IRF7 and UNC93B1 variants in an infant with recurrent herpes simplex virus infection
Megan H. Tucker, … , Nikita Raje, Venkatesh Sampath
Megan H. Tucker, … , Nikita Raje, Venkatesh Sampath
Published April 25, 2023
Citation Information: J Clin Invest. 2023;133(11):e154016. https://doi.org/10.1172/JCI154016.
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Research Article Genetics Infectious disease

IRF7 and UNC93B1 variants in an infant with recurrent herpes simplex virus infection

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.

Authors

Megan H. Tucker, Wei Yu, Heather Menden, Sheng Xia, Carl F. Schreck, Margaret Gibson, Daniel Louiselle, Tomi Pastinen, Nikita Raje, Venkatesh Sampath

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Figure 2

Analysis of scRNA-Seq transcriptome data for proband versus controls.

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Analysis of scRNA-Seq transcriptome data for proband versus controls. (A...
(A) Depiction of genes repressed in CD14, CD4-naive, CD8-naive, gDT, and CD4-naive cell populations for the proband compared with controls. Data shown are only from approximately half of the cells for the control and half of the cells for the proband. The x axis represents log2-fold gene expression, and the y axis represents the log10-adjusted (adj.) P value. (B) Heatmap showing the major upstream regulators predicted by IPA to be induced or suppressed in the proband compared with controls in the major peripheral blood cell types. A dot in the center of the box represents nonsignificant results. (C) Heatmap illustrating IPA predictions of gene expression changes relating to specific TLR pathways in different cell types in the proband compared with the control. A dot in the center of the box represents nonsignificant results. (D) TLR3 pathway–related genes repressed in CD14 monocytes in proband compared with controls. Data shown are only from exactly one-half of the CD14 monocyte population for our proband and controls. The x axis represents log2-fold gene expression, and the y axis represents the log10-adjusted P value. For the scRNA-Seq data, a Wilcoxon rank-sum test with Bonferroni’s correction was applied for analysis.