Community Research and Development Information Service - CORDIS

Final Report Summary - INMA (Immune and Neuromodulation Mediated by Alphaherpesviruses)

The three human alphaherpesviruses, herpes simplex virus type 1, type 2 (HSV-1 and HSV-2, respectively) and varicella zoster virus (VZV), are highly prevalent pathogens that establish latency in neurons of the peripheral nervous system. HSV-1 and HSV-2 cause a variety of diseases such as cold sores, genital herpes and encephalitis. Primary infection with VZV causes varicella, whereas reactivation causes zoster that may lead to post-herpetic neuralgia (PHN), the second most common type of neuropathic pain worldwide. The interaction of these viruses with the immune system determines the outcome of the infection. Colonization of neurons is essential for virus persistence and pathogenesis. In this project we aimed at investigating how the human alphaherpesviruses modulate proteins of the immune and nervous system, focusing on cytokines and neurotrophic factors.
During primary infection VZV infects leukocytes and uses them to disseminate throughout the host. Chemokines are chemoattractant cytokines that direct the migration of leukocytes. Therefore we investigated whether VZV could express a protein with the ability to modulate chemokine activity. We discovered that VZV glycoprotein C (gC) binds human chemokines with high affinity and enhances their activity, probably facilitating VZV spread. This, VZV gC constitutes a novel viral chemokine binding protein (vCKBP). This project was led by Victor Gonzalez-Motos, supported by the MC CIG. The results from this work were published in PLoS Pathogens (González-Motos et al., 2017, PLoS Pathogens 13(5):e1006346). This paper was highlighted with a “PLoS Pathogens Press Release” and subject of several radio and printed press notes. Due to our expertise in vCKBP and our participation in the “Cytokines Congress” celebrated in 2015 at Bamberg, Germany, we were invited to write a review on this topic by the “Cytokine & Growth Factor Reviews” (González-Motos et al., 2016 Cytokine & Growth Factor Reviews. 30: 71-80). For similar reasons I was also invited to be the Editor in Chief of a Special Issue on “Mechanisms of Extracellular Immunomodulation Mediated by Infectious Agents”. As part of this issue we published an Editorial (Viejo-Borbolla et al., 2017, Journal of Immunology Research, 5107527).
Understanding how VZV modulates leukocyte migration may facilitate the development of therapeutic strategies to inhibit VZV spread. Moreover, the mechanisms of pain induction by VZV remain elusive. Interestingly, chemokines are involved in pain induction. Therefore, it is possible that gC activity may participate in induction of pain by VZV following reactivation. Since zoster and PHN are more aggressive in the elderly and the European population is aging advances that may result in novel therapeutics to treat VZV-induced pain are of great importance. Further work is required to investigate whether VZV gC exacerbates pain.
The results obtained during the period funded by the MC CIG are the foundation for an application to the “Deutsche Forschungsgemeinschaft”. This is a joint application with the laboratory of Thomas Krey (Hannover Medical School, MHH) to investigate the mechanisms of gC-mediated enhancement of chemokine activity, the possible induction of pain by gC and to solve the structure of gC alone and in complex with a chemokine.
VZV is a human specific pathogen. Therefore the use of human cells is required to investigate its life cycle, including the establishment of latency in neurons and subsequent reactivation. To study these processes we have derived human neurons from inducible pluripotent stem cells (iPSC), as stated in the original application. We have extensively characterized these cells showing that they are peripheral neurons, the type of neurons in which VZV establishes latency. Moreover, we have established three latency/reactivation models for VZV using these neurons. These two projects have been carried out by Shuyong Zhu, a PhD student funded with the MC CIG. The results from these two projects are currently being written as two independent manuscripts and will be submitted shortly. As above, these results will be the base for further funding applications to study VZV latency and reactivation. Understanding how VZV establishes latency and reactivates is essential to avoid VZV-related complications. Since zoster and PHN occur following reactivation, this type of research may facilitate the discovery of inhibitors of VZV reactivation and thereby disease, mainly in the elderly.
As part of the MC CIG we also investigated the modulation of chemokines and neurotrophic factors by HSV-1 and HSV-2. As part of this project we participated in several related publications not funded by the MC CIG. We have discovered that a viral glycoprotein plays a relevant role during HSV infection of sensory neurons through the neurite end. We are currently writing these results as a manuscript to be submitted shortly.

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