| Infectious diseases can be conceptualized as the interaction of the pathogen, host, and environment. In these studies, we used the paradigm of neuroadapted Sindbis virus (NSV), the pathogen, which infects neurons of the central nervous system of mice, the host, causing hind-limb paralysis and fatal encephalomyelitis in most mouse strains in a controlled environment. To elucidate the role of host contributions to disease outcomes, we screened a panel of inbred mouse strains looking for genetic variation in percent mortality of mice after NSV infection. From this screen, we picked two mouse strains for further study: the C57BL/6 mouse strain showing 100% mortality, and the BALB/cBy mouse strain showing 0% mortality. We compared NSV pathogenesis in these two mouse strains, showing that C57BL/6 mice have more severe signs, higher virus replication, more extensive virus spread, faster infectious virus clearance, slower viral RNA clearance, and higher type I interferon and neutralizing antibody production than BALB/cBy mice. These studies generated phenotypic variations, at different steps in the viral pathogenesis pathways, for subsequent genetics studies; of which, we focused on differences in viral RNA levels in the brain, percent paralysis, and percent mortality. Our genetic analysis of these traits in reciprocal F1 crosses, congenics, recombinant inbreds, and F2 mice showed that a major quantitative trait locus (QTL), Nsv1 , at the distal end of chromosome two controlled early viral RNA replication and determined the likelihood of paralysis and mortality. We also characterized Sindbis virus infection of neuronal cell lines; of which, the CSM14.1 cell-line showed the most potential for studies involving innate mechanisms of clearance, reactivation, and persistance of virus in neurons.; Finally, some thoughts are offered on future directions towards identifying genes involved in susceptibility and resistance of mice to NSV infection and their functions. These studies add to our understanding of the host's genetic contribution to NSV-induced fatal encephalomyelitis. |
