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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} 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}

Tranylcypromine Reduces Herpes Simplex Virus 1 Infection in Mice.
H.-W. Yao, P.-H. Lin, F.-H. Shen, G.-C. Perng, Y.-Y. Tung, S.-M. Hsu, and S.-H. Chen (2014)
Antimicrob. Agents Chemother. 58, 2807-2815
   Abstract »    Full Text »    PDF »
Inefficient Type I Interferon-Mediated Antiviral Protection of Primary Mouse Neurons Is Associated with the Lack of Apolipoprotein L9 Expression.
M. Kreit, S. Paul, L. Knoops, A. De Cock, F. Sorgeloos, and T. Michiels (2014)
J. Virol. 88, 3874-3884
   Abstract »    Full Text »    PDF »
TLR3 impairment in human newborns.
L. Slavica, I. Nordstrom, M. N. Karlsson, H. Valadi, M. Kacerovsky, B. Jacobsson, and K. Eriksson (2013)
J. Leukoc. Biol. 94, 1003-1011
   Abstract »    Full Text »    PDF »
Deciphering the modulation of gene expression by type I and II interferons combining 4sU-tagging, translational arrest and in silico promoter analysis.
M. Trilling, N. Bellora, A. J. Rutkowski, M. de Graaf, P. Dickinson, K. Robertson, O. Prazeres da Costa, P. Ghazal, C. C. Friedel, M. M. Alba, et al. (2013)
Nucleic Acids Res. 41, 8107-8125
   Abstract »    Full Text »    PDF »
Both TRIF and IPS-1 Adaptor Proteins Contribute to the Cerebral Innate Immune Response against Herpes Simplex Virus 1 Infection.
R. Menasria, N. Boivin, M. Lebel, J. Piret, J. Gosselin, and G. Boivin (2013)
J. Virol. 87, 7301-7308
   Abstract »    Full Text »    PDF »
Acidic Amino Acid Residues in the Juxtamembrane Region of the Nucleotide-Sensing TLRs Are Important for UNC93B1 Binding and Signaling.
J. Kim, J. Huh, M. Hwang, E.-H. Kwon, D.-J. Jung, M. M. Brinkmann, M. H. Jang, H. L. Ploegh, and Y.-M. Kim (2013)
J. Immunol. 190, 5287-5295
   Abstract »    Full Text »    PDF »
The human gene connectome as a map of short cuts for morbid allele discovery.
Y. Itan, S.-Y. Zhang, G. Vogt, A. Abhyankar, M. Herman, P. Nitschke, D. Fried, L. Quintana-Murci, L. Abel, and J.-L. Casanova (2013)
PNAS 110, 5558-5563
   Abstract »    Full Text »    PDF »
STAT2 deficiency and susceptibility to viral illness in humans.
S. Hambleton, S. Goodbourn, D. F. Young, P. Dickinson, S. M. B. Mohamad, M. Valappil, N. McGovern, A. J. Cant, S. J. Hackett, P. Ghazal, et al. (2013)
PNAS 110, 3053-3058
   Abstract »    Full Text »    PDF »
Natural Killer Cell Functional Defects in Pediatric Patients With Severe and Recurrent Herpesvirus Infections.
B. W. Ornstein, E. B. Hill, T. L. Geurs, and A. R. French (2013)
The Journal of Infectious Disease 207, 458-468
   Abstract »    Full Text »    PDF »
Cleaved/Associated TLR3 Represents the Primary Form of the Signaling Receptor.
F. Toscano, Y. Estornes, F. Virard, A. Garcia-Cattaneo, A. Pierrot, B. Vanbervliet, M. Bonnin, M. J. Ciancanelli, S.-Y. Zhang, K. Funami, et al. (2013)
J. Immunol. 190, 764-773
   Abstract »    Full Text »    PDF »
The Role of UNC93B1 Protein in Surface Localization of TLR3 Receptor and in Cell Priming to Nucleic Acid Agonists.
J. Pohar, N. Pirher, M. Bencina, M. Mancek-Keber, and R. Jerala (2013)
J. Biol. Chem. 288, 442-454
   Abstract »    Full Text »    PDF »
UNC93B1 mediates differential trafficking of endosomal TLRs.
B. L. Lee, J. E. Moon, J. H. Shu, L. Yuan, Z. R. Newman, R. Schekman, and G. M. Barton (2013)
eLife Sci 2, e00291
   Abstract »    Full Text »    PDF »
Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features.
