TLR3 Deficiency in Patients with Herpes Simplex Encephalitis

doi:10.1126/science.1139522

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Science 317 (5844): 1522-1527

TLR3 Deficiency in Patients with Herpes Simplex Encephalitis

Shen-Ying Zhang,¹^,2^,3 Emmanuelle Jouanguy,¹^,2^,3 Sophie Ugolini,⁴ Asma Smahi,⁵ Gaëlle Elain,⁶ Pedro Romero,⁷ David Segal,⁸ Vanessa Sancho-Shimizu,¹^,2 Lazaro Lorenzo,¹^,2 Anne Puel,¹^,2 Capucine Picard,¹^,2^,9 Ariane Chapgier,¹^,2 Sabine Plancoulaine,¹^,2 Matthias Titeux,¹⁰ Céline Cognet,⁴ Horst von Bernuth,¹^,2 Cheng-Lung Ku,¹^,2 Armanda Casrouge,¹^,2 Xin-Xin Zhang,³ Luis Barreiro,¹¹ Joshua Leonard,⁸ Claire Hamilton,¹^,2 Pierre Lebon,¹² Bénédicte Héron,¹³ Louis Vallée,¹⁴ Lluis Quintana-Murci,¹¹ Alain Hovnanian,¹⁰ Flore Rozenberg,¹² Eric Vivier,⁴ Frédéric Geissmann,⁶ Marc Tardieu,¹⁵ Laurent Abel,¹^,2 Jean-Laurent Casanova¹^,2^,3^,16^*

Abstract: 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

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