Neuropathogenesis of Theiler’s Murine Encephalomyelitis Virus Infection, An Animal Model for Multiple Sclerosis

Abstract

Theiler's murine encephalomyelitis virus (TMEV) infection of mice is an experimental model for multiple sclerosis (MS). TMEV induces a biphasic disease in susceptible mouse strains. During the acute phase, 1 week after infection, TMEV causes polioencephalomyelitis characterized by infection and apoptosis of neurons in the gray matter of the brain. During the chronic phase, about 1 month after infection, virus infects glial cells and macrophages, and induces inflammatory demyelination with oligodendrocyte apoptosis and axonal degeneration in the white matter of the spinal cord. Although antibody, CD4 + , and CD8 + T cell responses against TMEV capsid proteins play important roles in neuropathogenesis, infectious virus with persistence is necessary to induce demyelination; in general, adoptive transfer of antibody or T cells alone did not induce central nervous system (CNS) disease. The TMEV model can be useful for testing new therapeutic strategies specifically as a viral model for MS. Therapies targeting adhesion molecules, axonal degeneration, and immunosuppression can be beneficial for pure autoimmune CNS demyelinating diseases, such as experimental autoimmune encephalomyelitis, but could be detrimental in virusinduced demyelinating diseases, such as progressive multifocal leukoencephalopathy.

Th17-biased RORγt transgenic mice become susceptible to a viral model for multiple sclerosis

“…We found that there was no difference in the incidence of seizures between wild-type (20%, 7/35) and RORγt Tg (27%, 9/33) mice ( P = 0.54, χ 2 ), and that the seizures occurred during a similar period of time, from days 3 to 8 p.i. Histologically, both mouse strains had similar amounts of inflammation and neuronal death in the CNS (Supplemental Figure 1A), where the majority of lesions were found in the gray matter, particularly the hippocampus (Supplemental Figures 1B and C) and few spinal cord segments had lesions, which is typical during the acute phase of TMEV-infection (21). Demyelination was not detected in the CNS in wild-type or RORγt Tg mice during the acute phase of disease.…”

“…Unlike an autoimmune model for MS, EAE, TMEV-IDD pathogenesis requires both virus persistence and immune effector cells. The damage caused during the chronic phase of disease requires both virus persistence and immune-mediated pathology (immunopathology) (21, 22). For example, adoptive transfer of effector T cells into naïve animals can induce demyelinating disease in EAE, while T cell transfer alone has not been shown to cause disease in the TMEV model.…”

Experimental In Vivo Models of Multiple Sclerosis: State of the Art

“…The latter can induce either a monophasic or a biphasic disease, depending on the mouse strain. The monophasic disease is inducible in most of the murine strains, whereas the biphasic form is inducible only in specific susceptible strains (64). The monophasic type and the first phase of the biphasic type are characterized by acute apoptosis of neurons in gray and white matter, appearing 1 week after the injection of the virus.…”

“…The neurological effects of TMEV seem to be mediated by the activation of T-lymphocytes, such as the CD8 + T-cells, rather than by a direct interaction of the virus with the myelin proteins; moreover, the permanence of the virus in the central nervous system seems to depend on the astrocyte activity that supports viral replication (67). In summary, TMEV is useful to reproduce acute or chronic/progressive phases of the disease (64,68).…”

Studies on the CNS Histopathology of EAE and Its Correlation with Clinical and Immunological Parameters

“…After an early, subtle disease period, susceptible mouse strains develop brain and spinal cord inflammation, demyelination and axonal damage. The clinical course resembles that of chronic, progressive MS (Tsunoda et al, 2010). However, EAE remains the most intensively studied animal model of MS.…”