Host genetic diversity drives variable central nervous system lesion distribution in chronic phase of Theiler’s Murine Encephalomyelitis Virus (TMEV) infection

Host genetic background is a significant driver of the variability in neurological responses to viral infection. Here, we leverage the genetically diverse Collaborative Cross (CC) mouse resource to better understand how chronic infection by Theiler’s Murine Encephalomyelitis Virus (TMEV) elicits diverse clinical and morphologic changes in the central nervous system (CNS). We characterized the TMEV-induced clinical phenotype responses, and associated lesion distributions in the CNS, in six CC mouse strains over a 90 day infection period. We observed varying degrees of motor impairment in these strains, as measured by delayed righting reflex, paresis, paralysis, seizures, limb clasping, ruffling, and encephalitis phenotypes. All strains developed neuroparenchymal necrosis and mineralization in the brain, primarily localized to the hippocampal regions. Two of the six strains presented with axonal degeneration with myelin loss of the nerve roots in the lumbar spinal cord. Moreover, we statistically correlated lesion distribution with overall frequencies of clinical phenotypes and phenotype progression to better understand how and where TMEV targets the CNS, based on genetic background. Specifically, we assessed lesion distribution in relation to the clinical progression of these phenotypes from early to late TMEV disease, finding significant relationships between progression and lesion distribution. Finally, we identified quantitative trait loci associated with frequency of lesions in a particular brain region, revealing several loci of interest for future study: lysosomal trafficking regulator (Lyst) and nidogen 1 (Nid1). Together, these results indicate that the genetic background influences the type and severity of clinical phenotypes, phenotypic resilience to TMEV, and the lesion distribution across strains.