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Abstract
Multiple sclerosis (MS) is a chronic neuroinflammatory condition of the central nervous system (CNS). It is a major cause of neurological disability in young adults, particularly women. What triggers the destruction of myelin sheaths covering nerve fibres is unknown. Both genetic and infectious agents have been implicated. Of the infectious agents, Epstein-Barr virus (EBV), a common herpesvirus, has the strongest epidemiological and serological evidence. However, the presence of EBV in the CNS and demonstration of the underlying mechanism(s) linking EBV to the pathogenesis of MS remain to be elucidated. We aimed at understanding the contribution of EBV infection in the pathology of MS. We examined 1055 specimens (440 DNA samples and 615 brain tissues) from 101 MS and 21 non-MS cases for the presence of EBV using PCR and EBER-in situ hybridization (EBER-ISH). EBV was detected by PCR and/or EBER-ISH in 91/101 (90%) of MS cases compared to only 5/21 (24%) of non-MS cases with other neuropathologies. None of the samples were PCR positive for other common herpesviruses (HSV-1, CMV, HHV-6). By quantitative PCR, EBV viral load in MS brain was mainly low to moderate in most cases. However, in 18/101 (18%) of MS cases, widespread but scattered presence of EBV infected cells was noted in the affected tissues by EBER-ISH. Immunohistochemical analysis of EBV gene expression in the 18 heavily infected cases, revealed that the EBV latent protein EBNA1, and to a lesser extent the early lytic protein BZLF1 were expressed. Furthermore, using double-staining we show for the first time that astrocytes and microglia, in addition to B-cells can also be infected. To the best of our knowledge, this is the most comprehensive study demonstrating that EBV is present and transcriptionally active in the brain of most cases of MS and supports a role for the virus in MS pathogenesis. Further studies are required to address the mechanism of EBV involvement in MS pathology.
Highlights
Over 2 million people worldwide suffer from multiple sclerosis (MS), a debilitating neurological disease of autoimmune nature [1]
Further examination revealed that these cases had prominent neuropathology, such as dementia, Alzheimer’s disease (AD), meningioma and palsylike tauopathy (PSPT)
We believe that the extent and degree to which tissues are examined for the presence of Epstein-Barr virus (EBV) is an important contributing factor to the differences observed
Summary
Over 2 million people worldwide suffer from multiple sclerosis (MS), a debilitating neurological disease of autoimmune nature [1]. In newly infected B-cells, BZLF1 is expressed, EBV lytic cycle is not induced [17] It seems that additional conditions, such as, unmethylation of EBV genome and methylation of promoters of certain genes transactivated by BZLF1 are required for a complete successful lytic cycle and production of new virions [17,19]. For this reason, the expression of BZLF1 does not necessarily translate into viral shedding
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