Theiler's Murine Encephalomyelitis Virus (TMEV) is a single stranded RNA murine cardiovirus from the family Picornaviridae that has been used as a mouse model for studying virally induced paralysis as well as encephalomyelitis comparable to Multiple sclerosis.[1] Depending on the mouse and viral strain, viral pathogenesis can range from negligible, to chronic or acute encephalomyelitis.
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The virus was discovered by Nobel Prize winning virologist Max Theiler in 1937 while working at the Rockefeller Institute.[2][3] Known mostly for his work with Yellow Fever, Theiler's encephalomyelitis virus was discovered during research on poliovirus-like symptoms in mice.
There are several different strains of TMEV that are characterized by their pathology as well as genetic sequencing and proteomics. The two major groups are listed below, but there are several other strains in the same group as DA (such as BeAn).
TMEV GDVII virus is characterized by acute encephalomyelitis in susceptible mice, with a high mortality rate and no viral persistence after viral clearance by the immune system. No demyelination occurs in surviving mice. The GDVII L protein is specific in that it down-regulates the anti-viral response by inhibition of Interferon Regulatory Factor 3 (IRF3) after it is activated by hyperphosphorylation, but before it is able to enhance Interferon-β transcription by binding to the gene's promoter.[4]
The TMEV DA strain, in contrast, is characterized by chronic encephalomeyelits in susceptible mice. Infection initiates in astrocytes and microglia, but persists in macrophages. This strain has been used as an acceptable model for human multiple sclerosis.[4] The DA strain has also been shown to inhibit IRF-3 phosphorylation, by inhibiting an unknown intermediate step after RIG-I/MDA5 activation of IKKε and TBK1 kinases. The L protein has been shown to be critical in this process, although the mechanism is unknown. The DA strain of TMEV also encodes for a L* protein that is likely involved in viral persistence in macrophages. This protein's influence on the murine immune system, therefore, could be beneficial in understanding immune-mediated demeyelination in diseases such as multiple sclerosis.[5]
Multiple Sclerosis is a currently untreatable disease that results in demyelination of the brain, which leads to severe neurological problems and eventually paralysis. The symptoms of MS are laregely immune mediated, but the mechanism of the immune system's initiation in this disease is unknown. It is likely that both genetic and environmental factors play a large role in the initiation and progression of the disease. One hypothesis to the initiation is that an infection stimmulates the innate immune system, which spreads viral epitopes along with myelin epitopes to T cells, which then are activated to "attack" the myelin cells. This is the proposed course of disease in TMEV infection in mice.
Many bacteria and viruses infect humans, without pathology in normal individuals. If certain individuals are genetically predisposed to immunological intolerance of these commensal organisms, pathology can occur. A recent human virus, the Saffold virus, has been shown to have high prevalences in humans (>90%), and may be an important link between the study of mouse TMEV-induced encephalomyelitis and human Multiple Sclerosis.[6]
The majority of mouse strains are unsucceptible to the pathology associated with TMEV infection. However, SJL/J mice are notoriously succeptible, and the majority of studies aimed at uncovering factors that could lead to MS utilize this strain.[7] The SJL/J strain was also the strain used by Max Theiler to study the progression of a polio-like disease in mice.