| Gene symbol | Gene name | Pathway involved | Inheritance pattern* | Clinical significance |
|---|---|---|---|---|
| UNC93B1 | unc-93 homolog B1, TLR signaling regulator | Endosomal TLR trafficking; upstream of TLR3/7/8/9-mediated type I IFN responses | AR; AD not established for HSE | First human gene clearly linked to isolated HSE susceptibility; impaired trafficking of TLR3 and related receptors reduces neuron-intrinsic antiviral defense against HSV-1 (pqac-00000020, pqac-00000022, pqac-00000024) |
| TLR3 | toll-like receptor 3 | TLR3–TRIF–TBK1–IRF3 interferon pathway | AR and AD | Deficiency predisposes to childhood HSE with incomplete penetrance; TLR3 defects are reported in ~5% of HSE patients and impair CNS-intrinsic IFN-mediated control of HSV-1 (pqac-00000019, pqac-00000020, pqac-00000024) |
| TICAM1 (TRIF) | TIR domain-containing adaptor molecule 1 | TLR3 adaptor signaling to TBK1/IRF3 | AR/AD reported in pathway defects; exact pattern varies by family | Loss impairs downstream TLR3 signaling and type I IFN induction, increasing risk of HSV CNS infection/HSE (pqac-00000017, pqac-00000024) |
| TRAF3 | TNF receptor-associated factor 3 | TLR3/RIG-I signaling to TBK1/IRF3 | AD reported for HSE-associated defects | Defects compromise antiviral interferon induction and are established monogenic causes of HSE susceptibility (pqac-00000017, pqac-00000019, pqac-00000024) |
| TBK1 | TANK-binding kinase 1 | TLR3/RIG-I signaling; IRF3 activation | AD reported for HSE-associated defects | Deficiency reduces interferon induction downstream of TLR3, predisposing to HSE and severe HSV CNS infection (pqac-00000017, pqac-00000019, pqac-00000024) |
| IRF3 | interferon regulatory factor 3 | Terminal transcription factor in TLR3/RIG-I/STING interferon signaling | AD reported; family-specific | HSE-associated variants impair IFN-α/β and IFN-λ responses in CNS-resident cells, enabling HSV-1 replication in brain tissue (pqac-00000019, pqac-00000024) |
| IKBKG (NEMO) | inhibitor of nuclear factor kappa B kinase regulatory subunit gamma | NF-κB and IRF3-linked antiviral signaling; TLR3/RIG-I/STING related | XL | Mutations impair IFN-α/β and IFN-λ production and can cause selective susceptibility to HSE despite relative systemic immune competence (pqac-00000017, pqac-00000020, pqac-00000022, pqac-00000024) |
| IFNAR1 | interferon alpha and beta receptor subunit 1 | Type I IFN receptor signaling | AR | Deficiency disrupts IFN-α/β immunity crucial for CNS defense against HSV-1 and is a significant cause of HSE susceptibility (pqac-00000017, pqac-00000019, pqac-00000024) |
| STAT1 | signal transducer and activator of transcription 1 | Type I/III (and also IFN-γ) interferon receptor signaling | AR complete deficiency; other forms vary | Deficiency impairs cellular responses to interferons and is linked to severe HSV CNS infection/HSE (pqac-00000017, pqac-00000020, pqac-00000022, pqac-00000024) |
| TYK2 | tyrosine kinase 2 | IFNAR downstream signaling | AR | Defects impair type I IFN signaling and are associated with susceptibility to HSE/severe HSV infection in some patients (pqac-00000019, pqac-00000024) |
| IRF9 | interferon regulatory factor 9 | ISGF3 complex; downstream IFNAR signaling | AR | Deficiency compromises ISG induction after IFNAR activation, predisposing to HSV CNS infection/HSE (pqac-00000017, pqac-00000024) |
| SNORA31 | small nucleolar RNA, H/ACA box 31 | IFN-independent, neuron-intrinsic antiviral defense | Presumed AR from reported deficiency cases | Identified as a noncanonical cause of HSE susceptibility; loss impairs cortical neuron intrinsic immunity to HSV-1 (pqac-00000017, pqac-00000018, pqac-00000022) |
| DBR1 | debranching RNA lariats 1 | RNA lariat metabolism; IFN-independent antiviral defense | AR | Variants impair RNA lariat metabolism and predispose to brainstem viral encephalitis/HSE-spectrum disease by weakening intrinsic antiviral restriction (pqac-00000018, pqac-00000022, pqac-00000023) |
| GTF3A | general transcription factor IIIA | 5S rRNA/RNA5SP141–RIG-I antiviral pathway | Not clearly established; likely AR in reported rare IEI | Newly identified mechanism of susceptibility in which disrupted RNA-mediated antiviral sensing compromises protection from HSV CNS infection (pqac-00000017, pqac-00000024) |
| RIPK3 | receptor interacting serine/threonine kinase 3 | Cell-death-dependent intrinsic antiviral defense; necroptosis/apoptosis control | AR | Inherited RIPK3 deficiency causes HSE by impairing neuronal death-mediated control of HSV-1 despite preserved IFN induction; highlights IFN-independent protection (pqac-00000021) |
| STAT2 | signal transducer and activator of transcription 2 | Type I IFN receptor signaling / ISGF3 | AR | Deficiency disrupts antiviral interferon signaling and is implicated in severe viral susceptibility; relevant to post-vaccine viral encephalitic vulnerability and broader HSV/CNS antiviral defense framework (pqac-00000019, pqac-00000000) |
| IFNAR2 | interferon alpha and beta receptor subunit 2 | Type I IFN receptor signaling | AR | Deficiency impairs IFN-α/β signaling and is relevant to severe viral CNS susceptibility within the IFNAR pathway, though stronger evidence exists for vaccine-strain viral disease than classic HSE (pqac-00000000) |
| TMEFF1 | tomoregulin-1 | Neuron-intrinsic restriction factor pathway | Not yet clearly defined | Emerging candidate restriction factor in brain immunity; proposed by Zhang & Casanova as part of newer antiviral pathways involved in HSE susceptibility (pqac-00000021) |

| *Inheritance abbreviations | Meaning |
|---|---|
| AR | autosomal recessive |
| AD | autosomal dominant |
| XL | X-linked |


*Table: This table summarizes key host genes implicated in susceptibility to viral encephalitis, especially childhood herpes simplex encephalitis, emphasizing the TLR3–interferon axis and newer neuron-intrinsic antiviral pathways. It is useful for linking monogenic immune defects to mechanism-based diagnosis and interpretation of severe HSV CNS infection.*