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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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 6

Neonatal human fibroblasts carrying the UNC93B1 variant p.P404S and the IRF7 variant p.R100P showed abolished responses to stimulation with poly(I:C) or HSV-1.

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Neonatal human fibroblasts carrying the UNC93B1 variant p.P404S and the ...
Neonatal human fibroblasts stably expressing dTomato alone (control Ø), UNC93B1 and IRF7 double WT, UNC93B1 and IRF7 double-mut, the IRF7 mut:UNC93B1 WT, and the UNC93B1 mut:IRF7 WT were used in this experiment. (A) Graphic representation of the plasmid structure and related mature protein. (B) Western blot shows the expression of IRF7, UNC93B1, and TLR3 in all stable cell lines and (C) densitometric analysis. n = 4. †††P < 0.05. (D) The fibroblast cell lines were incubated with HSV-1 at a MOI of 10 for 1 hour, HSV Virus copy was quantified from the cell lines after a 16-hour infection. n = 5. †††P < 0.05. (E) The fibroblast cell lines were incubated with HSV-1 at MOI of 10 for 1 hour, and the resulting gene expression 6 hours after infection is shown. n = 6. †††P < 0.05. (F) These cell lines were incubated with 1 μg/mL poly(I:C) for 24 hours, and mRNA expression is shown for IFNA and IFNB. *Control versus poly(I:C); **poly(I:C) Ø versus poly(I:C) plasmid; ***control Ø versus control plasmid; P < 0.05 (all). n = 3. A Mann-Whitney U test or ANOVA with post hoc Tukey’s test was used for statistical analysis after testing for normality of distribution.