TLR3 deficiency in herpes simplex encephalitis

Abstract

Objective: To determine the proportion of children with herpes simplex encephalitis (HSE) displaying TLR3 deficiency, the extent of TLR3 allelic heterogeneity, and the specific clinical features of TLR3 deficiency. Methods:We determined the sequence of all exons of TLR3 in 110 of the 120 patients with HSE enrolled in our study who do not carry any of the previously described HSE-predisposing mutations of TLR3 pathway genes (TLR3, UNC93B1, TRIF, TRAF3, and TBK1). All the new mutant TLR3 alleles detected were characterized experimentally in-depth to establish the causal relationship between the genotype and phenotype.Results: In addition to the 3 previously reported TLR3-deficient patients from the same cohort, 6 other children or young adults with HSE carry 1 of 5 unique or extremely rare (minor allele frequency ,0.001) missense TLR3 alleles. Two alleles (M374T, D592N) heterozygous in 3 patients are not deleterious in vitro. The other 3 are deleterious via different mechanisms: G743D1R811I and L360P heterozygous in 2 patients are loss-of-function due to low levels of expression and lack of cleavage, respectively, and R867Q homozygous in 1 patient is hypomorphic. The 3 patients' fibroblasts display impaired TLR3 responses and enhanced herpes simplex virus 1 susceptibility. Overall, TLR3 deficiency is therefore found in 6 (5%) of the 120 patients studied. There is high allelic heterogeneity, with 3 forms of autosomal dominant partial defect by negative dominance or haploinsufficiency, and 2 forms of autosomal recessive defect with complete or partial deficiency. Finally, 4 (66%) of the 6 TLR3-deficient patients had at least 1 late relapse of HSE, whereas relapse occurred in only 12 (10%) of the total cohort of 120 patients.Conclusions: Childhood-onset HSE is due to TLR3 deficiency in a traceable fraction of patients, in particular the ones with HSE recurrence. Mutations in TLR3 and TLR3 pathway genes should be searched and experimentally studied in children with HSE, and patients with proven TLR3 deficiency should be followed carefully. TLR3 is one of the most highly conserved TLRs in humans that have evolved under the strongest purifying selection.1 TLR3 recognizes double-stranded RNA (dsRNA), a by-product produced during the viral replication of most viruses, including herpes simplex virus 1 (HSV-1).2 The most common known clinical consequence of human TLR3 deficiency is childhood herpes simplex encephalitis (HSE). Childhood HSE is a rare life-threatening complication of primary infection with HSV-1, a common neurotropic dsDNA virus that is innocuous in most children.3 HSE is the most common form of sporadic viral encephalitis in Western countries. 4,5 The pathogenesis of HSE had long remained unclear. Our recent studies have demonstrated that HSE may result from singlegene inborn errors of TLR3-mediated immunity in some children, 6 with homozygous or

Toll-like receptor-3 gene polymorphism in patients with Japanese encephalitis

“…A recent study revealed that the polymorphism of TLR3 gene plays a role in the development of clinical tick-borne encephalitis in the Lithuanian population and may be associated with disease severity (Mickienė et al, 2014). Another recently published study also suggested that abnormalities of central nervous system-intrinsic TLR3 immunity might be important in the pathogenesis of herpes simplex encephalitis during the course of primary herpes simplex encephalitis 1 infection (Lim et al, 2014). In an isolated patient with influenza-associated encephalopathy, authors detected a novel missense mutation (F303S) in TLR3 gene (Hidaka et al, 2006).…”

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

“…A striking example is that mutations in genes controlling Toll-like receptor (TLR) 3-dependent type I and III IFN-mediated immunity confer susceptibility to herpes simplex encephalitis (HSE) (17)(18)(19)(20)(21)(22). Notably, these genetic defects often appear to display incomplete penetrance, in which case they can be designated as monogenic but not Mendelian (18,20,23). Common to the identified genetic defects in the TLR3 pathway is that they lead to reduced type I and III IFN induction in patients cells after HSV-1 infection or stimulation through the TLR3 pathway ex vivo.…”

The Role of Genetic Factors in the Development of Herpetic Encephalitis. A Case From Practice

“…Мутации в этом гене ассоциированы с риском развития энце-фалита, вызываемого вирусом простого герпеса. Было показано, что рецидивы энцефалита возни-кают у пациентов с дефектом TLR3 значительно чаще, чем обычно [1,7,12]. Данные о функцио-нальной значимости выявленного варианта отсут-ствуют, однако in silico предиктивные программы (PolyPhen2, SIFT, MutationTaster) расценивают его как патогенный.…”

“…TLR3-зависимая индукция ИФН-α/β или ИФН-λ является критической для защиты центральной нервной системы против вируса простого герпеса [10]. TLR3-сигнальный путь включает целый ряд молекул (TLR3, UNC93B1, TRIF, TRAF3, and TBK1), дефект генов которых ассоциирован с риском раз-вития герпетического энцефалита [7]. По резуль-татам исследования H.K.…”