Antiviral immune response dynamics during varicella-zoster virus infection in a human iPSC-derived neuronal model and in herpes zoster patients

Varicella-zoster virus (VZV) naturally infects more than 95% of the population which results in varicella (i.e., chickenpox). Upon infection, VZV particles may access sensory nerve endings in the skin and can be transported to neural ganglia, via retrograde axonal transport, where VZV latency is established. In more than one out of four people, VZV will eventually reactivate from this latent state causing herpes zoster (HZ, i.e. shingles). In addition, a substantial part of HZ patients suffers from long-lasting pain after the rash has disappeared, adding to the burden of disease. Although effective vaccines against HZ are now available, vaccination coverage worldwide is relatively low. Hence, VZV and HZ remain a major burden for the foreseeable future. The humanotropic and neurotropic nature of VZV is a major hurdle in the field which hampers the advancement of our understanding of VZV infection dynamics and pathogenesis. Due to VZV’s strictly humanotropic character, no small animal model can fully recapitulate VZV disease. To overcome this, we aimed to develop a human iPSC-derived neuronal model in a chambered system that separates cell bodies and axon termini, which allows mimicking the natural route of VZV infection via axon termini. We showed that, following VZV infection, activation of interferon-stimulated genes (ISGs) depends on exogenous interferon-α (IFNα). Indeed, VZV infection of hiPSC-neurons via their axon termini, resulted in VZV spread throughout the neuronal cultures, without the production of IFNα or ISGs which have direct antiviral effector functions. In contrast, exogenous treatment of hiPSC-neurons with IFNα resulted in a reduction of VZV spread and in the upregulation of ISGs. Taken together, we suggest that whilst hiPSC-neurons are good IFNα-responders, they seem poor IFNα-producers thereby being unable to limit VZV spread in hiPSC-neuronal cultures. Importantly, this may imply that other cell types within the nervous system are essential as IFNα-producers. Hence, we believe that future studies investigating innate immune responses to VZV infection of neuronal cells should be carried out by including additional immune cell types in the cultures. In the second part of this thesis, we investigated the adaptive immune response dynamics during VZV reactivation in HZ patients. We found that VZV-specific antibody titers were still significantly higher one year after the HZ episode as compared to controls, raising the possibility that continuous subclinical VZV reactivation may contribute to high VZV IgG titers in HZ patients. In the last part of this thesis, transcriptomic analyses on whole blood from HZ patients and controls were carried out. Our data showed activation of several host immune pathways during VZV reactivation, especially related to the type I IFN response, but also related to adaptive immune responses. In addition, we found that upregulation of complement component 4 binding protein alpha (C4BPA), a major inhibitor of the complement system, may be a potential risk factor for the development of HZ but this needs further investigation. Indeed, a genome-wide association study could reveal if genetic variants are implicated in HZ disease.

Publication year:2022

Keywords:Doctoral thesis

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