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

Area of Science:

• Neuroimmunology
• Virology
• Genetics

Background:

• Theiler's murine encephalomyelitis virus (TMEV) infection in mice serves as a model for viral-triggered neurological diseases like multiple sclerosis (MS).
• Genetic background, particularly major histocompatibility complex (MHC) haplotypes, influences susceptibility to TMEV-induced demyelination (TVID).
• Previous research indicated that MHC regions alone do not fully explain disease susceptibility in all mouse models.

Purpose of the Study:

• To investigate the genetic basis of TMEV-induced neurological diseases in genetically diverse mouse models.
• To identify novel genetic risk variants contributing to TMEV-induced pathology beyond MHC associations.
• To explore the utility of genetically diverse models in understanding complex neuroimmune interactions.

Main Methods:

• Infection of 15 genetically diverse Collaborative Cross (CC) mouse strains with TMEV.
• Assessment of neurological phenotypes and central nervous system (CNS) lesions.
• Analysis of RNA sequencing data from hippocampus and spinal cord tissues.

Main Results:

• All tested CC strains developed neurological phenotypes or CNS lesions after TMEV infection.
• Chronic radiculoneuropathy with axonal degeneration and myelin loss was observed in two specific strains (CC002 and CC023).
• The pathology in CC002 and CC023 differed from typical TVID and was hypothesized to result from convergent effects of multiple genetic risk variants.

Conclusions:

• Genetically diverse mouse models, like the Collaborative Cross, are crucial for uncovering complex neuroimmune interactions.
• Novel genetic targets associated with TMEV-induced neurodegeneration were identified.
• Susceptibility to TMEV-induced diseases is influenced by a complex interplay of multiple genetic factors beyond MHC.