M. Absoud, M. J. Lim, W. K. Chong, C. G. De Goede, K. Foster, R. Gunny, C. Hemingway, P. E. Jardine, R. Kneen, M. Likeman, et al. (2013)
Multiple Sclerosis Journal 19, 76-86
   Abstract »    Full Text »    PDF »
IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4-, MyD88-, and TIRAP- but not UNC-93B-deficient patients.
S. Weller, M. Bonnet, H. Delagreverie, L. Israel, M. Chrabieh, L. Marodi, C. Rodriguez-Gallego, B.-Z. Garty, C. Roifman, A. C. Issekutz, et al. (2012)
Blood 120, 4992-5001
   Abstract »    Full Text »    PDF »
Impaired Innate Immunity in Mice Deficient in Interleukin-1 Receptor-Associated Kinase 4 Leads to Defective Type 1 T Cell Responses, B Cell Expansion, and Enhanced Susceptibility to Infection with Toxoplasma gondii.
S. R. Bela, M. S. Dutra, E. Mui, A. Montpetit, F. S. Oliveira, S. C. Oliveira, R. M. E. Arantes, L. R. Antonelli, R. McLeod, and R. T. Gazzinelli (2012)
Infect. Immun. 80, 4298-4308
   Abstract »    Full Text »    PDF »
Atypical manifestations and poor outcome of herpes simplex encephalitis in the immunocompromised.
I. L. Tan, J. C. McArthur, A. Venkatesan, and A. Nath (2012)
Neurology 79, 2125-2132
   Abstract »    Full Text »    PDF »
Herpesvirus infections of the central nervous system in immunocompromised patients..
U. Meyding-Lamade and C. Strank (2012)
Therapeutic Advances in Neurological Disorders 5, 279-296
   Abstract »    PDF »
Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood.
M. Herman, M. Ciancanelli, Y.-H. Ou, L. Lorenzo, M. Klaudel-Dreszler, E. Pauwels, V. Sancho-Shimizu, R. Perez de Diego, A. Abhyankar, E. Israelsson, et al. (2012)
J. Exp. Med. 209, 1567-1582
   Abstract »    Full Text »    PDF »
Polymorphisms in Toll-like receptor 3 confer natural resistance to human herpes simplex virus type 2 infection.
A. Svensson, P. Tunback, I. Nordstrom, L. Padyukov, and K. Eriksson (2012)
J. Gen. Virol. 93, 1717-1724
   Abstract »    Full Text »    PDF »
Corneal Replication Is an Interferon Response-Independent Bottleneck for Virulence of Herpes Simplex Virus 1 in the Absence of Virion Host Shutoff.
T. J. Pasieka, V. D. Menachery, P. C. Rosato, and D. A. Leib (2012)
J. Virol. 86, 7692-7695
   Abstract »    Full Text »    PDF »
Heterozygous Carriage of a Dysfunctional Toll-like Receptor 9 Allele Affects CpG Oligonucleotide Responses in B Cells.
J. Knezevic, D. Pavlinic, W. A. Rose II, C. A. Leifer, K. Bendelja, J. Gabrilovac, M. Parcina, G. Lauc, A. V. Kubarenko, B. Petricevic, et al. (2012)
J. Biol. Chem. 287, 24544-24553
   Abstract »    Full Text »    PDF »
Host Genetic Factors in Susceptibility to Herpes Simplex Type 1 Virus Infection: Contribution of Polymorphic Genes at the Interface of Innate and Adaptive Immunity.
M. Moraru, E. Cisneros, N. Gomez-Lozano, R. de Pablo, F. Portero, M. Canizares, M. Vaquero, G. Roustan, I. Millan, M. Lopez-Botet, et al. (2012)
J. Immunol. 188, 4412-4420
   Abstract »    Full Text »    PDF »
Mapping of Clinical and Expression Quantitative Trait Loci in a Sex-Dependent Effect of Host Susceptibility to Mouse-Adapted Influenza H3N2/HK/1/68.
G. A. Boivin, J. Pothlichet, E. Skamene, E. G. Brown, J. C. Loredo-Osti, R. Sladek, and S. M. Vidal (2012)
J. Immunol. 188, 3949-3960
   Abstract »    Full Text »    PDF »
Spatiotemporal Inhibition of Innate Immunity Signaling by the Tbc1d23 RAB-GAP.
L. De Arras, I. V. Yang, B. Lackford, D. W. H. Riches, R. Prekeris, J. H. Freedman, D. A. Schwartz, and S. Alper (2012)
J. Immunol. 188, 2905-2913
   Abstract »    Full Text »    PDF »
A TRIF-Independent Branch of TLR3 Signaling.
