Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 14 September 2007:
Vol. 317. no. 5844, pp. 1522 - 1527
DOI: 10.1126/science.1139522
Prev | Table of Contents | Next

Research Articles

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*

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

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Revisiting Crohn's disease as a primary immunodeficiency of macrophages.
J.-L. Casanova and L. Abel (2009)
J. Exp. Med. 206, 1839-1843
   Abstract »    Full Text »    PDF »
Viral Myocarditis: From the Perspective of the Virus.
T. Yajima and K. U. Knowlton (2009)
Circulation 119, 2615-2624
   Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses.
T. H. Mogensen (2009)
Clin. Microbiol. Rev. 22, 240-273
   Abstract »    Full Text »    PDF »
The roles of TLRs, RLRs and NLRs in pathogen recognition.
T. Kawai and S. Akira (2009)
Int. Immunol. 21, 317-337
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
TLR2 and TLR9 Synergistically Control Herpes Simplex Virus Infection in the Brain.
L. N. Sorensen, L. S. Reinert, L. Malmgaard, C. Bartholdy, A. R. Thomsen, and S. R. Paludan (2008)
J. Immunol. 181, 8604-8612
   Abstract »    Full Text »    PDF »
Toll-Like Receptor 3 Has a Protective Role against West Nile Virus Infection.
S. Daffis, M. A. Samuel, M. S. Suthar, M. Gale Jr., and M. S. Diamond (2008)
J. Virol. 82, 10349-10358
   Abstract »    Full Text »    PDF »
Prevalence of herpes simplex virus type 1 glycoprotein G (gG) and gI genotypes in patients with herpetic keratitis.
R Duan, J M van Dun, L Remeijer, M Siemerink, P G H Mulder, P Norberg, A D M E Osterhaus, and G M G M Verjans (2008)
Br J Ophthalmol 92, 1195-1200
   Abstract »    Full Text »    PDF »
Pyogenic Bacterial Infections in Humans with MyD88 Deficiency.
H. von Bernuth, C. Picard, Z. Jin, R. Pankla, H. Xiao, C.-L. Ku, M. Chrabieh, I. B. Mustapha, P. Ghandil, Y. Camcioglu, et al. (2008)
Science 321, 691-696
   Abstract »    Full Text »    PDF »
Upregulation of the TLR3 Pathway by Kaposi's Sarcoma-Associated Herpesvirus during Primary Infection.
J. West and B. Damania (2008)
J. Virol. 82, 5440-5449
   Abstract »    Full Text »    PDF »
Analysis of the Neuroinflammatory Response to TLR7 Stimulation in the Brain: Comparison of Multiple TLR7 and/or TLR8 Agonists.
N. B. Butchi, S. Pourciau, M. Du, T. W. Morgan, and K. E. Peterson (2008)
J. Immunol. 180, 7604-7612
   Abstract »    Full Text »    PDF »
Structural Basis of Toll-Like Receptor 3 Signaling with Double-Stranded RNA.
L. Liu, I. Botos, Y. Wang, J. N. Leonard, J. Shiloach, D. M. Segal, and D. R. Davies (2008)
Science 320, 379-381
   Abstract »    Full Text »    PDF »
2007: Signaling Breakthroughs of the Year.
E. M. Adler, J. F. Foley, N. R. Gough, and L. B. Ray (2008)
Science Signaling 1, eg1
   Abstract »    Full Text »    PDF »
Selective predisposition to bacterial infections in IRAK-4 deficient children: IRAK-4 dependent TLRs are otherwise redundant in protective immunity.
C.-L. Ku, H. von Bernuth, C. Picard, S.-Y. Zhang, H.-H. Chang, K. Yang, M. Chrabieh, A. C. Issekutz, C. K. Cunningham, J. Gallin, et al. (2007)
J. Exp. Med. 204, 2407-2422
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)