Dissection of Neurotropic Theiler's Murine Encephalomyelitis Virus Induced Brain Atrophy in Single MHC Class I Mice of C57BL/6 Background.

Brain atrophy is a common feature of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and more recently SARS-CoV-2 infection for which the neuroinflammatory mechanism is not fully understood. Nevertheless, neuroinflammation and CD8 T cell accumulation is frequently observed in postmortem brain tissue of patients with neurodegeneration. We therefore developed a murine model of brain atrophy using the Theiler's murine encephalomyelitis virus (TMEV) infection model of multiple sclerosis. We employ single major histocompatibility complex (MHC) class I molecule conditional knockout mice generated by our program to analyze the contribution of immune cell infiltration and onset of atrophy. TMEV infected C57BL/6 mice that singularly express H-2K or H-2D were evaluated. TMEV infection of these mice resulted in ventricular atrophy at 14 d.p.i. However, H-2D expressing mice presented with significantly greater and continuous ventricular atrophy compared to H-2K expressing mice and MHC class I knockout control mice. Flow cytometric analysis revealed H-2D expressing mice had greater brain infiltrating CD8 T cell responses at 7 and 28 dpi which correlated with the extent of ventricular atrophy. Meanwhile, H-2K and MHC class I knockout mice also had distinct positive correlations with ventricular atrophy and global neuroinflammation in general. These findings support the role of immune cell infiltration into the CNS as a putative mechanism of ventricular atrophy following TMEV infection, with the progressive enlargement of ventricular atrophy observed in H-2D mice being associated with the presence of long-lived memory CD8 T cells residing in the brain.