Theiler's encephalomyelitis virus
Encyclopedia
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
. Depending on the mouse
and viral strain, viral pathogenesis
can range from negligible, to chronic or acute encephalomyelitis.
winning virologist Max Theiler
in 1937 while working at the Rockefeller Institute. Known mostly for his work with Yellow Fever
, Theiler's encephalomyelitis virus was discovered during research on poliovirus
-like symptoms in mice.
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).
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.
s and microglia
, but persists in macrophage
s. This strain has been used as an acceptable model for human multiple sclerosis. 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 kinase
s. 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.
, 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 epitope
s 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 virus
es 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.
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. The SJL/J strain was also the strain used by Max Theiler to study the progression of a polio-like disease in mice.
Paralysis
Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
as well as encephalomyelitis
Encephalomyelitis
Encephalomyelitis is a general term for inflammation of the brain and spinal cord, describing a number of disorders:* Acute disseminated encephalomyelitis or postinfectious encephalomyelitis, a demyelinating disease of the brain and spinal cord, possibly triggered by vaccination or viral...
comparable to Multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
. Depending on the mouse
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
and viral strain, viral pathogenesis
Viral pathogenesis
Viral pathogenesis is the study of how biological viruses cause diseases in their target hosts, usually carried out at the cellular or molecular level. It is a specialized field of study in virology.-See also:*pathogen*pathogenesis...
can range from negligible, to chronic or acute encephalomyelitis.
Discovery
The virus was discovered by Nobel PrizeNobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...
winning virologist Max Theiler
Max Theiler
Max Theiler was a South African/American virologist. He was awarded the Nobel Prize in Physiology or Medicine in 1951 for developing a vaccine against yellow fever.-Career development:...
in 1937 while working at the Rockefeller Institute. Known mostly for his work with Yellow Fever
Yellow fever
Yellow fever is an acute viral hemorrhagic disease. The virus is a 40 to 50 nm enveloped RNA virus with positive sense of the Flaviviridae family....
, Theiler's encephalomyelitis virus was discovered during research on poliovirus
Poliovirus
Poliovirus, the causative agent of poliomyelitis, is a human enterovirus and member of the family of Picornaviridae.Poliovirus is composed of an RNA genome and a protein capsid. The genome is a single-stranded positive-sense RNA genome that is about 7500 nucleotides long. The viral particle is...
-like symptoms in mice.
Strains
There are several different strains of TMEV that are characterized by their pathologyPathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
as well as genetic sequencing
Genetic sequencing
Genetic Sequencing may refer to:* DNA sequencing* Full genome sequencing...
and proteomics
Proteomics
Proteomics is the large-scale study of proteins, particularly their structures and functions. Proteins are vital parts of living organisms, as they are the main components of the physiological metabolic pathways of cells. The term "proteomics" was first coined in 1997 to make an analogy with...
. The two major groups are listed below, but there are several other strains in the same group as DA (such as BeAn).
GDVII
TMEV GDVII virus is characterized by acute encephalomyelitis in susceptible mice, with a high mortality rateMortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...
and no viral persistence after viral clearance by the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. 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
Hyperphosphorylation
Hyperphosphorylation occurs when a biochemical with multiple phosphorylation sites is fully saturated. Hyperphosphorylation is one of the signalling mechanisms used by the cell to regulate mitosis. When these mechanisms fail, developmental problems or cancer are a likely outcome...
, but before it is able to enhance Interferon-β transcription by binding to the gene's promoter.
DA
The TMEV DA strain, in contrast, is characterized by chronic encephalomeyelits in susceptible mice. Infection initiates in astrocyteAstrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
s and microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
, but persists in macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s. This strain has been used as an acceptable model for human multiple sclerosis. The DA strain has also been shown to inhibit IRF-3 phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
, by inhibiting an unknown intermediate step after RIG-I/MDA5 activation of IKKε and TBK1 kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
s. 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.
Analogies with Multiple Sclerosis/Pathology
Multiple Sclerosis is a currently untreatable disease that results in demyelination of the brainBrain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, which leads to severe neurological
Neurology
Neurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
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 epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
s along with myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
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
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
and virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es 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.
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. The SJL/J strain was also the strain used by Max Theiler to study the progression of a polio-like disease in mice.