Human TBK1: A Gatekeeper of Neuroinflammation

HSE, in a subset of children, is caused by impaired antiviral interferon (IFN) production due to monogenic mutations in the toll-like receptor 3 (TLR3)–IFN signaling pathway, including mutations in TBK1. Due to advances in sequencing technologies, several new amyotrophic lateral sclerosis (ALS) or ALS–frontotemporal dementia (ALS-FTD) genes have been identified, five of which are known to be involved in autophagy (SQSTM1, VCP, OPTN, UBQLN2, and TBK1). These mutations are thought to contribute to disease pathogenesis, possibly due to impaired autophagy. The genetic etiology of normal tension glaucoma (NTG) has recently been attributed to copy number variants (CNVs) found in chromosome region 12q14, specifically leading to duplications of the TBK1 gene. This duplication has been found to increase TBK1 transcript levels, suggesting a gain-of-function role for TBK1 in NTG. Recent developments in the field of selective autophagy have implicated this evolutionarily conserved process in innate immunity and pathogen clearance, including in neuronal cells. The importance of TANK binding kinase-1 (TBK1), a multimeric kinase that modulates inflammation and autophagy, in human health has been highlighted for the first time by the recent discoveries of mutations in TBK1 that underlie amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), normal tension glaucoma (NTG) or childhood herpes simplex encephalitis (HSE). Gain-of-function of TBK1 are associated with NTG, whereas loss-of-function mutations result in ALS/FTD or in HSE. In light of these new findings, we review the role of TBK1 in these seemingly unrelated, yet allelic diseases, and discuss the role of TBK1 in neuroinflammatory diseases. This discovery has the potential to significantly increase our understanding of the molecular basis of these poorly understood diseases. The importance of TANK binding kinase-1 (TBK1), a multimeric kinase that modulates inflammation and autophagy, in human health has been highlighted for the first time by the recent discoveries of mutations in TBK1 that underlie amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), normal tension glaucoma (NTG) or childhood herpes simplex encephalitis (HSE). Gain-of-function of TBK1 are associated with NTG, whereas loss-of-function mutations result in ALS/FTD or in HSE. In light of these new findings, we review the role of TBK1 in these seemingly unrelated, yet allelic diseases, and discuss the role of TBK1 in neuroinflammatory diseases. This discovery has the potential to significantly increase our understanding of the molecular basis of these poorly understood diseases. Tumor necrosis factor (TNF) receptor-associated factor NF-κB activator (TANK)-binding kinase 1 (TBK1) (see Glossary), also known as NF-κB-activating kinase (NAK) or T2K, has recently attracted the attention of human geneticists, immunologists, and neurologists alike for its critical role in central nervous system (CNS) pathology. It is a ubiquitously expressed serine–threonine kinase belonging to the ‘noncanonical IκB kinases’ (IKKs) recognized for its critical role in regulating type I interferon (IFN) production [1Fitzgerald K.A. et al.IKKɛ and TBK1 are essential components of the IRF3 signaling pathway.Nat. Immunol. 2003; 4: 491-496Crossref PubMed Scopus (0) Google Scholar]. TBK1 is involved in the activation of various cellular pathways leading to IFN and proinflammatory cytokine production following infection [1Fitzgerald K.A. et al.IKKɛ and TBK1 are essential components of the IRF3 signaling pathway.Nat. Immunol. 2003; 4: 491-496Crossref PubMed Scopus (0) Google Scholar], autophagic degradation of protein aggregates [27Stolz A. et al.Cargo recognition and trafficking in selective autophagy.Nat. Cell Biol. 2014; 16: 495-501Crossref PubMed Scopus (270) Google Scholar] or pathogens [2Thurston T.L.M. et al.The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria.Nat. 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Genet. 