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BACKGROUND: Neonatal herpes simplex virus (HSV) is a devastating disease with high mortality. In adults and children, genetic variants in the Toll-like receptor 3 (TLR3) pathway increase susceptibility to herpes simplex encephalitis (HSE), but the genetic basis of susceptibility to neonatal HSV is unknown. We hypothesized that deleterious variants in the TLR3 pathway increased vulnerability to HSE in neonates. We investigated immunogenetic studies in an infant with neonatal skin, eye, mouth (SEM) HSV followed by HSE.

OBJECTIVES: To combine exome sequencing with in vivo and in vitro immunological functional analysis to discover the immunogenetic basis of HSV vulnerability in proband.

DESIGN/METHODS: The proband developed SEM HSV1 on day 7 of life and recovered fully with acyclovir. At 1 year of age he presented with seizures and was diagnosed with HSV1 HSE. Exome sequencing was performed to identify pathogenic genetic variants. An immune work up including peripheral blood monocyte (PBMC) functional TLR assay was done. Wild type and mutated alleles were transfected into THP1 monocyte cell line stably expressing an interferon regulatory factor 3 (IRF3) promoter-driven luciferase reporter. Poly(I:C) (1ug/mL), a TLR3 ligand, was used to stimulate THP1 for 24hr prior to luciferase assay and qRT-PCR for interferon (IFN) α and β gene expression.

RESULTS: We identified rare missense mutations in IRF7 (Arg100Pro) and UNC93B1 (Pro404Ser) genes. Immune work up was normal except for a total loss of PBMC cytokine response to TLR3 stimulation. Luciferase assays in THP1 showed dramatically reduced TLR3-driven IRF3 promoter activity in response to poly(I:C) with IRF7 and UNC93B1 variants. Similarly, IFNα and IFNβ expression induced by poly(I:C) was enhanced by wild type IRF7 and UNC93B1 alleles, but strongly suppressed by mutant IRF7 and UNC93B1 alleles. Combining the 2 mutant alleles compounded disruption of TLR3 signaling.

CONCLUSION: We identified 2 variants (IRF7, UNC93B1) that disrupted TLR3-responsiveness to HSV in vitro and in vivo in an infant with recurrent HSV disease complicated by HSE. This is the first report of human HSV disease associated with IRF7 mutations. Neonatal HSV may be a phenotype for immunodeficiency due to variants in TLR3 pathway genes. Infants with severe neonatal HSV may warrant genetic screening to identify variants that increase risk of recurrence, and prolonged acyclovir prophylaxis should be considered.

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Recurrent Neonatal Herpes Simplex Virus Infection Associated With IRF7 And UNC93B1 Variants