Role of Dendritic Cells in Differential Susceptibility to Viral Demyelinating Disease

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Abstract
Although persistent viral diseases are a global health concern, the mechanisms of differential susceptibility to such infections among individuals are unknown. Here, we report that differential interactions between dendritic cells (DCs) and virus are critical in determining resistance versus susceptibility in the Theiler murine encephalomyelitis virus–induced demyelinating disease model of multiple sclerosis. This virus induces a chronic demyelinating disease in susceptible mice, whereas the virus is completely cleared in resistant strains of mice. DCs from susceptible mice are more permissive to viral infection, resulting in severe deficiencies in development, expansion, and function, in contrast to DCs from resistant mice. Although protective prior to viral infection, higher levels of type I interferons (IFNs) and IFN-γ produced by virus-infected DCs from susceptible mice further contribute to the differential inhibition of DC development and function. An increased DC number and/or acquired resistance of DCs to viral infection render susceptible mice resistant to viral persistence and disease progression. Thus, the differential permissiveness of DCs to infectious agents and its subsequent functional and developmental deficiencies determine the outcome of infection- associated diseases. Therefore, arming DCs against viral infection–induced functional decline may provide a useful intervention for chronic infection-associated diseases. Many chronic viral diseases are associated with prolonged viral persistence levels, which vary from one individual to another. However, the mechanisms of differential susceptibility to persistent viral infections are unknown. Theiler murine encephalomyelitis virus (TMEV) induces a chronic demyelinating disease similar to multiple sclerosis. In this study, we investigated the potential mechanisms of differential susceptibility to chronic viral persistence in the central nervous system following infection with TMEV. Our results indicate that differential interactions between virus and dendritic cells (DCs), leading to the induction of anti-viral immunity, are critical in determining resistance or susceptibility to virus-induced chronic demyelinating disease. DCs from susceptible mice are much more permissive to viral infection, resulting in severe deficiencies in their development, expansion, and function, whereas DCs from resistant mice are not permissive. Consequently, the DCs in susceptible mice are responsible for poor anti-viral T cell activation, permitting viral persistence and disease development in the host. Interestingly, the administration of additional DCs or pre-activated virus-resistant DCs enables susceptible mice to resist persistent viral infection and disease development. This knowledge may be useful in devising effective means to induce strong anti-viral immune responses, thereby protecting the host from virus-associated chronic diseases caused by persistent viral infection.

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