Childhood herpes simplex encephalitis (HSE) is a life-threatening complication of primary infection by herpes simplex virus 1 (HSV-1), a common virus that is innocuous in most children. HSE is the most common sporadic viral encephalitis in Western countries and acyclovir-treated survivors often suffer from severe neurological sequels. The pathogenesis of HSE remained unclear until we recently showed that the disease may result from monogenic traits specifically impairing immunity to HSV-1 in the central nervous system (CNS), at least in some children. So far, we have described two children who presented with HSE because of autosomal recessive UNC-93B deficiency and two others who presented with HSE due to autosomal dominant TLR3 deficiency. By inference from experiments conducted using fibroblasts, we found that the pathogenesis of HSE in these patients involves impaired interferon (IFN)-alpha/beta and -lambda production upon stimulation of UNC-93B- dependent TLR3 by dsRNA viral intermediates in the CNS, which results in increased viral replication and enhanced cell death. Only four of the 92 patients tested carried either genetic defect. We now hypothesize that pediatric HSE in other children results from other single-gene inborn errors of immunity. The principal objective of the present application is to identify novel HSE-causing genes by following a hypothesis-free and hypothesis-generating, genome-wide screening approach focused on consanguineous families. In this approach, we will search for and characterize HSE-predisposing genes by genome-wide linkage and homozygosity mapping, taking advantage of 19 consanguineous kindreds. We have already obtained preliminary evidence that there are at least two homozygous regions linked to HSE, in which new HSE- predisposing genes HSEL1 and HSEL2 are likely to be identified. Our project is highly innovative, clearly feasible, and supported by promising preliminary evidence. From a basic biological standpoint, this research will provide unique insight into the mechanisms of immunity to HSV-1 in the CNS. The elucidation of the molecular genetic basis of HSE will also illuminate the pathogenesis of a devastating pediatric illness, making molecular diagnoses available for patients and genetic counseling possible for families. This new information will pave the way for new therapeutic avenues, such as the use of IFN-alpha in addition to acyclovir. Finally, the genetic dissection of HSE will provide proof-of-principle that sporadic, life-threatening infectious diseases in otherwise healthy children may result from collections of single-gene inborn errors of immunity. This paradigm shift for primary immunodeficiencies will create novel avenues for the investigation of infectious diseases.

Public Health Relevance

We recently provided proof-of-principle that herpes simplex encephalitis (HSE) in childhood may result from inborn errors of immunity. TLR3 and UNC-93B deficiencies are the first two identified genetic etiologies of HSE. We now aim to test the hypothesis that pediatric HSE in children born to consanguineous parents results from other inborn errors of immunity, by utilizing genome-wide approaches to search for novel HSE-predisposing single-gene lesions.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IMM-K (52))
Program Officer
Johnson, David R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rockefeller University
Other Domestic Higher Education
New York
United States
Zip Code
Conley, Mary Ellen; Casanova, Jean-Laurent (2014) Discovery of single-gene inborn errors of immunity by next generation sequencing. Curr Opin Immunol 30:17-23
Perez de Diego, Rebeca; Mulvey, Claire; Casanova, Jean-Laurent et al. (2014) Proteomics in immunity and herpes simplex encephalitis. Expert Rev Proteomics 11:21-9
Zhang, Shen-Ying; Herman, Melina; Ciancanelli, Michael J et al. (2013) TLR3 immunity to infection in mice and humans. Curr Opin Immunol 25:19-33
Casanova, Jean-Laurent; Abel, Laurent (2013) The genetic theory of infectious diseases: a brief history and selected illustrations. Annu Rev Genomics Hum Genet 14:215-43
Perez de Diego, Rebeca; Mulvey, Claire; Crawford, Mark et al. (2013) The proteome of Toll-like receptor 3-stimulated human immortalized fibroblasts: implications for susceptibility to herpes simplex virus encephalitis. J Allergy Clin Immunol 131:1157-66
Hambleton, Sophie; Salem, Sandra; Bustamante, Jacinta et al. (2011) IRF8 mutations and human dendritic-cell immunodeficiency. N Engl J Med 365:127-38
Audry, Magali; Ciancanelli, Michael; Yang, Kun et al. (2011) NEMO is a key component of NF-*B- and IRF-3-dependent TLR3-mediated immunity to herpes simplex virus. J Allergy Clin Immunol 128:610-7.e1-4
Guo, Yiqi; Audry, Magali; Ciancanelli, Michael et al. (2011) Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med 208:2083-98
PĂ©rez de Diego, Rebeca; Sancho-Shimizu, Vanessa; Lorenzo, Lazaro et al. (2010) Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Immunity 33:400-11