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Science 314 (5797): 308-312

Copyright © 2006 by the American Association for the Advancement of Science

Herpes Simplex Virus Encephalitis in Human UNC-93B Deficiency

Armanda Casrouge,1* Shen-Ying Zhang,1,2* Céline Eidenschenk,1* Emmanuelle Jouanguy,1,2* Anne Puel,1 Kun Yang,1,2 Alexandre Alcais,1 Capucine Picard,1,3 Nora Mahfoufi,1 Nathalie Nicolas,1 Lazaro Lorenzo,1 Sabine Plancoulaine,1 Brigitte Sénéchal,4 Frédéric Geissmann,4 Koichi Tabeta,5{dagger} Kasper Hoebe,5 Xin Du,5 Richard L. Miller,6 Bénédicte Héron,7 Cyril Mignot,7 Thierry Billette de Villemeur,7 Pierre Lebon,8 Olivier Dulac,9 Flore Rozenberg,8 Bruce Beutler,5 Marc Tardieu,10 Laurent Abel,1 Jean-Laurent Casanova1,2,11{ddagger}

Abstract: Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is the most common form of sporadic viral encephalitis in western countries. Its pathogenesis remains unclear, as it affects otherwise healthy patients and only a small minority of HSV-1–infected individuals. Here, we elucidate a genetic etiology for HSE in two children with autosomal recessive deficiency in the intracellular protein UNC-93B, resulting in impaired cellular interferon-{alpha}/ß and -{lambda} antiviral responses. HSE can result from a single-gene immunodeficiency that does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies. Other severe infectious diseases may also reflect monogenic disorders of immunity.

1 Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes, INSERM, U550, Faculté de Médecine Necker, Paris 75015, France.
2 French-Chinese Laboratory of Genomics and Life Sciences, Rui-jin Hospital, Shanghai Jiaotong University, Shanghai 200025, China.
3 Centre d'Etude des Déficits Immunitaires, Hôpital Necker, Paris 75015, France.
4 Laboratoire d'Etude des Cellules Mononucléées, Hôpital Necker, Paris 75015, France.
5 Scripps Research Institute, La Jolla, CA 92037, USA.
6 3M Center, St. Paul, MN 55144, USA.
7 Service de Neurologie Pédiatrique, Hôpital Trousseau, Paris 75012, France.
8 Service de Virologie, Hôpital Saint-Vincent de Paul, Paris 75014, France.
9 Service de Neurologie Pédiatrique, Hôpital Necker, Paris 75015, France.
10 Service de Neurologie Pédiatrique et INSERM U802, Hôpital de Bicêtre, Kremlin-Bicêtre 94270, France.
11 Unité d'Immunologie et d'Hématologie Pédiatriques, Hôpital Necker, Paris 75015, France.

* These authors contributed equally to this work.

{dagger} Present address: Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8514, Japan.

{ddagger} To whom correspondence should be addressed. E-mail: casanova{at}necker.fr

