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Science 317 (5844): 1522-1527

Copyright © 2007 by the American Association for the Advancement of Science

TLR3 Deficiency in Patients with Herpes Simplex Encephalitis

Shen-Ying Zhang,123 Emmanuelle Jouanguy,123 Sophie Ugolini,4 Asma Smahi,5 Gaëlle Elain,6 Pedro Romero,7 David Segal,8 Vanessa Sancho-Shimizu,12 Lazaro Lorenzo,12 Anne Puel,12 Capucine Picard,129 Ariane Chapgier,12 Sabine Plancoulaine,12 Matthias Titeux,10 Céline Cognet,4 Horst von Bernuth,12 Cheng-Lung Ku,12 Armanda Casrouge,12 Xin-Xin Zhang,3 Luis Barreiro,11 Joshua Leonard,8 Claire Hamilton,12 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,12 Jean-Laurent Casanova12316*

Abstract: Some Toll and Toll-like receptors (TLRs) provide immunity to experimental infections in animal models, but their contribution to host defense in natural ecosystems is unknown. We report a dominant-negative TLR3 allele in otherwise healthy children with herpes simplex virus 1 (HSV-1) encephalitis. TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1, which spreads from the epithelium to the CNS via cranial nerves. TLR3 is also expressed in epithelial and dendritic cells, which apparently use TLR3-independent pathways to prevent further dissemination of HSV-1 and to provide resistance to other pathogens in TLR3-deficient patients. Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS, which suggests that neurotropic viruses have contributed to the evolutionary maintenance of 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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Cutting Edge: Priming of CD8 T Cell Immunity to Herpes Simplex Virus Type 1 Requires Cognate TLR3 Expression In Vivo.
G. M. Davey, M. Wojtasiak, A. I. Proietto, F. R. Carbone, W. R. Heath, and S. Bedoui (2010)
J. Immunol. 184, 2243-2246
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VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis.
T. R. Wuest and D. J.J. Carr (2010)
J. Exp. Med. 207, 101-115
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Severe Meningoencephalitis Due to Late Reactivation of Varicella-Zoster Virus in an Immunocompetent Child.
R. Spiegel, D. Miron, D. Lumelsky, and Y. Horovitz (2010)
J Child Neurol 25, 87-90
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Infectious Encephalitis in France in 2007: A National Prospective Study.
A. Mailles, J.-P. Stahl, and behalf of the Steering Committee and the Investiga (2009)
Clinical Infectious Diseases 49, 1838-1847
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Encephalitis: Why We Need to Keep Pushing the Envelope.
C. Glaser and K. C. Bloch (2009)
Clinical Infectious Diseases 49, 1848-1850
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Evasion of the Mucosal Innate Immune System by Herpes Simplex Virus Type 2.
T. Peng, J. Zhu, A. Klock, K. Phasouk, M.-L. Huang, D. M. Koelle, A. Wald, and L. Corey (2009)
J. Virol. 83, 12559-12568
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Dephosphorylation of eIF2{alpha} Mediated by the {gamma}134.5 Protein of Herpes Simplex Virus 1 Facilitates Viral Neuroinvasion.
D. Verpooten, Z. Feng, T. Valyi-Nagy, Y. Ma, H. Jin, Z. Yan, C. Zhang, Y. Cao, and B. He (2009)
J. Virol. 83, 12626-12630
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Control of Herpes Simplex Virus Replication Is Mediated through an Interferon Regulatory Factor 3-Dependent Pathway.
V. D. Menachery and D. A. Leib (2009)
J. Virol. 83, 12399-12406
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Host Genetic Variation Affects Resistance to Infection with a Highly Pathogenic H5N1 Influenza A Virus in Mice.
A. C. M. Boon, J. deBeauchamp, A. Hollmann, J. Luke, M. Kotb, S. Rowe, D. Finkelstein, G. Neale, L. Lu, R. W. Williams, et al. (2009)
J. Virol. 83, 10417-10426
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Toll-Like Receptor 3 Mediates Establishment of an Antiviral State against Hepatitis C Virus in Hepatoma Cells.
N. Wang, Y. Liang, S. Devaraj, J. Wang, S. M. Lemon, and K. Li (2009)
J. Virol. 83, 9824-9834
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Herpes Simplex Encephalitis during Treatment with Tumor Necrosis Factor-{alpha} Inhibitors.
R. D. Bradford, A. C. Pettit, P. W. Wright, M. J. Mulligan, L. W. Moreland, D. A. McLain, J. W. Gnann, and K. C. Bloch (2009)
Clinical Infectious Diseases 49, 924-927
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Early Triggering of Exclusive IFN-{gamma} Responses of Human V{gamma}9V{delta}2 T Cells by TLR-Activated Myeloid and Plasmacytoid Dendritic Cells.
M.-C. Devilder, S. Allain, C. Dousset, M. Bonneville, and E. Scotet (2009)
J. Immunol. 183, 3625-3633
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Revisiting Crohn's disease as a primary immunodeficiency of macrophages.
J.-L. Casanova and L. Abel (2009)
J. Exp. Med. 206, 1839-1843
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Viral Myocarditis: From the Perspective of the Virus.
T. Yajima and K. U. Knowlton (2009)
Circulation 119, 2615-2624
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HSV ICP0 recruits USP7 to modulate TLR-mediated innate response.
S. Daubeuf, D. Singh, Y. Tan, H. Liu, H. J. Federoff, W. J. Bowers, and K. Tolba (2009)
Blood 113, 3264-3275
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Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses.
T. H. Mogensen (2009)
Clin. Microbiol. Rev. 22, 240-273
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The roles of TLRs, RLRs and NLRs in pathogen recognition.
T. Kawai and S. Akira (2009)
Int. Immunol. 21, 317-337
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Control of TANK-binding Kinase 1-mediated Signaling by the {gamma}134.5 Protein of Herpes Simplex Virus 1.
D. Verpooten, Y. Ma, S. Hou, Z. Yan, and B. He (2009)
J. Biol. Chem. 284, 1097-1105
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A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity.
H. Negishi, T. Osawa, K. Ogami, X. Ouyang, S. Sakaguchi, R. Koshiba, H. Yanai, Y. Seko, H. Shitara, K. Bishop, et al. (2008)
PNAS 105, 20446-20451
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