M. Yamashita, S. Chattopadhyay, V. Fensterl, Y. Zhang, and G. C. Sen (2012)
J. Immunol. 188, 2825-2833
   Abstract »    Full Text »    PDF »
Role of Specific Innate Immune Responses in Herpes Simplex Virus Infection of the Central Nervous System.
J. P. Wang, G. N. Bowen, S. Zhou, A. Cerny, A. Zacharia, D. M. Knipe, R. W. Finberg, and E. A. Kurt-Jones (2012)
J. Virol. 86, 2273-2281
   Abstract »    Full Text »    PDF »
Severe Viral Infections and Primary Immunodeficiencies.
L. K. Dropulic and J. I. Cohen (2011)
Clinical Infectious Diseases 53, 897-909
   Abstract »    Full Text »    PDF »
Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity.
Y. Guo, M. Audry, M. Ciancanelli, L. Alsina, J. Azevedo, M. Herman, E. Anguiano, V. Sancho-Shimizu, L. Lorenzo, E. Pauwels, et al. (2011)
J. Exp. Med. 208, 2083-2098
   Abstract »    Full Text »    PDF »
H5N1 Influenza Virus Pathogenesis in Genetically Diverse Mice Is Mediated at the Level of Viral Load.
A. C. M. Boon, D. Finkelstein, M. Zheng, G. Liao, J. Allard, K. Klumpp, R. Webster, G. Peltz, and R. J. Webby (2011)
mBio 2, e00171-11
   Abstract »    Full Text »    PDF »
BAD-LAMP is a novel biomarker of nonactivated human plasmacytoid dendritic cells.
A. Defays, A. David, A. de Gassart, F. De Angelis Rigotti, T. Wenger, V. Camossetto, P. Brousset, T. Petrella, M. Dalod, E. Gatti, et al. (2011)
Blood 118, 609-617
   Abstract »    Full Text »    PDF »
Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or I{kappa}B{alpha} Deficiency.
C. Picard, J.-L. Casanova, and A. Puel (2011)
Clin. Microbiol. Rev. 24, 490-497
   Abstract »    Full Text »    PDF »
Increased Cell-Mediated Immune Responses in Patients with Recurrent Herpes Simplex Virus Type 2 Meningitis.
E. Franzen-Rohl, D. Schepis, M. Lagrelius, K. Franck, P. Jones, J.-A. Liljeqvist, T. Bergstrom, E. Aurelius, K. Karre, L. Berg, et al. (2011)
Clin. Vaccine Immunol. 18, 655-660
   Abstract »    Full Text »    PDF »
Early ''Relapse'' After Herpetic Encephalitis: Extensive White Matter Lesions in an Infant With Interferon Production Deficit.
R. Maia, C. Gouveia, A. Moreira, J. L. Casanova, V. Sancho-Shimizu, and M. J. Brito (2011)
J Child Neurol 26, 369-372
   Abstract »    PDF »
A Functional Toll-Like Receptor 3 Gene (TLR3) May Be a Risk Factor for Tick-borne Encephalitis Virus (TBEV) Infection.
E. Kindberg, S. Vene, A. Mickiene, A. Lundkvist, L. Lindquist, and L. Svensson (2011)
The Journal of Infectious Disease 203, 523-528
   Abstract »    Full Text »    PDF »
EBV Lytic-Phase Protein BGLF5 Contributes to TLR9 Downregulation during Productive Infection.
M. van Gent, B. D. Griffin, E. G. Berkhoff, D. van Leeuwen, I. G. J. Boer, M. Buisson, F. C. Hartgers, W. P. Burmeister, E. J. Wiertz, and M. E. Ressing (2011)
J. Immunol. 186, 1694-1702
   Abstract »    Full Text »    PDF »
Leprosy and the Human Genome.
E. A. Misch, W. R. Berrington, J. C. Vary Jr., and T. R. Hawn (2010)
Microbiol. Mol. Biol. Rev. 74, 589-620
   Abstract »    Full Text »    PDF »
Secretion of the Human Toll-like Receptor 3 Ectodomain Is Affected by Single Nucleotide Polymorphisms and Regulated by Unc93b1.
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 »
Interferon Regulatory Factor 3-Dependent Pathways Are Critical for Control of Herpes Simplex Virus Type 1 Central Nervous System Infection.
V. D. Menachery, T. J. Pasieka, and D. A. Leib (2010)
J. Virol. 84, 9685-9694
   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)
Rheumatology 49, 876-881
   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 »
Human genetics of infectious diseases: a unified theory.
J.-L. Casanova and L. Abel (2007)
EMBO J. 26, 915-922
   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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