Because the latent varicella zoster virus (VZV) is a lifelong condition, researchers are working to understand how it evolves to evade and manipulate the natural immune response, according to a study in Frontiers in Immunology.

VZV is an extremely common human herpesvirus, with prevalence rates greater than 90% in most populations around the world, according to the study authors. The primary infection causes chickenpox, which then establishes a lifelong latency in sensory neurons. It can reactive years later, causing shingles, which can cause severe post-herpetic neuralgia and can persist for months to years.

The innate immune response against VZV involves the body’s recognition of the viral pathogen, which triggers either inflammatory cytokine secretion or cell death. However, a major obstacle for investigators researching VZV immune response is that it reacts differently in different cells and species.

According to the study authors, programmed cell death, or apoptosis, is a critical part of the innate immune response because it allows for the rapid elimination of damaged or infected cells. Earlier research has shown that VZV can modulate apoptosis in ways specific to different cell types, such as inducing apoptosis in multiple skin cell types and immune cells, such as T cells, B cells, and monocytes. However, investigators have noted that VZV does not induce cell death in neurons.

This cell type-specific behavior is essential for VZV research, the authors said, because the inhibition of apoptosis in neurons is critical for the virus to maintain its latent state and be reactivated later. However, the authors noted that induction of apoptosis within human fibroblasts may aid in viral dissemination. Based on these findings, the authors said it will be important to understand whether VZV can protect other cell types when expressed by itself.

Open reading frame (ORF) genes also play an important role, as VZV encodes them with anti-apoptotic mechanisms, according to the study. Interestingly, the authors said that when expressed alone or deleted from VZV, ORF genes have an anti-apoptotic effect in cell types in which VZV typically induced apoptosis. The authors said future studies should investigate whether these genes delay the onset of apoptosis in vulnerable cell types during VZV infection, because this could be an important part of VZV pathogenesis.

When cytokine secretion is induced, interferons become key actors that medicate their induction or upregulation through several interferon-stimulated genes. Interferons play important roles in controlling many viral infections, so the authors said it is unsurprising that it plays a role in VZV.

For instance, patients with primary immunodeficiencies characterized by defects in interferon signaling are also associated with acute VZV infections. The authors said there have recently been 4 cases of otherwise healthy children presenting with severe VZV in both the lungs and the central nervous system. They were all identified as having missense mutations in individual subunits of ribonucleic acid polymerase III, which can drive interferon production, according to the study.

With a host of ways to manipulate and modulate the innate immune response, understanding the ways VZV functions within each different cell type is essential to understanding the formation and effectiveness of the immune response. Dissecting the mechanisms of this immunomodulation could provide important insights into VZV pathogenesis and will be important when designing new vaccines and antivirals, the study authors concluded.

REFERENCE
Gerada C, Campbell T, Kennedy J, McSharry B, et al. Manipulation of the Innate Immune Response by Varicella Zoster Virus. Frontiers in Immunology; January 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992605/. Accessed October 29, 2020.