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

RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...

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 The genus contains the following species: * ''Cardiovirus dhusarah'' (Cardiovirus F) ...

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 ...

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

paralysis Paralysis (: paralyses; also known as plegia) is a loss of Motor skill, motor function in one or more Skeletal muscle, muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory d ...

, 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 Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

. 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 Host (biology), hosts, often at the cellular or molecular level. It is a specialized field of study in virology. Pathogenesis is a quali ...

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, the ...

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

poliovirus 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, numbered 1, 2, and 3. Poliovirus is composed ...

-like paralysis symptoms in mice. That year Theiler had completed work on developing a vaccine for yellow fever, 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 disease. 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 the context of modern medical treatme ...

as well as genetic sequencing and

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

. 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 Statistical population, population, scaled to the size of that population, per unit of time. Mortality rate is typically ...

and no viral persistence after viral clearance by the

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

. No

demyelination A demyelinating disease refers to any disease affecting the nervous system where the myelin sheath surrounding neurons is damaged. This damage disrupts the transmission of signals through the affected nerves, resulting in a decrease in their con ...

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 Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural ...

, 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" and , , "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 en ...

s and

microglia Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...

, but persists in

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

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 biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

, 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 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 (biology), 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 ...

and

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...

, which often leads to severe

neurological Neurology (from , "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 nervous system, which comprises the brain, the s ...

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 r ...

, 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 part of an antibody that binds to the epitope is called a paratope. Although e ...

s, along with

myelin Myelin Sheath ( ) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon. The myelinated axon can be lik ...

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 (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

and

virus A virus is a 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 archaea. Viruses are ...

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 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 75% of cases are asymptomatic; mild symptoms which can occur include sore throat and fever; in a proportion of cases more severe ...

-like disease in mice.

References

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