Unraveling the immune signature of herpes zoster: Insights into pathophysiology and the HLA risk profile

Abstract

The varicella-zoster virus (VZV) infects over 95% of the population and establishes latency afterwards. Reactivation of VZV causes herpes zoster (HZ), commonly known as shingles, which presents as a painful rash in mostly the elderly and people with a weakened immune system. However, HZ might occur in otherwise healthy individuals too. In this study, we have studied the immune signature of HZ to better understand HZ's pathophysiology. We provide a general overview of the antiviral state and the activation of innate and adaptive immune responses during HZ. Differential gene expression and gene ontology analyses revealed upregulation of several genes and host immune pathways during herpes zoster, especially related to type I IFN response but also related to adaptive immune responses. Intriguingly, no differences in gene expression were noted during convalescence between HZ patients and controls. Furthermore, we conducted the largest HLA association study on HZ to date using the UK Biobank and identified seven protective and four risk HLA alleles associated with the development of herpes zoster. These findings reveal key genes and pathways involved in the host immune response to symptomatic VZV reactivation and provide new molecular insights into the development of HZ.

Longitudinal Analysis Over Decades Reveals the Development and Immune Implications of Type I Interferon Autoantibodies in an Aging Population

“…While aging and prior autoimmune reactivity appear to pre-dispose an individual to develop anti-IFN-I autoAbs, the ‘two-hit’ hypothesis suggests that (auto)immunization with IFN-I is a subsequently required trigger in this process (Hale, 2023). Our finding of a statistical association (albeit weak) between prior recorded virus infections such as reactivated herpes zoster, which activates a clear endogenous IFN-I response in patients (Vandoren et al, 2024), and development of anti-IFN-I autoAbs provides some support to the idea that autoimmunization may occur. Similar support comes from our anecdotal finding that anti-IFN-I autoAbs developed in a patient immediately following hospitalization with severe pneumonia possibly caused by influenza A virus, again a scenario where endogenous IFN-I and inflammatory responses will be activated (Dunning et al, 2018).…”