Document Type

Article

Publication Date

6-1-2023

Identifier

DOI: 10.1172/JCI154016; PMCID: PMC10231989

Abstract

Neonatal herpes simplex virus (HSV) infection is a devastating disease with substantial morbidity and mortality. The genetic basis of susceptibility to HSV in neonates remains undefined. We evaluated a male infant with neonatal skin/eye/mouth (SEM) HSV-1 disease, who had complete recovery after acyclovir but developed HSV-1 encephalitis at 1 year of age. An immune workup showed an anergic PBMC cytokine response to TLR3 stimulation but no other TLRs. Exome sequencing identified rare missense variants in IFN-regulatory factor 7 (IRF7) and UNC-93 homolog B1 (UNC93B1). PBMC single-cell RNA-Seq done during childhood revealed decreased expression of several innate immune genes and a repressed TLR3 pathway signature at baseline in several immune cell populations, including CD14 monocytes. Functional studies in fibroblasts and human leukemia monocytic THP1 cells showed that both variants individually suppressed TLR3-driven IRF3 transcriptional activity and the type I IFN response in vitro. Furthermore, fibroblasts expressing the IRF7 and UNC93B1 variants had higher intracellular viral titers with blunting of the type I IFN response upon HSV-1 challenge. This study reports an infant with recurrent HSV-1 disease complicated by encephalitis associated with deleterious variants in the IRF7 and UNC93B1 genes. Our results suggest that TLR3 pathway mutations may predispose neonates to recurrent, severe HSV.

Journal Title

The Journal of clinical investigation

Volume

133

Issue

11

MeSH Keywords

Infant, Newborn; Humans; Male; Infant; Factor VII; Toll-Like Receptor 3; Leukocytes, Mononuclear; Herpes Simplex; Herpesvirus 1, Human; Encephalitis, Herpes Simplex; Interferon Type I; Membrane Transport Proteins

Keywords

Genetics; Infectious disease; Molecular genetics

Comments

Grant support

Funding for this project was partially supported by funds from Children’s Mercy Hospital Institute of Research. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Publisher's Link: https://www.jci.org/articles/view/154016

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