Theiler's murine encephalomyelitis virus (TMEV) is a single-stranded

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

murine The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families ex ...

cardiovirus Cardiovirus are a group of viruses within order ''Picornavirales'', family ''Picornaviridae''. Vertebrates serve as natural hosts for these viruses. Taxonomy There are currently six species in the genus: * '' Cardiovirus A'' * '' Cardiovirus B' ...

from the family ''

Picornaviridae Picornaviruses are a group of related nonenveloped RNA viruses which infect vertebrates including fish, mammals, and birds. They are viruses that represent a large family of small, positive-sense, single-stranded RNA viruses with a 30 ...

''. It has been used as a mouse model for studying virally induced

paralysis Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 5 ...

, as well as

encephalomyelitis Encephalomyelitis is inflammation of the brain and spinal cord. Various types of encephalomyelitis include: * '' Acute disseminated encephalomyelitis'' or ''postinfectious encephalomyelitis'', a demyelinating disease of the brain and spinal cord, ...

comparable to multiple sclerosis. Depending on the

mouse A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

and

viral strain In biology, a strain is a genetic variant, a subtype or a culture within a biological species. Strains are often seen as inherently artificial concepts, characterized by a specific intent for genetic isolation. This is most easily observed in mic ...

, viral pathogenesis can range from negligible, to chronic or acute encephalomyelitis.

Discovery

The virus was discovered by

virologist Virology is the scientific study of biological viruses. It is a subfield of microbiology that focuses on their detection, structure, classification and evolution, their methods of infection and exploitation of host cells for reproduction, thei ...

Max Theiler Max Theiler (30 January 1899 – 11 August 1972) was a South African-American virologist and physician. He was awarded the Nobel Prize in Physiology or Medicine in 1951 for developing a vaccine against yellow fever in 1937, becoming the firs ...

in 1937 while working at the Rockefeller Institute. Theiler discovered the encephalomyelitis virus during research on

poliovirus A poliovirus, the causative agent of polio (also known as poliomyelitis), is a serotype of the species ''Enterovirus C'', in the family of '' Picornaviridae''. There are three poliovirus serotypes: types 1, 2, and 3. Poliovirus is composed of a ...

-like paralysis symptoms in mice. That year Theiler had completed work on developing a vaccine for

yellow fever Yellow fever is a viral disease of typically short duration. In most cases, symptoms include fever, chills, loss of appetite, nausea, muscle pains – particularly in the back – and headaches. Symptoms typically improve within five days. In ...

, for which he is best known; in 1951 he received the Nobel Prize for that achievement.

Strains

The several different strains of TMEV are characterized by their

pathology Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in ...

as well as genetic sequencing and

proteomics Proteomics is the large-scale study of proteins. Proteins are vital parts of living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replication of DNA. In ...

. The two major groups are listed below; 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 rate Mortality rate, or death rate, is a measure of the number of deaths (in general, or due to a specific cause) in a particular population, scaled to the size of that population, per unit of time. Mortality rate is typically expressed in units of d ...

and no

viral persistence Viral means "relating to viruses" (small infectious agents). Viral may also refer to: Viral behavior, or virality Memetic behavior likened that of a virus, for example: * Viral marketing, the use of existing social networks to spread a ma ...

after viral clearance by the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...

. No

demyelination A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...

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 occurs when a biochemical with multiple phosphorylation sites is fully saturated. Hyperphosphorylation is one of the signaling mechanisms used by the cell to regulate mitosis. When these mechanisms fail, developmental problems ...

, 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 encephalomyelitis in susceptible mice. Infection initiates in

astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...

s and

microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune ...

, but persists in macrophages. This strain has been used as an acceptable model for human multiple sclerosis. and epilepsy. The DA strain has also been shown to inhibit IRF-3

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

, by inhibiting an unknown intermediate step after RIG-I/MDA5 activation of IKKε and TBK1

kinase In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...

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 demyelination in diseases such as multiple sclerosis.

Analogies with multiple sclerosis/pathology

Multiple sclerosis is a chronic disease that results in demyelination of the axons in

brain The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...

and

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spin ...

, which often leads to severe

neurological Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...

problems and eventually paralysis. The symptoms of MS are largely 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. There are a number of animal models for MS. A common one is known as

Experimental autoimmune encephalomyelitis Experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE), is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with ro ...

, while TMEV occurs via injection of TMEV, and is thus distinct from EAE. One hypothesis for the initiation is that an infection stimulates the innate immune system, specifically perivascular

. This allows the entrance of T-cells, and microglia spread viral

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 epitope is the specific piece of the antigen to which an antibody binds. The ...

s, along with

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...

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 (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...

and

virus A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...

es infect humans without pathology in normal individuals. If certain individuals are genetically predisposed to immunological intolerance of these commensal organisms, pathology can occur. The Saffold virus, a human virus discovered in 2007, has been shown to have high prevalence in humans (>90%). It may be an important link between the study of mouse TMEV-induced encephalomyelitis and human multiple sclerosis. The majority of mouse strains are not susceptible to the pathology associated with TMEV infection. As SJL/J mice are notoriously susceptible, the majority of studies exploring factors that could lead to MS utilize this strain. Max Theiler also used the SJL/J strain to study the progression of a

polio Poliomyelitis, commonly shortened to polio, is an infectious disease caused by the poliovirus. Approximately 70% of cases are asymptomatic; mild symptoms which can occur include sore throat and fever; in a proportion of cases more severe sym ...

-like disease in mice.

References

{{Taxonbar, from=Q7777784 Animal viral diseases Cardioviruses Rodent diseases