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* Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT 84322;
Department of Biology, Utah State University, Logan, UT 84322;
Centre d’Immunologie de Marseille-Luminy, Centre National de la Recherche Scientifique-Institut National de la Sante et de la Recherche Medicale, Marseille, France; and
Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520
TLR3 was the first member of the TLR family of pattern recognition receptors found to detect a conserved viral molecular pattern, dsRNA, yet supporting evidence for a major role in host defense against viral pathogens is limited. Punta Toro virus (PTV) has been shown to produce severe infection in mice, modeling disease caused by the related highly pathogenic Rift Valley fever phlebovirus in humans and domesticated ungulates. Using TLR3-deficient mice, we investigated the involvement of TLR3 in host defense against PTV infection. Compared with wild-type, TLR3–/– mice demonstrate increased resistance to lethal infection and have reduced liver disease associated with hepatotropic PTV infection. Infectious challenge produced comparable peak liver and serum viral loads; however, TLR3–/– mice were able to clear systemic virus at a slightly faster rate. Cytokine profiling suggests that TLR3 plays an important role in PTV pathogenesis through the overproduction of inflammatory mediators, which may be central to the observed differences in survival and disease severity. Compared with TLR3-deficient mice, IL-6, MCP-1, IFN-
, and RANTES were all present at higher levels in wild-type animals. Most dramatic was the exaggerated levels of IL-6 found systemically and in liver tissue of infected wild-type mice; however, IL-6-deficient animals were found to be more susceptible to lethal PTV infection. Taken together, we conclude that the TLR3-mediated response to PTV infection is detrimental to disease outcome and propose that IL-6, although critical to establishing antiviral defense, contributes to pathogenesis when released in excess, necessitating its controlled production as is seen with TLR3–/– mice.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Contract NO1-AI-15435 from the Virology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Brian B. Gowen, Institute for Antiviral Research, Utah State University, 5600 Old Main, Logan, UT 84322. E-mail address: bgowen{at}cc.usu.edu
3 Abbreviations used in this paper: RVFV, Rift Valley fever virus; ALT, alanine aminotransferase; IAV, influenza A virus; MCMV, mouse CMV; PTV, Punta Toro virus; WNV, West Nile virus.
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