A Photodermatologic Perspective on Shingles: A Narrative Review Exploring the Skin Microbiome as a Variable in the Effect of UV Radiation on VZV Reactivation

Introduction

Varicella Zoster Virus (VZV), one of the nine herpes viruses, causes varicella upon primary infection and subsequent herpes zoster (HZ) during reactivation (Cohen, 2013). The innate immune defense in primary infection delays viral replication in the skin and allows adaptive immunity to develop, leading to the characteristic rash associated with varicella (Cohrs et al., 2008; Mehta et al., 2004). T-cell immunity plays a key role in the host’s recovery from primary infection (Mueller et al., 2008). The virus then remains dormant in the host’s neurons, usually in the dorsal root ganglia, cranial nerve ganglia, or autonomic ganglia. Later in life, VZV can reactivate and travel to the skin through axonal transport, resulting in characteristic shingles skin lesions along a dermatome (Kennedy et al., 2003).

While much is understood about the immunological mechanisms underlying VZV reactivation, there remains a significant gap in knowledge concerning the contributors to reactivation. This article aims to explore this gap by examining existing literature on VZV reactivation, the immunosuppressive effects of ultraviolet radiation (UVR), and the role of the skin microbiome in immune modulation. By elucidating these relationships, the resulting research could inform the development of preventive strategies against VZV reactivation.

Contributors to VZV Reactivation

The specific conditions contributing to the reactivation of VZV, leading to the formation of zoster lesions, remain incompletely described. Nevertheless, existing evidence has established an association between reactivation and a decline in T-cell recognition of VZV antigens and reduced T-cell proliferation in response to VZV antigens (Hayward and Herberger, 1987; Mueller et al., 2008). Various other risk factors for VZV reactivation, such as age and stress, have also been identified. These are presumed to be linked to diminished immune system functionality responsible for maintaining viral dormancy (Tseng et al., 2011; Yawn et al., 2007).

Another noteworthy risk factor for HZ is sex, with females exhibiting more reported incidences than males across most age groups (Opstelten et al., 2002). Existing research consistently suggests that hormonal disparities between genders likely play a role in influencing HZ incidence by impacting the body’s response to virus reactivation (Thomas and Hall, 2004). However, the precise mechanism by which hormones increase HZ incidence and the specific hormones involved remain unclear.

UVR and VZV Reactivation

In addition to the established risk factors for VZV reactivation (Table 1), studies have uncovered a relationship between seasonality, UVR, and VZV reactivation. Gallerani and Manfredini (2000) were the first to find significant seasonal variation in VZV reactivation, with a notable peak in episode frequency among both the overall sample and the male subgroup of patients admitted to the emergency department with HZ in Ferrara, Italy, from January 1992 to December 1998. Subsequent analysis examining the age at disease onset and individuals experiencing multiple episodes did not identify any significant differences compared with the overall sample. Data on 48,388 patients in Japan from 1997 to 2006 similarly showed an uptick in HZ cases during the summer months (Toyama and Shiraki, 2009). Importantly, these studies and others suggest different underlying mechanisms for the incidence of chickenpox and shingles, with primary varicella infection rates at a minimum in August/September, probably explained by the respiratory spread of VZV (Hope-Simpson, 1965).

Several recent studies have proposed that the increase in VZV reactivation during summer months is, at least in large part, attributable to UVR specifically. Using Thailand’s national-level disease data, Bakker et al. (2021) tested 14 mathematical models that found that ambient levels of UVR were correlated with shingles. Ecological studies from Taiwan and Australia also found a correlation between the UV index and HZ incidence over time (Lai et al., 2021); Miller and Kelly, 2008). A similar relationship was also found between ground-level solar UV and the incidence of zoster in a Polish population over 2 years (Zak-Prelich et al., 2002). This particular study also examined the location of zoster lesions, finding that lesions occurring on exposed body sites such as the face were significantly more abundant in summer months, supporting the hypothesis that UV radiation itself likely contributes to VZV reactivation rather than other factors associated with seasonality. Finally, an analysis of three prospective cohort studies (looking at 205,756 participants) found that, in addition to ambient UVR being associated with overall zoster incidence, a history of severe sunburn was associated with a modest increased risk of HZ in both men and women (Kawai et al., 2020).

The Gallerani study, as well as the Polish and cohort studies, all found that seasonal variation occurred in total zoster cases due to an increase in cases among males, but not among females. (Gallerani and Manfredini, 2000; Zak-Prelich et al., 2002). Researchers have hypothesized that a possible explanation for the difference in reactivation for females and males could be that men tend to have more outside activities than women, such as gardening or walking, and thus more solar UV exposure.

