Theiler's virus-induced demyelinating disease as an infectious model of progressive multiple sclerosis

Abstract

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease of unknown etiology. However, several studies suggest that infectious agents, e.g., Human Herpes Viruses (HHV), may be involved in triggering the disease. Molecular mimicry, bystander effect, and epitope spreading are three mechanisms that can initiate immunoreactivity leading to CNS autoimmunity in MS. Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) is a pre-clinical model of MS in which intracerebral inoculation of TMEV results in a CNS autoimmune disease that causes demyelination, neuroaxonal damage, and progressive clinical disability. Given the spectra of different murine models used to study MS, this review highlights why TMEV-IDD represents a valuable tool for testing the viral hypotheses of MS. We initially describe how the main mechanisms of CNS autoimmunity have been identified across both MS and TMEV-IDD etiology. Next, we discuss how adaptive, innate, and CNS resident immune cells contribute to TMEV-IDD immunopathology and how this relates to MS. Lastly, we highlight the sexual dimorphism observed in TMEV-IDD and MS and how this may be tied to sexually dimorphic responses to viral infections. In summary, TMEV-IDD is an underutilized murine model that recapitulates many unique aspects of MS; as we learn more about the nature of viral infections in MS, TMEV-IDD will be critical in testing the future therapeutics that aim to intervene with disease onset and progression.

Keywords: TMEV-IDD; Theiler’s; demyelinating disease; multiple sclerosis; viral MS model.

FIGURE 1

Shared mechanisms of autoimmunity in the viral hypotheses of MS and the TMEV-IDD model of MS. (A) Mechanisms of molecular mimicry in EBV (top) and TMEV infection (bottom). Viral peptides, e.g., EBNA-1, share structural homology with CNS resident self-peptides, e.g., GlialCAM. Natural immunization to these viruses induces autoimmunity toward the CNS resident proteins. (B) Mechanisms of bystander effect in EBV (top) and TMEV infection (bottom). Responses by resident immune cells to latent or reactivated virus in the CNS induces collateral damage to adjacent tissues. (C) Mechanisms of epitope spreading in EBV (top) and TMEV infection (bottom). Peptides released by apoptotic or damaged cells are used to activate self-reactive lymphocytes. In a positive feedback cycle, the autoimmune reaction by these cells releases additional cellular debris. As this cycle continues, the set of self-peptides that are recognized by auto-reactive lymphocytes increases via clonal expansion. This figure was illustrated using Biorender.com.

FIGURE 2

TMEV-IDD models how childhood exposures to common viruses may induce autoimmunity upon adulthood. By mapping the ages of mice in the TMEV-IDD model to human correlates (Wang et al., 2020), we observe that the acute phase of the TMEV infection occurs during childhood, and the chronic phase begins in early adulthood. Red line represents relative clinical disability accumulation in TMEV-IDD over time and the green line shows this with respect to human years. I.C, intracranial. This figure was illustrated using Biorender.com.