Functional IRF3 deficiency in a patient with herpes simplex encephalitis

Abstract

Andersen et al. identify a novel genetic etiology of herpes encephalitis in an adult patient carrying a heterozygous loss-of-function mutation in the IRF3 gene. This mutation results in impaired INF production in response to viral infection

The toll-like receptor 3 pathway in homeostasis, responses to injury and wound repair

“…These findings were supported by subsequent analysis of patients with defects in genes encoding the TLR3 signalling components TRIF, TBK-1 and IRF3 [35][36][37]. An impaired TLR3-inducible type-1 IFN response to HSV-1 in neurons and oligodendrocytes in the central nervous system (CNS) was subsequently linked with this condition [32][33][34][35][36][37]. These findings are also consistent with studies in mouse models of DNA virus infections.…”

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

“…With respect to RNA virus infections, all 4 patients' cells responded with normal expression of type I and III IFNs to all viruses tested (Figure 5, F and G). Examination of the induction of IFNA2 and IFNL1 in cells from patients carrying mutations previously shown to confer susceptibility to HSE revealed that only IRF3 deficiency, but not TLR3 or TRIF deficiency, conferred reduced VZV-stimulated IFN expression (Supplemental Figure 13, A and B) (17,18,22). This IRF3 defect also ablated induction of IFNL1 by HSV-1 but did not affect the response to influenza A (IAV) infection (Supplemental Figure 13, C and D).…”

“…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).…”

Severe infectious diseases of childhood as monogenic inborn errors of immunity

“…We analyzed genome-wide linkage data and both blood and fibroblastic responses to herpes simplex virus and various viral intermediates in children with isolated HSE from this IFN-α/β-based angle, and we discovered mutations affecting five genes governing the TLR3-mediated IFN-α/β pathway (116)(117)(118)(119)(120)(121). Another group recently identified a mutation in a sixth gene (122). TLR3 can recognize viral dsRNA intermediates.…”