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   Abstract »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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R. Qi, S. Hoose, J. Schreiter, K. V. Sawant, R. Lamb, C. T. Ranjith-Kumar, J. Mills, L. S. Mateo, J. L. Jordan, and C. C. Kao (2010)
J. Biol. Chem. 285, 36635-36644
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Microbe Hunting.
W. I. Lipkin (2010)
Microbiol. Mol. Biol. Rev. 74, 363-377
   Abstract »    Full Text »    PDF »
Up-regulation of the endoplasmic reticulum transmembrane protein UNC93B in the B cells of patients with active systemic lupus erythematosus.
S. Nakano, S. Morimoto, S. Suzuki, T. Watanabe, H. Amano, and Y. Takasaki (2010)
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   Abstract »    Full Text »    PDF »
Beta interferon plus gamma interferon efficiently reduces acyclovir-resistant herpes simplex virus infection in mice in a T-cell-independent manner.
W.-Y. Huang, Y.-H. Su, H.-W. Yao, P. Ling, Y.-Y. Tung, S.-H. Chen, X. Wang, and S.-H. Chen (2010)
J. Gen. Virol. 91, 591-598
   Abstract »    Full Text »    PDF »
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
   Abstract »    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 »
Clinical Correlates of Herpes Simplex Virus Viremia among Hospitalized Adults.
W. R. Berrington, K. R. Jerome, L. Cook, A. Wald, L. Corey, and C. Casper (2009)
Clinical Infectious Diseases 49, 1295-1301
   Abstract »    Full Text »    PDF »
Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing.
R. Fukui, S.-i. Saitoh, F. Matsumoto, H. Kozuka-Hata, M. Oyama, K. Tabeta, B. Beutler, and K. Miyake (2009)
J. Exp. Med. 206, 1339-1350
   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 »
Human Genetic Factors and Respiratory Syncytial Virus Disease Severity.
I. Miyairi and J. P. DeVincenzo (2008)
Clin. Microbiol. Rev. 21, 686-703
   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 »
Enhanced Pathogenesis of an Attenuated Herpes Simplex Virus for Mice Lacking Stat1.
T. J. Pasieka, B. Lu, and D. A. Leib (2008)
J. Virol. 82, 6052-6055
   Abstract »    Full Text »    PDF »
Glycoprotein-Dependent and TLR2-Independent Innate Immune Recognition of Herpes Simplex Virus-1 by Dendritic Cells.
A. Reske, G. Pollara, C. Krummenacher, D. R. Katz, and B. M. Chain (2008)
J. Immunol. 180, 7525-7536
   Abstract »    Full Text »    PDF »
Multiple Intracranial Tuberculomas Associated With Partial Status Epilepticus and Refractory Infantile Spasms.
C. Zorn-Olexa, V. Laugel, A. d. S. Martin, L. Donato, and M. Fischbach (2008)
J Child Neurol 23, 459-462
   Abstract »    PDF »
Melkersson-Rosenthal syndrome.
M. Kanerva, K. Moilanen, S. Virolainen, A. Vaheri, and A. Pitkaranta (2008)
Otolaryngology -- Head and Neck Surgery 138, 246-251
   Abstract »    Full Text »    PDF »
Doctor, Why Is My Herpes So Bad? The Search Continues.
D. M. Koelle and T. L. Bergemann (2008)
The Journal of Infectious Disease 197, 331-334
   Full Text »    PDF »
In the Literature.
S. Deresinski (2008)
Clinical Infectious Diseases 46, v-vi
   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 »
TLR3 Deficiency in Patients with Herpes Simplex Encephalitis.
S.-Y. Zhang, E. Jouanguy, S. Ugolini, A. Smahi, G. Elain, P. Romero, D. Segal, V. Sancho-Shimizu, L. Lorenzo, A. Puel, et al. (2007)
Science 317, 1522-1527
   Abstract »    Full Text »    PDF »
Polymorphisms in TLR2 Are Associated with Increased Viral Shedding and Lesional Rate in Patients with Genital Herpes Simplex Virus Type 2 Infection.
P.-Y. Bochud, A. S. Magaret, D. M. Koelle, A. Aderem, and A. Wald (2007)
The Journal of Infectious Disease 196, 505-509
   Abstract »    Full Text »    PDF »
Primary Immunodeficiencies: A Field in Its Infancy.
J.-L. Casanova and L. Abel (2007)
Science 317, 617-619
   Abstract »    Full Text »    PDF »
Genetic Susceptibility, HIV Infection, and the Kidney.
K. Kiryluk, J. Martino, and A. G. Gharavi (2007)
Clin. J. Am. Soc. Nephrol. 2, S25-S35
   Abstract »    Full Text »    PDF »
The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling.
M. M. Brinkmann, E. Spooner, K. Hoebe, B. Beutler, H. L. Ploegh, and Y.-M. Kim (2007)
J. Cell Biol. 177, 265-275
   Abstract »    Full Text »    PDF »
Preferential Activation of Toll-Like Receptor Nine by CD46-Utilizing Adenoviruses.
M. Iacobelli-Martinez and G. R. Nemerow (2007)
J. Virol. 81, 1305-1312
   Abstract »    Full Text »    PDF »
A Fast Procedure for the Detection of Defects in Toll-like Receptor Signaling.
H. von Bernuth, C.-L. Ku, C. Rodriguez-Gallego, S. Zhang, B.-Z. Garty, L. Marodi, H. Chapel, M. Chrabieh, R. L. Miller, C. Picard, et al. (2006)
Pediatrics 118, 2498-2503
   Abstract »    Full Text »    PDF »

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