Abstract
Infection by Theiler’s murine encephalomyelitis virus (TMEV) is a model for neurological outcomes caused by virus infection because it leads to diverse neurological conditions in mice, depending on the strain infected. To extend knowledge on the heterogeneous neurological outcomes caused by TMEV and identify new models of human neurological diseases associated with antecedent infections, we analyzed the phenotypic consequences of TMEV infection in the Collaborative Cross (CC) mouse population. We evaluated 5 different CC strains for outcomes of long-term infection (3 months) and acute vs. early chronic infection (7 vs. 28 days post-infection), using neurological and behavioral phenotyping tests and histology. We correlated phenotypic observations with haplotypes of genomic regions previously linked to TMEV susceptibility to test the hypothesis that genomic diversity within CC mice results in variable disease phenotypes in response to TMEV. None of the 5 strains analyzed had a response identical to that of any other CC strain or inbred strain for which prior data are available, indicating that strains of the CC can produce novel models of neurological disease. Thus, CC strains can be a powerful resource for studying how viral infection can cause different neurological outcomes depending on host genetic background.
Highlights
Viral infections may precede the onset of several neurological conditions, including epilepsy, Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)[1,2,3,4,5,6,7,8,9,10,11,12,13,14]
A cohort of animals, hereafter referred to as Group B, was evaluated at 7 and 28 days post infection to identify phenotypic differences related to the acute phase of Theiler’s murine encephalomyelitis virus (TMEV) infection. (Phenotypes of Group A mice were measured for ~90 days; see Materials and Methods.) We evaluated viral clearance in Group B mice by measuring TMEV transcript expression in the brain (Fig. 1)
TMEV measurements at 7 dpi were highest in CC041 mice, while expression was lowest in CC013, followed by CC061 and CC019 mice, respectively
Summary
Viral infections may precede the onset of several neurological conditions, including epilepsy, Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)[1,2,3,4,5,6,7,8,9,10,11,12,13,14]. TMEV produces complications, which vary by mouse strain, that closely approximate human neurological conditions associated with antecedent viral infections. Since infection-associated neurological conditions in mice vary depending on genetic background, Log[2] RQ www.nature.com/scientificreports/. Our findings confirmed that the genetic diversity present in CC strains contributes to phenotypically diverse neurological conditions resulting from TMEV infection
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