Abstract
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.
Highlights
Antecedent infections have been suggested as contributing factors to chronic neurological conditions such as multiple sclerosis, epilepsy, Parkinson’s Disease, and amyotrophic lateral sclerosis [1]
Clinical phenotypes are driven by infection status and genetic background at 90 dpi
Locations of central nervous system (CNS) lesions correlate with progression of neurological phenotypes To identify relationships between lesion distribution and progression of clinical disease phenotypes between the acute and chronic phases of the infection, we statistically evaluated the strength of connections between progression scores and lesion locations (Fig 2B)
Summary
Antecedent infections have been suggested as contributing factors to chronic neurological conditions such as multiple sclerosis, epilepsy, Parkinson’s Disease, and amyotrophic lateral sclerosis [1]. The severity, prognosis, and clinical presentation of these diseases are influenced in part by a milieu of factors such as age, sex, and other comorbidities. Along with these factors, genetic background is likely a critical driver of infection responses and subsequent neurological disease phenotypes. Genetic background is likely a critical driver of infection responses and subsequent neurological disease phenotypes These disease phenotypes may share some common characteristics which, in turn, contribute to the degree of severity and long-term prognosis of the neuropathology. Genetic differences among individuals can influence disease onsets and outcomes, and the efficacy of medical interventions
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