The prevailing explanation for the association between UVR and VZV reactivation is radiation-mediated immunosuppression (Kawai et al., 2020). It has already been established that UV irritation directly affects the body’s immune response, contributing to skin carcinogenesis and several inflammatory skin conditions such as photodermatoses and photoaggravated disorders (Patra et al, 2019). UVR is known to induce innate immunity and suppress adaptive immunity in healthy individuals (Norval, 2006). Chronic UVR exposure further results in photoaging, cutaneous malignancies, and genetic mutations (D’Orazio et al., 2013). Mechanically, UV rays lead to reactive oxygen species formation and DNA damage to keratinocytes, triggering the signaling pathway for cytokine synthesis and release (Norval, 2006). Generation of oxygen radicals through photochemical reactions leads to disruptions including DNA cleavage, enzyme activity, alterations of cell metabolism, and keratinocyte apoptosis (Rünger and Kappes, 2008). These harmful effects, in addition to keratinocyte-produced cytokines, amplify the inflammatory responses in the skin while causing an immunosuppressive response of T-cells, dendritic cells, and B-cells (Norval, 2006). Histamine, an inflammatory mediator found in high levels in irritated tissues after UV irradiation, further contributes to inflammation and erythema (Hruza and Pentland, 1993). It is, therefore, reasonable to assume that direct UV-induced inflammation and immunosuppression may be the mechanism responsible for UVR-induced reactivation of VZV. The photoprotective effects of melanin against UVR are therefore also cited as a possible explanation for why Black individuals have an almost 50% reduction in risk of developing HZ than White individuals (Kawai et al, 2020).

However, while it is established that UVR is correlated with VZV reactivation and that UVR causes immunosuppression in the skin, one aspect that has not been adequately researched is the possible effect of the skin microbiome in modulating the effect of UVR-induced reactivation of VZV.

UVR and Skin Microbiome

The skin hosts a diverse community of microorganisms known as the skin microbiome. The majority of these residing organisms are benign or even advantageous to their host. The colonization process of the skin is influenced by the skin surface’s ecology, a factor greatly affected by topographical location, inherent host characteristics, and external environmental elements (Grice and Segre, 2011).

The skin microbiome plays a crucial role in maintaining skin homeostasis, safeguarding against invading pathogens, and influencing the modulation of the immune system (Grice and Segre, 2011). Recent research has also found that the skin microbiome may regulate gene expression in the skin. Specifically, it affects levels of toll-like receptors and antimicrobial proteins, as well as genes related to the interleukin-1 family (Lee and Kim, 2022). Additionally, the skin microbiome participates in the regulation of genes responsible for epidermal differentiation and development, as well as in influencing the process of wound healing (Grice and Segre, 2011). Numerous skin conditions are therefore linked to an imbalance in the skin microbiome (termed dysbiosis), including atopic dermatitis, seborrheic dermatitis, alopecia areata, psoriasis, and acne (De Pessemier et al, 2021).

Preliminary research also seems to suggest that microbiome diversity may affect rates of VZV reactivation. It is already known that antibiotics create a level of dysbiosis in the gut microbiome, which can lead to immunosuppression and increased rates of varicella and HZ infection (Armstrong et al., 2022).

Given the effects that UVR has on VZV reactivation and the important role the skin microbiome plays in maintaining immune balance, the question arises: how does UVR affect the skin microbiome? Research is still ongoing, but preliminary studies suggest that there may be a complex relationship between UVR, the skin microbiome, and immune responses. Recent research on sun exposure and the skin microbiome reveals that specific bacteria, particularly from the Sphingomonas and Erythrobacteraceae families, become enriched after seasonal sun exposure. Notably, a strain from Sphingomonas was found to be highly resistant to UV irradiation, reducing reactive oxygen species levels in human keratinocytes (Harel et al, 2023). These findings provide proof-of-concept for the skin microbiome’s potential role in protecting against UV-induced damage, a mechanism that could help mitigate the risk of VZV reactivation.

Exposure to UV radiation also modulated the structure of the skin microbiome, with a significant rise in Actinobacteria and a reduction in Proteobacteria and Firmicutes (Patra et al, 2016). This effect was observed after repeated exposure, suggesting a long-term influence of UVR on the skin microbiome composition. Further studies, including work by Wang et al. (2024), indicate that the skin microbiome may also influence immune modulation via commensals such as Lactobacillus rhamnosus GG, which has been shown to induce type I interferons and thus could provide a novel therapeutic approach for treating herpesvirus infections, including VZV. Moreover, Armstrong et al. (2022) found that antibiotic use, which can disrupt the skin microbiome, is associated with an increased risk of VZV reactivation, suggesting that maintaining microbiome balance may be critical in preventing such infections.

Emerging research has also highlighted the role of gut microbiota in modulating immune responses to herpes viruses, as shown by Chai et al. (2024). Their study suggests that alterations in gut bacterial composition can significantly impact VZV risk through inflammatory response modulation. This further emphasizes the need to consider dietary interventions, probiotics, and microbiota-targeted therapies as potential strategies to reduce VZV reactivation. Additionally, UVR-induced changes to the microbiome could generate immune-modulating pathogen-associated molecular patterns (Patra et al., 2016), which may offer insights into novel therapeutic interventions. Incorporating these findings into clinical strategies could pave the way for microbiome-based approaches, such as probiotic supplementation, to support immune resilience against VZV reactivation.

Conclusion

This article has sought to review the existing literature on VZV reactivation, the immunosuppressive effects of UVR, and the role of the skin microbiome in immune modulation. While the relationship between UVR and VZV reactivation is well-established, there is still much to learn about how UVR affects the skin microbiome, and how these effects influence VZV reactivation. Future research should aim to elucidate these complex interactions and explore the potential for new preventive strategies against VZV reactivation. By gaining a better understanding of these relationships, we may be able to develop more effective methods for preventing and treating this disease.