2011; 12: 745-755Crossref PubMed Scopus (840) Google Scholar]. The recent discoveries of TBK1 heterozygous mutations in four human diseases have demonstrated the nonredundant role of this multifaceted protein in the CNS in particular [6Herman M. et al.Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood.J. Exp. Med. 2012; 209: 1567-1582Crossref PubMed Scopus (0) Google Scholar, 7Cirulli E.T. et al.Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.Science. 2015; 347: 1436-1441Crossref PubMed Google Scholar, 8Freischmidt A. et al.Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia.Nat. 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These novel findings have emerged following the first identification of a series of genetic etiologies defining disease (HSE) or after a period of stagnant gene discovery (ALS, FTD, NTG). The data implicate new molecular pathways in disease pathogenesis. Consequently, discerning these pathways may lead to a better understanding of the causal mechanisms underlying such neurological disorders. Moreover, knowledge gained from further molecular investigation could be used to develop new and perhaps more effective therapies for these neurological diseases, which currently have limited treatment options. TBK1 was first identified as a TANK-interacting protein in mice [12Pomerantz J.L. Baltimore D. NF-κB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase.EMBO J. 1999; 18: 6694-6704Crossref PubMed Google Scholar], with a role in controlling NF-κB-mediated responses as demonstrated in luciferase reporter assays of HEK293T cells cotransfected with TBK1 and the NF-κB promoter [13Tojima Y. et al.NAK is an IκB kinase-activating kinase.Nature. 2000; 404: 778-782Crossref PubMed Scopus (0) Google Scholar]. However, in contrast to canonical IKKs (IKKα and IKKβ) that control NF-κB activation, the noncanonical IKKs (TBK1 and IKKɛ) have since been found to play a more important role in the activation of transcription factors of the IFN-inducing IFN-regulatory factor (IRF) family [14Chau T-L. et al.Are the IKKs and IKK-related kinases TBK1 and IKK-ɛ similarly activated?.Trends Biochem. Sci. 2008; 33: 171-180Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. TBK1 has been shown to play a key role in multiple cellular pathways, particularly inflammation and autophagy. TBK1 sits at the crossroads of multiple pathways, including NF-κB and IRF3, and controls multiple target genes, including type I and type III IFNs. Pattern recognition receptors (PRRs) such as toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and cytosolic DNA receptors all play important roles in the recognition of invading pathogens leading to IFN production (Figure 2, Key Figure). The engagement of such innate immune sensors by their cognate ligands, such as lipopolysaccharide (LPS), double-stranded RNA (dsRNA), or DNA, results in the production of cytokines that alert neighboring cells (including immune cells) of danger and foreign invasion, subsequently promoting the early events of defense against infection. Engagement of TLR3 by dsRNA recruits its adaptor TIR domain-containing adaptor-inducing IFN-β (TRIF), eventually activating TBK1, found in complex with NAK-associated protein 1 (NAP1) and IKKɛ (Figure 1). Activated TBK1 phosphorylates IRF3 leading to its homodimerization and translocation to the nucleus, where it drives the expression of antiviral type I and type III IFNs (IFNα/β/λ) [1Fitzgerald K.A. et al.IKKɛ and TBK1 are essential components of the IRF3 signaling pathway.Nat. Immunol. 2003; 4: 491-496Crossref PubMed Scopus (0) Google Scholar, 15Sharma S. et al.Triggering the interferon antiviral response through an IKK-related pathway.Science. 2003; 300: 1148-1151Crossref PubMed Scopus (1060) Google Scholar, 16Yamamoto M. et al.Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway.Science. 2003; 301: 640-643Crossref PubMed Scopus (1924) Google Scholar]. Besides membrane-bound TLRs, cytosolic RLRs [RIG-I, melanoma differentiation-associated 5 (MDA5)] activated by viral RNA [17Loo Y-M. Gale M. Immune signaling by RIG-I-like receptors.Immunity. 