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. 2024 Sep 23;230(3):706-715.
doi: 10.1093/infdis/jiad609.

Unraveling the Immune Signature of Herpes Zoster: Insights Into the Pathophysiology and Human Leukocyte Antigen Risk Profile

Romi Vandoren  1   2   3 , Marlies Boeren  2   4   5   6   7 , Jolien Schippers  2   6   7 , Esther Bartholomeus  2   6   7 , Kerry Mullan  1   2   3 , Nele Michels  8 , Olivier Aerts  9 , Julie Leysen  9 , An Bervoets  9 , Julien Lambert  9 , Elke Leuridan  10 , Johan Wens  8 , Karin Peeters  2   6   7 , Marie-Paule Emonds  11 , Hilde Jansens  12 , Jean-Laurent Casanova  13   14   15   16   17 , Paul Bastard  13   14   15   18 , Arvid Suls  2   19 , Viggo Van Tendeloo  2   5 , Peter Ponsaerts  5 , Peter Delputte  4 , Benson Ogunjimi  2   6   7   20 , Kris Laukens  1   2   3 , Pieter Meysman  1   2   3
Affiliations

Unraveling the Immune Signature of Herpes Zoster: Insights Into the Pathophysiology and Human Leukocyte Antigen Risk Profile

Romi Vandoren et al. J Infect Dis. .

Abstract

The varicella-zoster virus (VZV) infects >95% of the population. VZV reactivation causes herpes zoster (HZ), known as shingles, primarily affecting the elderly and individuals who are immunocompromised. However, HZ can occur in otherwise healthy individuals. We analyzed the immune signature and risk profile in patients with HZ using a genome-wide association study across different UK Biobank HZ cohorts. Additionally, we conducted one of the largest HZ human leukocyte antigen association studies to date, coupled with transcriptomic analysis of pathways underlying HZ susceptibility. Our findings highlight the significance of the major histocompatibility complex locus for HZ development, identifying 5 protective and 4 risk human leukocyte antigen alleles. This demonstrates that HZ susceptibility is largely governed by variations in the major histocompatibility complex. Furthermore, functional analyses revealed the upregulation of type I interferon and adaptive immune responses. These findings provide fresh molecular insights into the pathophysiology and activation of innate and adaptive immune responses triggered by symptomatic VZV reactivation.

Keywords: HLA association; gene expression analysis; genome-wide association study; herpes zoster; type I interferon response.

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Conflict of interest statement

Potential conflicts of interest. J.-L. C. is an inventor on patent application PCT/US2021/042741 (filed 22 July 2021; submitted by The Rockefeller University), which covers diagnosis of susceptibility to, and treatment of, viral disease and viral vaccines, including COVID-19 and vaccine-associated diseases. B. O., K. L., and P. M. are employees and/or stockholders of Immunewatch, which is a spin-off company focusing on the development of artificial intelligence–based models that give insights into the T-cell response. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Overview of the UK Biobank data used for the genome-wide association studies. The filtered data set was divided into 3 ethnicity groups based on the metadata included in the UK Biobank. The number of variants per group are shown, as well as the gender distribution over the control participants and cases of herpes zoster. Figure made with BioRender.
Figure 2.
Figure 2.
Manhattan plot of the White subpopulation identified an association of the MHC locus (green) with HZ. A, The Manhattan plot depicts different genetic variants (n = 48 015) and their association with the development of HZ. The plot was made via the qqman package in R. B, QQ plot for the association analysis depicts the expected vs observed P values. C, Manhattan plot of the zoomed-in MHC locus on chromosome 6 identifies variants in HLA-related genes, including MICB. The most highly associated variant (P = 2.521e-07) is annotated with dbSNP. HLA, human leukocyte antigen; HZ, herpes zoster; MHC, major histocompatibility complex; MICB, MHC class I polypeptide–related sequence B.
Figure 3.
Figure 3.
Differential expression analysis identifies overexpression of innate and adaptive immune transcripts in active HZ disease. Volcano plots represent top differential expression transcripts: A, HZ active vs HZ after 1 year; B, HZ active vs control. Dotted orange lines represent the cutoffs for the FDR (0.1) and logFC (±0.58). Scatter plots of logFC: C, HZ active vs HZ after 1 year and HZ active vs control; D, HZ active vs HZ after 1 year and HZ after 1 year vs control. Red, significantly upregulated in both; blue, significantly downregulated in both; orange, significantly dysregulated in both with opposite logFC; gray, nonsignificant in at least 1 analysis. Dotted gray lines represent x = 0 and y = 0 logFC. Gray dots denote nonsignificant transcripts (FDR >0.1); colored dots indicate significant dysregulation. Figures were made with ggVolcanoR. FDR, false discovery rate; HZ, herpes zoster; logFC, log2 fold change.
Figure 4.
Figure 4.
Heat map of differentially expressed genes from blood taken during HZ vs 1 year after HZ. Heat map shows clustering of gene expression profiles from blood taken during the acute HZ episode (HZ_XX, light blue) and clustering of those 1 year after the HZ episode (HZ_XX.1Y, pink/red). HZ, herpes zoster.
See this image and copyright information in PMC

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