Abstract
Although persistent viral infection-associated diseases are a major health issue, the underlying cellular mechanisms of differential susceptibility to such persistent infections among individuals are unknown. Theiler’s virus (TMEV), a natural mouse pathogen, induces a chronic demyelinating disease similar to multiple sclerosis in susceptible mice. Resistant mice completely clear the virus and do not develop chronic demyelinating disease. Here, we compared interactions between TMEV and dendritic cells (DCs) in these mice. Our results indicate that immature DCs from susceptible mice are significantly more permissive to viral infection and infection-induced DC maturation arrest than those from resistant mice, despite the production of higher levels of anti-viral cytokines, including type I/II IFNs. Further studies showed that the timing of DC exposure to type I/II IFNs is critical in controlling viral infection. Moreover, a greater level of type I/II IFNs, which are induced in DCs from susceptible mice by TMEV infection, resulted in severe inhibition of DC cytokine production in response to LPS. Thus, differential interactions between DCs and TMEV, leading to a preferential deficiency in DC maturation and activation of DCs from susceptible mice, may be a mechanism through which TMEV establishes persistent infection and chronic demyelinating disease.
(Supported by NS23349, NS28752 and NS33008)