2011; 34: 680-692Abstract Full Text Full Text PDF PubMed Scopus (600) Google Scholar, 18Ishii K.J. et al.A toll-like receptor-independent antiviral response induced by double-stranded B-form DNA.Nat. Immunol. 2006; 7: 40-48Crossref PubMed Scopus (545) Google Scholar, 19Paz S. et al.Induction of IRF-3 and IRF-7 phosphorylation following activation of the RIG-I pathway.Cell. Mol. Biol. 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Finally, Asp-Glu-Ala-Asp (DEAD)-box helicase 3, X-linked (DDX3X) protein has also been shown to directly interact with TBK1 in RAW264.7 murine macrophages following DNA and viral RNA recognition, thereby leading to IFNβ production [24Soulat D. et al.The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response.EMBO J. 2008; 27: 2135-2146Crossref PubMed Scopus (130) Google Scholar] (summarized in Figure 2). Recent studies have described TBK1 as an important player in yet another critical cellular function, autophagy. Autophagy is an evolutionarily conserved homeostatic process of self-degradation that contributes to the maintenance of cell function at critical times by balancing resources through the turnover of long-lived proteins and organelles and also the clearance of intracellular pathogens [25Klionsky D.J. Autophagy: from phenomenology to molecular understanding in less than a decade.Nat. Rev. Mol. Cell Biol. 2007; 8: 931-937Crossref PubMed Scopus (1054) Google Scholar]. Autophagy is achieved by directing bulk cargo, such as protein aggregates, for degradation and/or recycling in lysosomes. It is a highly regulated process that is orchestrated by various autophagy-related proteins (ATGs) such as beclin-1 (ATG6), which functions to coordinate assembly of the autophagosome. (reviewed in [26Klionsky D.J. Schulman B.A. Dynamic regulation of macroautophagy by distinctive ubiquitin-like proteins.Nat. Struct. Mol. Biol. 2014; 21: 336-345Crossref PubMed Scopus (80) Google Scholar, 27Stolz A. et al.Cargo recognition and trafficking in selective autophagy.Nat. Cell Biol. 2014; 16: 495-501Crossref PubMed Scopus (270) Google Scholar]). Although autophagy is traditionally thought to be a nonselective process, there is accumulating evidence that autophagy proteins recognize specific cargo. This specificity is mediated by recruitment of autophagy receptors such as optineurin, p62, nuclear dot protein 52 kDa (NDP52), and neighbor of BRCA1 gene 1 (NBR1) [3Wild P. et al.Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth.Science. 2011; 333: 228-233Crossref PubMed Scopus (525) Google Scholar, 27Stolz A. et al.Cargo recognition and trafficking in selective autophagy.Nat. Cell Biol. 2014; 16: 495-501Crossref PubMed Scopus (270) Google Scholar, 28Kirkin V. et al.A role for NBR1 in autophagosomal degradation of ubiquitinated substrates.Mol. Cell. 2009; 33: 505-516Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 29Matsumoto G. et al.Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins.Mol. 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For post-mitotic cells such as neuronal cells, autophagy is an essential survival mechanism by which toxic proteins are eliminated, as they are not able to dilute these proteins through mitosis [31Komatsu M. et al.Loss of autophagy in the central nervous system causes neurodegeneration in mice.Nature. 2006; 441: 880-884Crossref PubMed Scopus (1929) Google Scholar, 32Hara T. et al.Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice.Nature. 2006; 441: 885-889Crossref PubMed Scopus (2079) Google Scholar]. A direct role of TBK1 in recycling protein aggregates has been shown via its role in phosphorylating the autophagy receptor optineurin [33Korac J. et al.Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates.J. Cell Sci. 2013; 126: 580-592Crossref PubMed Scopus (108) Google Scholar]. TBK1 has been reported to colocalize with optineurin and cell aggregates in HeLa cells in vitro as well as in vivo in a superoxide dismutase 1 (SOD1) transgenic mouse model of ALS [33Korac J. et al.Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates.J. Cell Sci. 2013; 126: 580-592Crossref PubMed Scopus (108) Google Scholar]. TBK1 has also been found to play a role in the autophagic elimination of invading intracellular pathogens such as Salmonella and Mycobacteria, in human and murine cell lines [2Thurston T.L.M. et al.The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria.Nat. Immunol. 2009; 10: 1215-1221Crossref PubMed Scopus (412) Google Scholar, 3Wild P. et al.Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth.Science. 2011; 333: 228-233Crossref PubMed Scopus (525) Google Scholar, 4Pilli M. et al.TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation.Immunity. 2012; 37: 223-234Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar]. The role of TBK1 in selective autophagy has been extensively studied in Salmonella, where it associates with optineurin and NDP52, targeting ubiquitinated Salmonella for autophagic clearance (Figure 2) [2Thurston T.L.M. et al.The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria.Nat. Immunol. 2009; 10: 1215-1221Crossref PubMed Scopus (412) Google Scholar, 34Morton S. et al.Enhanced binding of TBK1 by an optineurin mutant that causes a familial form of primary open angle glaucoma.FEBS Lett. 2008; 582: 997-1002Crossref PubMed Scopus (0) Google Scholar]. NDP52 is thought to act upstream of optineurin by directing TBK1 into the vicinity of interaction; TBK1 is then able to phosphorylate optineurin. TBK1 is also involved in autophagic clearance of Mycobacterium tuberculosis in RAW264.7 mouse macrophages, where it has been shown to phosphorylate the autophagy receptor p62, enhancing its binding to polyubiquitinated bacteria [4Pilli M. et al.TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation.Immunity. 2012; 37: 223-234Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar]. Moreover, TBK1 is particularly crucial for the maturation of the autophagosome into the hydrolytic autophagolysosome leading to degradation of p62 and its affiliated cargo [4Pilli M. et al.TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation.Immunity. 2012; 37: 223-234Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar]. Autophagy is also critical in herpes simplex virus 1 (HSV1) infections, demonstrated by the virus's ability to inhibit host autophagy through two virally encoded products, US11 and ICP34.5 [35Lussignol M. et al.The herpes simplex virus 1 Us11 protein inhibits autophagy through its interaction with the protein kinase PKR.J. Virol. 2013; 87: 859-871Crossref PubMed Scopus (0) Google Scholar, 36Chou J. et al.Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture.Science. 1990; 250: 1262-1266Crossref PubMed Google Scholar, 37Orvedahl A. et al.HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein.Cell Host Microbe. 2007; 1: 23-35Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar]. Although TBK1 has not been directly implicated in HSV1-mediated autophagy, the virally encoded autophagy antagonist ICP34.5 has been shown to bind and inhibit TBK1 in a mouse model of HSV1 infection [38Ma Y. et al.Inhibition of TANK binding kinase 1 by herpes simplex virus 1 facilitates productive infection.J. Virol. 2012; 86: 2188-2196Crossref PubMed Scopus (36) Google Scholar]. This interaction has been suggested to play a role in limiting the propagation and dissemination of HSV1 to the CNS (35]. Hence, TBK1 has been implicated in pathogen clearance via autophagy, contributing to cell-autonomous immunity. The two TBK1-regulated processes, autophagy and IFN induction, are not mutually exclusive, as crosstalk between them has been reported. For instance, upon HSV1 infection cGAS has been shown to bind Beclin-1, leading to suppression of IFN production and simultaneously to an increase in the autophagosomal clearance of cytosolic viral DNA in mouse bone marrow-derived macrophages (BMDMs) [39Liang Q. et al.Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses.Cell Host Microbe. 