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 excep ...

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 nm i ...

''. 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 50 ...

, 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, p ...

comparable to

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

. 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 Viral pathogenesis is the study of the process and mechanisms by which viruses cause diseases in their target hosts, often at the cellular or molecular level. It is a specialized field of study in virology. Pathogenesis is a qualitative descriptio ...

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, their ...

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 first ...

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 an ...

-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 Genetic Sequencing may refer to: * DNA sequencing * Whole genome sequencing Whole genome sequencing (WGS), also known as full genome sequencing, complete genome sequencing, or entire genome sequencing, is the process of determining the entiret ...

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 de ...

and no viral persistence 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 cancer cells and objects such as wood splinte ...

. 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 Interferon regulatory factor 3, also known as IRF3, is an interferon regulatory factor. Function IRF3 is a member of the interferon regulatory transcription factor (IRF) family. IRF3 was originally discovered as a homolog of IRF1 and IRF2. IR ...

(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 endo ...

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 de ...

, but persists in

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

s. This strain has been used as an acceptable model for human

. 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, wh ...

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

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

s. The

L protein L, or l, is the twelfth letter in the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is ''el'' (pronounced ), plural ''els''. History Lamedh ...

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 In computational learning theory, induction of regular languages refers to the task of learning a formal description (e.g. grammar) of a regular language from a given set of example strings. Although E. Mark Gold has shown that not every regular l ...

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 A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

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 spi ...

, 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 ...

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 p ...

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 ...

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 among ...

and

virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...

es infect humans without pathology in normal individuals. If certain individuals are genetically predisposed to immunological intolerance of these

commensal organism Commensalism is a long-term biological interaction (symbiosis) in which members of one species gain benefits while those of the other species neither benefit nor are harmed. This is in contrast with mutualism, in which both organisms benefit fro ...

s, pathology can occur. The

Saffold virus Saffold virus (SAFV) is a single-stranded RNA human virus belonging to the family ''Picornaviridae''. Discovered in 2007, it is the first human virus in the genus ''Cardiovirus'' and may provide a link to the development of multiple sclerosis or ...

, 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 s ...

-like disease in mice.

References

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