Comparative Analysis of Genetic Risk for Viral-Induced Axonal Loss in Genetically Diverse Mice

Among mouse models of neurological disease, Theiler's murine encephalomyelitis virus (TMEV) provides a unique platform by using a naturally occurring viral trigger, paralleling the role of infections like Epstein-Barr virus in multiple sclerosis (MS). Just as not all individuals with predisposing viral infections develop the same neurological disease, not all mouse strains develop the same diseases following TMEV infection, so susceptibility is dictated by genetic background. For example, certain sets of alleles, called haplotypes, of the major histocompatibility complex (MHC) region have been associated with susceptibility to TMEV-induced demyelination (TVID) and MS. However, our previous work revealed that these MHC susceptibility haplotypes are not the sole contributors to TMEV-induced diseases in all mice. We infected mice from the genetically diverse Collaborative Cross (CC), a resource designed to reflect human population-level genetic variation. All 15 CC strains tested exhibited some form of neurological phenotype or CNS lesion following TMEV infection. However, chronic radiculoneuropathy characterized by axonal degeneration with myelin loss was observed in the CNS of only two strains, CC002 and CC023, which had markedly different immune responses and clinical profiles throughout the course of infection. Moreover, the pathology seen in CC002 and CC023 was not the same as what is typically seen in TVID. We used previous results from RNA sequencing of the hippocampus and spinal cord to test our hypothesis that myelin loss in these strains resulted from the convergent biological effects of multiple genetic risk variants, many previously unassociated with TMEV-induced diseases. These findings identify novel genetic targets and demonstrate the utility of genetically diverse models for uncovering complex neuroimmune interactions.