2014; 15: 228-238Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar]. Similarly, following mycobacterial infection, mouse BMDMs were shown to induce type I IFN and to trigger autophagic clearance of the pathogen in a TBK1-dependent manner, via cGAS [40Watson R.O. et al.The cytosolic sensor cGAS detects Mycobacterium tuberculosis DNA to induce type i interferons and activate autophagy.Cell Host Microbe. 2015; 17: 811-819Abstract Full Text Full Text PDF PubMed Google Scholar]. Although mouse models of TBK1 deficiency have contributed to our fundamental understanding of TBK1 function, particularly in immunity (Box 1), they have not been predictive of the phenotypes associated with human TBK1 mutations, since neurological phenotypes have not been assessed.Box 1Mouse Models of TBK1 DeficiencyTBK1 is highly conserved in mammals, with human TBK1 protein sharing 99% homology with its mouse ortholog [13Tojima Y. et al.NAK is an IκB kinase-activating kinase.Nature. 2000; 404: 778-782Crossref PubMed Scopus (0) Google Scholar]. However, characterization of TBK1 function in vivo remains a major challenge, as homozygous deletion of TBK1 in mice results in embryonic lethality at embryonic day 14.5 due to severe hepatic tissue loss and apoptosis [99Bonnard M. et al.Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-κB-dependent gene transcription.EMBO J. 2000; 19: 4976-4985Crossref PubMed Google Scholar].However, mice homozygous for a truncated allele (TBK1Δ/Δ) are viable, with minimal expression of truncated TBK1, which lacks kinase activity [100Marchlik E. et al.Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality.J. Leukoc. Biol. 2010; 88: 1171-1180Crossref PubMed Scopus (0) Google Scholar]. Macrophages from these mice have shown reduced IRF3 DNA-binding activity and IFNβ induction on LPS induction. Heterozygous mice with one truncated allele (TBK1Δ/+) are also viable although their immunological response to infection has not been studied [100Marchlik E. et al.Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality.J. Leukoc. Biol. 2010; 88: 1171-1180Crossref PubMed Scopus (0) Google Scholar].Much of our understanding of TBK1 function in viral infections and on stimulation with the synthetic analog of dsRNA poly I:C in vitro has come from observations in TBK1-deficient (TBK1−/−) mouse embryonic fibroblasts (MEFs) or from macrophages exhibiting either impaired IFN responses (IFNβ/α) or IFN-induced responses such as IFNγ-inducible protein 10 (IP-10) and Mx1 [38Ma Y. et al.Inhibition of TANK binding kinase 1 by herpes simplex virus 1 facilitates productive infection.J. Virol. 2012; 86: 2188-2196Crossref PubMed Scopus (36) Google Scholar, 101McWhirter S.M. et al.IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts.Proc. Natl Acad. Sci. U.S.A. 2004; 101: 233-238Crossref PubMed Scopus (0) Google Scholar, 102Miyahira A.K. et al.TANK-binding kinase-1 plays an important role during in vitro and in vivo type I IFN responses to DNA virus infections.J. Immunol. 2009; 182: 2248-2257Crossref PubMed Scopus (0) Google Scholar, 103Perry A.K. et al.Differential requirement for TANK-binding kinase-1 in type I interferon responses to toll-like receptor activation and viral infection.J. Exp. Med. 2004; 199: 1651-1658Crossref PubMed Scopus (238) Google Scholar]. It should be noted that the functional role of autophagy in TBK1-deficient mouse models remains to be characterized. TBK1 is highly conserved in mammals, with human TBK1 protein sharing 99% homology with its mouse ortholog [13Tojima Y. et al.NAK is an IκB kinase-activating kinase.Nature. 2000; 404: 778-782Crossref PubMed Scopus (0) Google Scholar]. However, characterization of TBK1 function in vivo remains a major challenge, as homozygous deletion of TBK1 in mice results in embryonic lethality at embryonic day 14.5 due to severe hepatic tissue loss and apoptosis [99Bonnard M. et al.Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-κB-dependent gene transcription.EMBO J. 2000; 19: 4976-4985Crossref PubMed Google Scholar]. However, mice homozygous for a truncated allele (TBK1Δ/Δ) are viable, with minimal expression of truncated TBK1, which lacks kinase activity [100Marchlik E. et al.Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality.J. Leukoc. Biol. 2010; 88: 1171-1180Crossref PubMed Scopus (0) Google Scholar]. Macrophages from these mice have shown reduced IRF3 DNA-binding activity and IFNβ induction on LPS induction. Heterozygous mice with one truncated allele (TBK1Δ/+) are also viable although their immunological response to infection has not been studied [100Marchlik E. et al.Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality.J. Leukoc. Biol. 2010; 88: 1171-1180Crossref PubMed Scopus (0) Google Scholar]. Much of our understanding of TBK1 function in viral infections and on stimulation with the synthetic analog of dsRNA poly I:C in vitro has come from observations in TBK1-deficient (TBK1−/−) mouse embryonic fibroblasts (MEFs) or from macrophages exhibiting either impaired IFN responses (IFNβ/α) or IFN-induced responses such as IFNγ-inducible protein 10 (IP-10) and Mx1 [38Ma Y. et al.Inhibition of TANK binding kinase 1 by herpes simplex virus 1 facilitates productive infection.J. Virol. 2012; 86: 2188-2196Crossref PubMed Scopus (36) Google Scholar, 101McWhirter S.M. et al.IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts.Proc. Natl Acad. Sci. U.S.A. 2004; 101: 233-238Crossref PubMed Scopus (0) Google Scholar, 102Miyahira A.K. et al.TANK-binding kinase-1 plays an important role during in vitro and in vivo type I IFN responses to DNA virus infections.J. Immunol. 2009; 182: 2248-2257Crossref PubMed Scopus (0) Google Scholar, 103Perry A.K. et al.Differential requirement for TANK-binding kinase-1 in type I interferon responses to toll-like receptor activation and viral infection.J. Exp. Med. 2004; 199: 1651-1658Crossref PubMed Scopus (238) Google Scholar]. It should be noted that the functional role of autophagy in TBK1-deficient mouse models remains to be characterized. HSE is a devastating neuroinflammatory disease caused by HSV1 infection of the CNS. HSV1 is a neurotropic dsDNA alphaherpesvirus usually causing asymptomatic or benign disease in the general population. With an incidence of 1–2 individuals per million annually (equivalent to about 1/10, 000 births), HSE is a rare and typically sporadic manifestation of HSV1 infection [41Whitley R.J. Gnann J.W. Viral encephalitis: familiar infections and emerging pathogens.Lancet. 2002; 359: 507-513Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar]. The peak incidence of HSE follows a bimodal curve, affecting children between 3 months and 6 years of age, coincident with the time of primary HSV-1 infection, and adults over 50 years of age, probably due to reactivation of latent HSV1 infection [42Abel L. et al.Age-dependent Mendelian predisposition to herpes simplex virus type 1 encephalitis in childhood.J. Pediatr. 2010; 157: 623-629Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Parental consanguinity of HSE patients is paradoxically higher than in the general population [41Whitley R.J. Gnann J.W. Viral encephalitis: familiar infections and emerging pathogens.Lancet. 2002; 359: 507-513Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar]. HSV1 is thought to reach the CNS through the nasal or oral epithelium via the olfactory or trigeminal nerves [43De Tiège X. et al.The spectrum of herpes simplex encephalitis in children.Eur. J. Paediatr. 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Med. 1986; 314: 144-149Crossref PubMed Google Scholar]. HSE has never been associated with any particularly neurovirulent strain of HSV1 and hence it was considered a rare idiopathic complication of HSV1 infection until the identification of defects in single genes within the TLR3–IFN pathway–TBK1–leading to diseases such as autosomal-dominant (AD) TBK1 deficiency [6Herman M. et al.Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood.J. Exp. Med. 2012; 209: 1567-1582Crossref PubMed Scopus (0) Google Scholar, 47Casrouge A. et al.Herpes simplex virus encepha