Theiler's murine encephalomyelitis virus infection of SJL/J and C57BL/6J mice: Models for multiple sclerosis and epilepsy

Abstract

Mouse models are great tools to study the mechanisms of disease development. Theiler's murine encephalomyelitis virus is used in two distinct viral infection mouse models to study the human diseases multiple sclerosis (MS) and epilepsy. Intracerebral (i.c.) infection of the SJL/J mouse strain results in persistent viral infection of the central nervous system and a MS-like disease, while i.c. infection of the C57BL/6J mouse strain results in acute seizures and epilepsy. Our understanding of how the immune system contributes to the development of two disparate diseases caused by the same virus is presented.

Keywords: Epilepsy; Immune response; Mouse model; Multiple sclerosis (MS); Seizures; Theiler's murine encephalomyelitis virus (TMEV).

Figure 1. Schematic representation of two distinct mouse models using TMEV infection

A) TMEV-IDD: I.c infection of SJL/J mice with TMEV results in persistent viral infection that lasts throughout the lifespan of the mouse. This results in a biphasic disease. An acute phase occurs between 3-10 days post infection. Viral persistence in the CNS results in chronic neuroinflammation leading to a MS-like phase, which appears after 30 days post infection. In this phase weakness of the hind limbs and an ataxic paralysis are observed. This model mimics some of the pathological and clinical features observed in MS patients with the progressive form of the disease. B) TMEV infection of the susceptible SJL/J mouse strain induces low type I (IFN-α and IFN-β) and type II (IFN-γ) IFN responses during the acute phase. Additionally, CD8⁺ T cell effector function is suppressed by the elevated induction of Tregs in this mouse strain, resulting in viral persistence and demyelination. C) Virus-induced seizures/epilepsy: I.c infection of C57BL/6J mice with TMEV results in acute seizures in 50% of the infected mice between 3–10 days post infection. After viral clearance, a variable latent period occurs where no behavioral seizures are observed. After the latent period, approximately 50% of the mice that have experienced acute seizures develop epilepsy. D) TMEV infection of the C57BL/6 mouse strain results in an efficient induction of antiviral immune response by type I and type II IFNs. Also, the lower number of Tregs induced in this mouse strain after TMEV infection allows for viral clearance by CD8⁺ T effector cells.

Figure 2. Demyelination as a result of TMEV infection of the CNS

A) Healthy neurons have an intact myelin sheath, produced by oligodendrocytes. Nodes of Ranvier between myelin sheaths facilitate the saltatory conduction mechanism (curved red arrows). B) Immune cell infiltration during TMEV-IDD: myelin-specific and/or viral-specific T cells, together with other inflammatory immune cells, infiltrate the CNS through the blood-brain barrier. In response to viral infection, antigen-presenting cells (APCs) process and present viral peptides to T cells, which become activated resulting in the secretion of pro-inflammatory cytokines leading to the recruitment of other immune cells such as macrophages, resulting in tissue damage and release of self-antigens. Self-antigens can also be released through direct lysis of virus-infected neurons and oligodendrocytes. Self-antigens are processed and presented by APCS to T cells, a process called epitope spreading. The structural and sequence homology shared between viral-peptides and self-peptides can also result in the activation of virus-specific T cell in the periphery. These T cells when migrate into the CNS, react against self-antigens (molecular mimicry), leading to tissue damage. Prolonged inflammation in the CNS results in immune-mediated tissue damage, where myelin is targeted, leading to demyelination. In the absence of myelin, impulse conduction by neurons is impaired resulting in clinical signs of the disease.

Figure 3. Infection of SJL/J mice with TMEV leads to demyelination

Spinal cord sections obtained from a PBS injected mouse (A) and a TMEV infection mouse (B), both at 8-weeks post injection/infection, and stained with Luxol fast blue. Infiltration of inflammatory cells into the CNS is observed. Perivascular cuffing (dashed red arrows) in the white matter; meningitis (solid red arrow) and demyelination (black arrows) are indicated.