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* Institute of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark; and
Institute of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
Viruses are recognized by the innate immune system through pattern recognition receptors (PRRs). For instance, HSV virions and genomic DNA are recognized by TLR2 and TLR9, respectively. Although several viruses and viral components have been shown to stimulate cells through TLRs, only very few studies have defined essential roles for single TLRs in innate immune defense in vivo. This could suggest that PRRs act in concert to mount the first line of defense against virus infections. To test this hypothesis we have examined the host response of C57BL/6, TLR2–/–, TLR9–/–, and TLR2/9–/– mice toward HSV-2 infection. After a systemic infection, the cytokine serum response was markedly reduced in the double knockout mice, but only partly affected in either strain of the single knockout mice. This was supported by in vitro data showing that HSV-induced cytokine expression relayed on TLR2 and TLR9 in a cytokine- and cell type-dependent manner. With respect to the cellular response to infection, we found that recruitment but not activation of NK cells was impaired in TLR2/9–/– mice. Importantly, the viral load in the brain, but not liver, was significantly higher in the brain of TLR2/9–/– mice whereas the viral loads in organs of single knockout mice were statistically indistinguishable from C57BL/6 mice. In the brain we found that TNF-
and the IFN-stimulated gene CXCL9 were expressed during infection and were dependent on either TLR2 or TLR9. Thus, TLR2 and TLR9 synergistically stimulate innate antiviral activities, thereby protecting against HSV infection in the brain.
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 research grants from The Danish Medical Research Council (Grant 271-06-0438), The Lundbeck Foundation (Grant R17-A1526), Elvira og Rasmus Riisforts almenvelgørende Fond, Aarhus University Research Foundation, Augustinus Fonden, and Fonden af 17-12-1981. L.N.S. was supported by a fellowship from the Faculty of Health Science, Aarhus University, and L.M. was the recipient of a postdoctoral fellowship from the Danish Medical Research Council.
2 Address correspondence and reprint requests to Dr. Søren R. Paludan, Institute of Medical Microbiology and Immunology, The Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark. E-mail address: srp{at}microbiology.au.dk
3 Abbreviations used in this paper: PRR, pattern recognition receptor; BM-DC, bone marrow-derived dendritic cell; cDC, conventional dendritic cell; DC, dendritic cell; DKO, double knockout; ISG, IFN-stimulated gene; KO, knockout; pDC, plasmacytoid dendritic cell; p.i., postinfection; SL, spleen leukocyte; WT, wild type.
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