Double trouble: How simultaneous immune challenges can result in CNS disease
Although viruses have been implicated in central nervous system (CNS) diseases of unknown etiology, such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), the identification of viral triggers in such diseases has been largely unsuccessful. To determine if peripheral infections could contribute to neuropathogenic disease, we developed a mouse model in which immune cells generated to a peripheral infection are recruited to the CNS, where they then mediate immunopathogenesis. In this model, mice are infected with both CNS-restricted measles virus (MV), and peripherally restricted lymphocytic choriomeningitis virus (LCMV). While infection with either virus alone resulted in no illness, co-infection caused disease in all mice, with ∼50% of these mice dying from seizures. Coinfection in all mice correlated with a 12-fold increase in the number of CD8+ cells in the CNS as compared to MV infection alone. Tetramer analysis revealed that at least 50% of these infiltrating CD8+ T cells were of LCMV-specificity Challenge of mice with other combinations of peripherally and CNS-restricted viruses resulted in an identical immunological outcome. Thus, despite no apparent viral cross-reactivity, activated lymphocytes specific for a peripheral infection are readily recruited to the CNS, triggering neurological disease that does not occur with either infection alone. In this model, disease appears to be attributable to massive edema and transtentorial brainstem herniation, similar to that observed in mice challenged intracerebrally (IC) with LCMV. These results indicate that T cell misrecruitment under conditions of concomitant immune insults can trigger novel neuropathogenic outcomes.