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Background <p>Growing evidence indicates that Epstein-Barr virus (EBV), a gammaherpesvirus, plays a central role in the pathogenesis of multiple sclerosis (MS). The presence of EBV-infected cells in the central nervous system (CNS) of MS patients, but not in neurologically healthy individuals, suggests that viral persistence in the CNS may drive MS. However, why there is such a long interval between initial infection and the development of disease is unknown.</p> Methods <p>To model the effects of EBV infection on the brain, we intracerebrally infected mice with murine gammaherpesvirus-68 (MHV68), a virus genetically related to EBV that causes transient pathology strikingly similar to that seen in humans after acute EBV infection. One month following MHV68 infection, we administered myelin oligodendrocyte glycoprotein (MOG) peptide to evaluate the effects of prior MHV68 infection on the response to an additional inflammatory stimulus of the CNS. Virus persistence, microglial activation and immune cell infiltration were evaluated over time using flow cytometry.</p> Results <p>Intracerebral MHV68 infection induced mild brain demyelination and ataxia, a common symptom of MS, that both quickly resolved. However, administration of MOG peptide one month later led to more severe brain demyelination and more sustained ataxia, suggesting that prior MHV68 infection sensitized the mice to a newly introduced immune stimulus. Further investigation revealed that following CNS infection, MHV68 persisted in microglia, where it induced a primed phenotype marked by elevated MHC-II expression and heightened immune reactivity for at least six months. Primed microglia displayed increases in the labile iron pool, and iron chelation reduced microglial priming. Early antiviral treatment during MHV68 infection completely prevented subsequent MOG-induced demyelinating disease.</p> Conclusions <p>These findings support a two-step mechanism by which CNS infection with a gammaherpesvirus closely related to EBV sensitizes the host to a second unrelated immune stimulus that triggers MS-like disease manifestations. Chronic priming of microglia resulting from the initial infection contributes to this process, and prevention of such priming with early antiviral treatment also prevents neuropathology following the second stimulus. EBV infection may similarly sensitize humans to a second stimulus and, if so, treatment of acute EBV infection may avert subsequent MS development.</p>

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Early antiviral treatment following gammaherpesvirus-68 infection of the central nervous system prevents subsequent multiple sclerosis-like disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月8日

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  • Alexander Muselman,
  • Sameera Kongara,
  • Nathan Hsu,
  • Asha Aggarwal,
  • Joanna Yu,
  • Jayakumar Rajadas,
  • Edgar G. Engleman

摘要

Background

Growing evidence indicates that Epstein-Barr virus (EBV), a gammaherpesvirus, plays a central role in the pathogenesis of multiple sclerosis (MS). The presence of EBV-infected cells in the central nervous system (CNS) of MS patients, but not in neurologically healthy individuals, suggests that viral persistence in the CNS may drive MS. However, why there is such a long interval between initial infection and the development of disease is unknown.

Methods

To model the effects of EBV infection on the brain, we intracerebrally infected mice with murine gammaherpesvirus-68 (MHV68), a virus genetically related to EBV that causes transient pathology strikingly similar to that seen in humans after acute EBV infection. One month following MHV68 infection, we administered myelin oligodendrocyte glycoprotein (MOG) peptide to evaluate the effects of prior MHV68 infection on the response to an additional inflammatory stimulus of the CNS. Virus persistence, microglial activation and immune cell infiltration were evaluated over time using flow cytometry.

Results

Intracerebral MHV68 infection induced mild brain demyelination and ataxia, a common symptom of MS, that both quickly resolved. However, administration of MOG peptide one month later led to more severe brain demyelination and more sustained ataxia, suggesting that prior MHV68 infection sensitized the mice to a newly introduced immune stimulus. Further investigation revealed that following CNS infection, MHV68 persisted in microglia, where it induced a primed phenotype marked by elevated MHC-II expression and heightened immune reactivity for at least six months. Primed microglia displayed increases in the labile iron pool, and iron chelation reduced microglial priming. Early antiviral treatment during MHV68 infection completely prevented subsequent MOG-induced demyelinating disease.

Conclusions

These findings support a two-step mechanism by which CNS infection with a gammaherpesvirus closely related to EBV sensitizes the host to a second unrelated immune stimulus that triggers MS-like disease manifestations. Chronic priming of microglia resulting from the initial infection contributes to this process, and prevention of such priming with early antiviral treatment also prevents neuropathology following the second stimulus. EBV infection may similarly sensitize humans to a second stimulus and, if so, treatment of acute EBV infection may avert subsequent MS development.