Encephalopathy, Acute, Infection-Induced (Herpes-Specific), Susceptibility To, 2

A number sign (#) is used with this entry because of evidence that susceptibility to acute infection-induced (herpes-specific) encephalopathy-2 (IIAE2) is caused by homozygous, compound heterozygous, or heterozygous mutation in the TLR3 gene (603029) on chromosome 4q35.

Description

Herpes simplex encephalitis (HSE) is a severe viral infection of the central nervous system (CNS) resulting most commonly from infection with HSV-1 and occasionally by HSV-2. The disease peaks in childhood between 3 months and 3 years of age, although later onset can also occur, and affected individuals usually have neurologic sequelae, including seizures and cognitive or motor impairment. Some individuals may have recurrences of an acute episode of HSE; however, patients have no clear susceptibility to infection to other viruses. The virus gains entry to the CNS through a neuronal route via the trigeminal or olfactory nerves, not via the blood. Replication of this enveloped double-stranded DNA (dsDNA) virus involves the production and accumulation of RNA species, including dsRNA, which are recognized by the intracellular TLR3 signaling pathway. The susceptibility to HSV in particular appears to result from impaired TLR3-dependent interferon production by nonhematopoietic cells that reside within the CNS (review by Zhang et al., 2013; summary by Mork et al., 2015).

For a general phenotypic description of herpes simplex encephalitis and a discussion of genetic heterogeneity of acute infection-induced encephalopathy, see 610551.

Clinical Features

Guo et al. (2011) reported a 19-year-old man (patient P), born of unrelated Polish parents, who developed HSE at age 8 years. He presented with herpes labialis before and after this HSE episode. Clinical features associated with HSE included high fever, vomiting, confusion, meningitis with increased CSF inflammatory cells, abnormal MRI signals and necrosis in the right temporal lobe, and slowing of the EEG. Serology showed HSV-1 IgG and IgM antibodies. The clinical signs were well controlled with acyclovir, but the patient had major neurologic sequelae, including epilepsy, and cognitive and motor disabilities. However, he had no subsequent acute events or other severe infectious diseases, particularly with viruses. He had antibody evidence of exposure to HSV-2, varicella zoster virus (VZV), Epstein-Barr virus, and influenza A virus. He was also immunized with live measles/mumps/rubella vaccine with no adverse effect. The patient's father and 1 of his brothers had developed herpes labialis at some time in their lives, but none developed HSE after serologically documented HSV-1 infection.

Lim et al. (2014) reported 6 unrelated patients with HSE. Clinical features of the episodes included fever, seizures, EEG abnormalities, positive results for HSV-1 antibodies in serum or CSF, detectable HSV-1 virus in the CSF, and positive response to acyclovir. The outcome of the patients was highly variable. Three patients (P1, P5, and P6) had recurrent HSE episodes; in vitro cellular studies in these 3 patients showed impaired interferon production, indicating a biologic functional defect and TLR3 deficiency. A 44-year-old woman (P1), who had her first HSE episode at ages 8 months, had mental retardation, hemiparesis, and encephalomalacia. She had another episode at age 35 years, at which time MRI showed evidence of severe brain damage extending to the brainstem. P5 had HSE at ages 2.5, 22, and 28 years. He made a full recovery from the first episode and attended regular school. The second and third episodes were characterized by seizures; he had full recovery from the second episode, but mild cognitive defects after the third. P6 had HSE at age 24 years, and subsequently had recurrent seizures associated with inflammation, atrophy, and gliosis in the right temporal lobe. He had only minor deficits in executive functions. Three additional patients with HSE and TLR3 variants had normal in vitro studies of interferon production. P2 was a 9-year-old girl who remained healthy following 1 episode of HSE at age 12 months. P3 was a 43-year-old woman with a single episode at age 3 years followed by left homonymous hemianopia and a mild epileptic syndrome, and P4 was a 6-year-old girl with herpetic lesions around the mouth and onset of HSE around 1 years of age. She had no additional episodes.

Mork et al. (2015) reported a Danish man who presented with HSE at age 59 years. He did not have an apparent history of recurrent labial or genital herpes. He reportedly had severe neurologic sequelae after this CNS infection, but clinical details were not provided.

Inheritance

The transmission pattern of HSE in the families reported by Lim et al. (2014) was consistent with autosomal dominant or autosomal recessive inheritance with incomplete penetrance.

Mapping

Zhang et al. (2007) showed that susceptibility to HSE can result from mutation in the TLR3 gene, which maps to chromosome 4q35.

