Resilience in Long-Term Viral Infection: Genetic Determinants and Interactions

Area of Science:

• Neuroscience
• Virology
• Immunology

Background:

• Theiler's murine encephalomyelitis virus (TMEV) infection in mice serves as a model for human neurological diseases like epilepsy and demyelination.
• Traditional studies categorize mouse strains as susceptible or resistant to TMEV based on viral persistence and severe phenotypes.
• A need exists to explore a wider range of responses to TMEV infection to better model human disease variability.

Purpose of the Study:

• To investigate the spectrum of TMEV infection outcomes in genetically diverse Collaborative Cross (CC) mouse strains.
• To identify distinct TMEV response profiles and their associated gene expression signatures.
• To uncover candidate genes and regulatory mechanisms underlying differential TMEV responses.

Main Methods:

• Infection of 19 Collaborative Cross (CC) mouse strains with TMEV.
• Evaluation of chronic infection, phenotypic severity, and viral persistence at 90 days post-infection.
• Analysis of gene expression profiles in hippocampi and thoracic spinal cords.
• Clustering of strains based on phenotypic and viral load data to define response profiles.
• Identification of gene expression signatures and candidate alleles associated with each profile.

Main Results:

• Identification of three main TMEV response profiles: resistant, susceptible, and a novel "resilient" group.
• The resilient group exhibited TMEV persistence alongside mild neurological phenotypes.
• Each response profile demonstrated a distinct gene expression signature.
• Candidate alleles and regulatory pathways (including miRNA) were identified for each profile, particularly in resilient strains.

Conclusions:

• The Collaborative Cross mouse resource reveals a broader spectrum of TMEV responses than previously recognized.
• A "resilient" TMEV response profile, characterized by viral persistence and mild symptoms, is identified.
• Distinct gene expression signatures and candidate alleles are associated with each TMEV response profile, offering insights into disease mechanisms and potential therapeutic targets.