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Some Toll and Toll-like receptors (TLRs) provide immunity toexperimental infections in animal models, but their contributionto host defense in natural ecosystems is unknown. We reporta dominant-negative TLR3 allele in otherwise healthy childrenwith herpes simplex virus 1 (HSV-1) encephalitis. TLR3 is expressedin the central nervous system (CNS), where it is required tocontrol HSV-1, which spreads from the epithelium to the CNSvia cranial nerves. TLR3 is also expressed in epithelial anddendritic cells, which apparently use TLR3-independent pathwaysto prevent further dissemination of HSV-1 and to provide resistanceto other pathogens in TLR3-deficient patients. Human TLR3 appearsto be redundant in host defense to most microbes but is vitalfor natural immunity to HSV-1 in the CNS, which suggests thatneurotropic viruses have contributed to the evolutionary maintenanceof TLR3.
1 Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM), U550, Faculty Necker, Paris 75015, France. 2 University Paris René Descartes, Paris 75015, France. 3 French-Chinese Laboratory of Genetics and Life Sciences, Rui Jin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China. 4 Marseille-Luminy Immunology Institute, Marseille 13288, France. 5 Department of Genetics, INSERM, U781, Necker Hospital, Paris 75015, France. 6 Laboratory of Mononuclear Cell Biology, INSERM, U838, Necker Hospital, Paris 75015, France. 7 Ludwig Institute for Cancer Research, Lausanne Branch, University Hospital, Lausanne 1005, Switzerland. 8 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. 9 Center for the Study of Immunodeficiencies, Necker Hospital, Paris 75015, France. 10 INSERM, U563, University Toulouse Paul Sabatier, Toulouse 31000, France. 11 Centre National de la Recherche Scientifique, URA3012, Pasteur Institute, Paris 75015, France. 12 Virology, Cochin-Saint-Vincent de Paul Hospital, University Paris René Descartes, Paris 75014, France. 13 Pediatric Neurology, Trousseau Hospital, Paris 75012, France. 14 Pediatric Neurology, University Hospital, Lille 59037, France. 15 Pediatric Neurology, Bicêtre Hospital, University Paris Sud, Kremlin-Bicêtre 94270, France. 16 Pediatric Hematology-Immunology, Necker Hospital, Paris 75015, France.
* To whom correspondence should be addressed. E-mail: casanova{at}necker.fr
