Herpes simplex encephalitis (HSE) of childhood is a life-threatening central nervous system (CNS)-specific complication of primary infection by herpes simplex virus 1 (HSV-1). We showed that HSE may result from a novel group of primary immunodeficiencies (PIDs), with autosomal dominant (AD) TLR3 and autosomal recessive (AR) UNC-93B deficiency. We recently discovered an AR form of TLR3 deficiency, as well as AD TRIF, TRAF3 and TBK1 defects (unpublished). Moreover, other children with mycobacterial disease and lethal HSE bear mutations in STAT1 (AR) or NEMO (X-linked recessive, XR). These results indicate that lesions in the TLR3-dependent, interferon (IFN)-inducing pathway predispose to HSE. The pathogenesis of HSE involves a specific pathway in the CNS, as the lesions observed are restricted to this system. Our observations in skin-derived fibroblasts from patients further suggest that the molecular pathogenesis of HSE involves impaired viral dsRNA-triggered, TLR3-dependent IFN production in the CNS, resulting in increased viral replication and enhanced cell death. However, the cellular basis of the pathogenesis of HSE remains unclear, as TLR3-IFN and anti-HSV-1 immunity have not been investigated in CNS cells. TLR3 was reported to be expressed and functional in neurons, oligodendrocytes, astrocytes, and microglial cells, leading to IFN production. Moreover, these four cell types can be infected by HSV-1 in vitro. We hypothesize that the pathogenesis of HSE involves impaired TLR3-IFN immunity in at least one of the four CNS resident cell types, particularly non-hematopoietic neurons, astrocytes and oligodendrocytes. To test this hypothesis, we intend to investigate TLR3-IFN and anti-HSV-1 immunity in CNS cells. As we have no access to primary cells from the patients'CNS, we will take advantage of the fibroblasts available from healthy controls, from HSE patients bearing all known HSE genetic etiologies (mutations in UNC93B1, TLR3, TRIF, TRAF3, TBK1, STAT1, and NEMO) and from patients with other inborn errors of IFN immunity (mutation in TYK2) to derive induced pluripotent stem cells (iPSCs). These iPSCs will then be differentiated into neurons, oligodendrocytes, and astrocytes. TLR3-IFN and anti-HSV-1 immunity will be assessed in the three iPSC-derived CNS cell types from healthy controls and from HSE patients. Also, cells from selected HSE patients with an intact TLR3-IFN pathway in fibroblasts will be investigated, to search for a CNS-specific cellular phenotype. We have already successfully generated iPSCs from one UNC-93B-deficient patient with HSE and from one healthy control. These iPSCs possess stemness and pluripotency gene expression signature. We have also shown that stem cell-derived CNS cells from healthy controls can be tested for TLR3-IFN and anti-HSV-1 immunity. In sum, this approach will allow us (i) to specify which CNS cell types are responsible for HSE in patients bearing genetic deficiencies in the TLR3-IFN pathway, (ii) to search for CNS-specific HSE-causing cellular phenotypes in other patients and (iii) to provide proof-of-principle for the iPSCs-mediated investigation of the cellular pathogenesis of non-hematopoietic PIDs.

Public Health Relevance

Herpes simplex encephalitis (HSE), a life-threatening viral infection of the central nervous system (CNS), is caused, at least in some children, by inborn errors of interferon (IFN)-mediated immunity.
We aim to define the CNS resident cells, neurons, oligodendrocytes and/or astrocytes which are actually responsible for HSE. In order to do so, we will derive CNS cells from selected patients'skin fibroblasts-derived induced pluripotent stem cells (iPSCs) and test IFN-mediated anti-viral immunity.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IMM-K (52))
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Wong, May
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Rockefeller University
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New York
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