Immune Responses to Viral and Environmental Factors Influence Neurological Disease in a Genetically Diverse Mouse Population

Abstract

Infection by a single virus or exposure to an immunotoxicant can evoke diverse immune responses leading to neurological disorders dependent on the host’s genetic background. Predisposing risk factors for neurological dysfunction and immunological responses vary among genetically diverse individuals, resulting in a myriad of potential neurological outcomes to viral infections and immunotoxicants. Therefore, Theiler’s Murine Encephalomyelitis Virus (TMEV) and perfluorooctanoic acid (PFOA) were used to study neurological and immunological responses in heterogeneous Collaborative Cross (CC) mice. The CC resource consists of genetically distinct and reproducible mouse lines, providing a population model of genetic heterogeneity similar to those observed in humans. In mice, TMEV infection influences neurological responses such as epilepsy, limb weakness, and paralysis, depending on the infected mouse strain. Exposure to environmental immunotoxicants also contribute to neurological disease owing to their suppressive immune effects. PFOA exposure has been linked to the imbalance of effector cell responses of the immune system, rendering the host susceptible to viral and environmental stressors. Susceptibility to disease symptoms have been associated with several genetic risk factors and play a role in determining a host’s immunological response to pathogens. To test the hypothesis that the host’s genetic background influences disease diversity following viral infection and exposure to potential immunotoxicants, we characterized associations between neurological effects and immunological responses influenced by TMEV infection through the use of a phenotyping pipeline and measuring cytokine and chemokine levels. In addition, we identified serum biomarkers influencing TMEV-induced disease across both phases of infection. Once we established a baseline response to TMEV infection in the heterogeneous mouse model, we evaluated the potential immunosuppressive effects of PFOA by identifying changes in cytokine and chemokine levels influenced by a co-exposure to TMEV. Thus, providing significant information on PFAS-related immune alterations and highlighting their impact on neurological disease after a viral infection. Overall, these findings provide insight into the complex roles of immune response in the pathogenesis of neurological diseases influenced by a diverse genetic background. Ultimately, the purpose of these studies is to improve model fidelity for research and preventive treatments associated with human neurological disease.