNV mortality in mice and increases viral burden in the brain. Compared to congenic wild type controls, TLR3^-/- mice showed relatively modest changes in peripheral viral loads. Consistent with this, little difference in multi-step viral growth kinetics or IFN-/ induction was observed between wild type and TLR3^-/- fibroblasts, macrophages and dendritic cells. In contrast, a deficiency of TLR3 was associated with enhanced viral replication in primary cortical neuron cultures and greater WNV infection in CNS neurons after intracranial inoculation. Taken together, our data suggests that TLR3 serves a protective role against WNV in part, by restricting replication in neurons.

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