Gammaherpesvirus Latency Accentuates EAE Pathogenesis: Relevance to Epstein-Barr Virus and Multiple Sclerosis

Abstract

Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS), yet EBV's role in MS remains elusive. We utilized murine gamma herpesvirus 68 (γHV-68), the murine homolog to EBV, to examine how infection by a virus like EBV could enhance CNS autoimmunity. Mice latently infected with γHV-68 developed more severe EAE including heightened paralysis and mortality. Similar to MS, γHV-68EAE mice developed lesions composed of CD4 and CD8 T cells, macrophages and loss of myelin in the brain and spinal cord. Further, T cells from the CNS of γHV-68 EAE mice were primarily Th1, producing heightened levels of IFN-γ and T-bet accompanied by IL-17 suppression, whereas a Th17 response was observed in uninfected EAE mice. Clearly, γHV-68 latency polarizes the adaptive immune response, directs a heightened CNS pathology following EAE induction reminiscent of human MS and portrays a novel mechanism by which EBV likely influences MS and other autoimmune diseases.

Latent Gammaherpesvirus 68 Infection Induces Distinct Transcriptional Changes in Different Organs

“…Latent murine gammaherpesvirus 68 (MHV68, ␥HV-68, MuHV-4) also modulates adenovirus and plasmodium infections (5,6). MHV68 is implicated in exacerbating experimental autoimmune encephalomyelitis (EAE), a rodent model for multiple sclerosis (7,8), as well as a mouse model of inflammatory bowel disease (9). Together, these studies are consistent with chronic or latent herpesvirus infection having substantial effects on host immune responses to unrelated antigens.…”

Coinfections: Another Variable in the Herpesvirus Latency-Reactivation Dynamic

“…In the EAE model, there is increased T cell infiltrate and more T cells making IFN-␥ in the brains and spinal cords of mice with EAE and MHV68 infection (8). These data point to an important question; i.e., if latency changes the basal level of activation of macrophages, NK cells, and possibly other cell types, then how are T cells changed by latent infection?…”

“…However, gammaherpesvirus infection can also exacerbate disease. For example, latent infection with MHV68 increases the severity of experimental autoimmune encephalomyelitis (EAE), as well as the mortality rate of mice infected with malaria parasites (1,8,9). The mechanisms underlying these differences in outcomes are not well understood; however, different inflammatory responses are a likely explanation.…”

Viruses in human central nervous system — invasion, transmission, and latency: a literature review

“…Вирусы герпеса обнаружены в обонятельной луковице, гипоталамусе, гиппокампе, миндалине. Активно накапливаются доказательства в пользу предположения о возможности участия вирусов не только в воспалительных процессах в ЦНС, но и возникновении нейродегенеративных, опухолевых, сосудистых заболеваний [84][85][86][87][88]. Так, по данным полногеномных исследований различных неврологи-ческих заболеваний показано, что 7 дифференциально экспрессирующихся генов (CTSS, PTX3, CHI3L1, Mx1, CXCL16, BIRC3, BST2) при заражении HHV6A астро-цитов человека HA1800 также дифференциально экспрессируются при нескольких неврологических заболеваниях [89].…”

“…В настоящее время новые технологии исследо-вания жизненного цикла вирусов и метаболических аспектов их взаимодействия с клеткой хозяина, в том числе интравитальное наблюдение за жизнедеятель-ностью клетки, культивирование нейронов, секвени-рование генома единственной клетки, использование в качестве экспериментальных животных гумани-зированных мышей, активно внедряются в лабора-торную практику, что способствует исследованию механизмов участия вирусов в формировании таких заболеваний, как болезнь Альцгеймера, рассеянный склероз, глиома [84][85][86][87][88].…”