Molecular Genetics

In 2 unrelated French children with herpes simplex encephalitis but no UNC93B (608204) deficiency, Zhang et al. (2007) detected a heterozygous pro554-to-ser (P554S; 603029.0001) mutation in the TLR3 gene. The mutation occurred on different TLR3 haplotypes in the children. Stimulation of heterozygous dermal fibroblasts or monocyte-derived dendritic cells with polyinosinic:polycytidylic acid (poly(I:C)), but not lipopolysaccharide, showed hyporesponsiveness in patient cell lines that could be reversed by transfection of wildtype TLR3. Infection with HSV-1, or vesicular stomatitis virus, but not other viruses, resulted in weaker IFNB (147640) and IFNL (IL29; 607403) production and increased viral replication in heterozygous TLR3-deficient fibroblasts. Myeloid and plasmacytoid dendritic cells, however, responded normally to poly (I:C), possibly explaining why HSE is a non-blood-borne viral encephalitis. Zhang et al. (2007) proposed that TLR3 is vital for natural immunity to HSV-1 in the CNS and suggested that neurotropic viruses have contributed to the evolutionary maintenance of TLR3.

In a 19-year-old man (patient P), born of unrelated Polish parents, with herpes simplex encephalitis at 8 years of age, Guo et al. (2011) identified compound heterozygous missense mutations in the TLR3 gene (P554S and E746X; 603029.0003). Both mutations were found in the patient's leukocytes and fibroblasts, and the mutations segregated with the disorder in the family. Neither mutation was able to rescue the deficits in interferon production in response to poly(I:C) when transfected into TLR3-null cells, consistent with a loss of function. Patient fibroblasts showed complete lack of beta- and gamma-interferon production in response to poly(I:C) and lack of interferon production, as well as increased viral replication and cell death, when infected in vitro with HSV-1 and vesicular stomatitis virus (VSV); however, they showed normal interferon response when infected with multiple other viruses. Moreover, patient leukocytes showed normal interferon response to poly(I:C) and when exposed to multiple viruses, including HSV-1 and VSV. The findings suggested that TLR3 is vital for protective immunity to primary HSV-1 infection in the CNS, but is largely redundant for systemic host defense, which also explains the lack of disseminated disease in this patient.

In 6 unrelated patients with herpes simplex encephalitis, Lim et al. (2014) identified 5 different missense mutations in the TLR3 gene (see, e.g., 603029.0004-603029.0006). The mutations were found by direct Sanger sequencing of the TLR3 gene in 110 patients with HSE who did not carry mutations in previously described HSE-related genes. Four patients carried a heterozygous mutation, 1 carried a heterozygous complex mutation with 2 different missense variants on the same allele, and 1 patient had a homozygous mutation. In vitro functional expression studies showed variable effects of the mutations: mutations in 3 patients (R867Q, G743D+R811O, and L360P) showed defective protein expression and/or functional impairment, with decreased or absent interferon production in response to poly(I:C), consistent with TLR3 deficiency. Fibroblasts derived from these 3 patients showed severely impaired interferon production in response to stimulation and increased HSV-1 replication compared to controls. These mutations also showed different in vitro molecular effects, including partial loss of function, complete loss of function, dominant-negative effects, and haploinsufficiency. The other 3 patients with HSE carried 1 of 2 missense variants (M374T and D592N) that showed similar expression and activity as the wildtype protein. Most families showed evidence of incomplete penetrance, with multiple unaffected family members carrying the same TLR3 variants.

In a 58-year-old Danish man (P9) with adult-onset herpes simplex encephalitis, Mork et al. (2015) identified a heterozygous missense mutation in the TLR3 gene (L297V; 603029.0007). The mutation was found by whole-exome sequencing of a cohort of 16 patients with adult-onset HSE and confirmed by Sanger sequencing. Patient peripheral blood mononuclear cells did not show significantly lower responses to poly(I;C) stimulation or HSV-1 infection compared to controls, but the authors suggested that these results do not exclude the existence of functionally impaired interferon responses in other cell types, particularly those in the CNS. The findings suggested that TLR3 variants may also contribute to HSE susceptibility in adults.

Pathogenesis

Lafaille et al. (2012) tested the hypothesis that the pathogenesis of Herpes simplex encephalitis involves nonhematopoietic central nervous system (CNS)-resident cells. Lafaille et al. (2012) derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3 (603029)- and UNC93B (608204)-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes, and oligodendrocytes. The induction of interferon-beta and/or interferon-lambda-1 in response to stimulation by the double-stranded RNA analog poly(I:C) was dependent on TLR3 and UNC93B in all cells tested. However, the induction of IFNB and IFNL in response to HSV-1 infection was impaired selectively in UNC93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC93B- and TLR3-deficient cells with the corresponding wildtype allele showed that the genetic defect was the cause of the poly(I:C) and the HSV-1 phenotypes. The viral infection phenotype was rescued further by treatment with exogenous IFN-alpha (IFNA; 147660) or IFNB but not IFNL. Thus, impaired TLR3- and UNC93B-dependent IFN-alpha/beta intrinsic immunity to HSV-1, in the CNS in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3 pathway deficiencies.