Inborn errors underlying herpes simplex encephalitis: From TLR3 to IRF3.

Most humans experience herpes simplex virus 1 (HSV-1) infection at some point in their lives, with no ill effects. Only a very small number develop HSV-1 encephalitis (HSE), which has an estimated prevalence of about 1/10,000. HSE is more common in childhood, affecting previously healthy individuals during primary infection. In the course of HSE, only the brain is affected. HSE is the most common form of sporadic, as opposed to epidemic, viral encephalitis in the Western world. Although sporadic, rather than familial, HSE can be caused by inborn errors of single genes. Mutations of five genes of the Toll-like receptor 3 (TLR3) signaling pathway have been identified in children with HSE: TLR3, UNC93B1, TRIF, and, more surprisingly, TRAF3 and TBK1, which encode downstream, nonspecific components of the pathway. These mutations impair central nervous system (CNS)–intrinsic interferon (IFN)-α/β production in response to HSV-1. In this issue, autosomal dominant (AD) interferon regulatory factor 3 (IRF3) deficiency is reported by Andersen et al. as a new genetic etiology of HSE.

Insight from Shen-Ying Zhang (left) and Jean-Laurent Casanova (right)

The transcription factor IRF3 controls multiple IFN-α/β–inducing pathways, including that of TLR3, which can be triggered by dsRNA, and those of other RNA and DNA sensors. IRF3 is normally activated by the kinases TBK1 and IKKε. The new IRF3 missense mutant, found in an adolescent with HSE, cannot undergo serine phosphorylation or dimerization and thus cannot activate transcription. In the heterozygous leukocytes of this patient, haploinsufficiency for IRF3 impairs the induction of antiviral IFN-α/β in response to various stimuli. Moreover, IFN-β induction in heterozygous fibroblasts stimulated by poly(I:C), which mimics dsRNA and for which recognition in fibroblasts depends on TLR3, is also impaired. IFN-β induction by HSV-1 is also impaired in these fibroblasts. Overall, the AD IRF3 deficiency is consistent with a key role for IRF3 in IFN-α/β induction, with a broad cellular phenotype, including impaired TLR3 and HSV-1 responses, reminiscent of that seen in AD TRAF3 and TBK1 deficiencies.

Mutations in six genes (TLR3, UNC93B1, TRIF, TRAF3, TBK1, and IRF3), all involved in the TLR3 signaling pathway, have been found in HSE patients. TLR3, UNC93B1, and TRIF are specifically involved in TLR3 signaling. TRAF3, TBK1, and IRF3 are also involved in signaling of other RNA and DNA sensors (RIG-I, MDA5, and cGAS). TLR3 signaling is initiated by the recognition of dsRNA, inducing activation of the IRF3 and NF-κB pathways via TRIF, leading to the production of IFN-α/β and/or IFN-λ. TLR3, UNC-93B, TRIF, TRAF3, TBK1, and IRF3 deficiencies are associated with impaired IFN-α/β and/or IFN-λ production upon stimulation of TLR3 or infection with HSV-1. A mutation in the gene encoding IRF3 is described in the paper by Andersen et al.

Despite the broad cellular impact of AD IRF3 deficiency, affecting multiple signaling pathways and cell types, its clinical phenotype in the single patient studied is surprisingly narrow, restricted to HSE. Moreover, clinical penetrance may be incomplete, as a heterozygous relative of unknown HSV-1 infection status is healthy. This neatly illustrates that not all cellular phenotypes translate into clinical phenotypes and that this translation varies from individual to individual. The molecular basis underlying these intriguing observations is not understood and will require further study. Incomplete clinical penetrance has been observed for most known genetic etiologies of HSE, consistent with the general view of HSE as sporadic. Overall, the study reported in this issue shows that human IRF3 is a key component of TLR3-dependent, IFN-α/β–mediated, CNS-intrinsic immunity to HSV-1. It adds weight to the emerging notion that impaired TLR3–IFN-α/β intrinsic immunity can underlie childhood HSE, suggesting that IFN-α treatment may be beneficial to patients.