Orthoreovirus

Orthoreovirus is a genus of viruses, in the family Reoviridae, in the subfamily Spinareovirinae. Vertebrates serve as natural hosts. There are currently five species in this genus including the type species Mammalian orthoreovirus. Diseases associated with this genus include mild upper respiratory tract disease, gastroenteritis, and biliary atresia. Mammalian orthoreovirus 3 (strain dearing-T3D) induces cell death preferentially in transformed cells and therefore displays inherent oncolytic properties.The virus known as orthoreovirus comes from the Greek work Ortho, meaning 'straight' and the reovirus, which comes from taking the letters: R, E, and O from 'respiratory enteric orphan virus'. The Orthoreovirus was named an orphan virus because it was not known to be associated with any known disease. It was discovered in the early 1950s when it was isolated from the respiratory as well as gastrointestinal tracts of both sick and healthy individuals Orthoreovirus is part of the family known as Reoviridae. Its genome is composed of segmented double-stranded RNA (dsRNA), thus it is classified as a group III virus according to the Baltimore classification system of viruses. This family of viruses is taxonomically classified into 12 distinct genera. These genera are sorted out taking into account the number of dsRNA genomes. The Orthoreovirus genus has 10 segments that have been isolated from a large range of hosts including mammals, birds, and reptiles. These genera are further divided into two phenotypic groups: fusogenic and non-fusogenic. The way that they are determined to belong to a specific group is if the virus is able to cause multinucleated cells known as syncytial cells. According to this classification, mammalian orthoreoviruses (MRV) are known to be non-fusogenic, meaning it does not produce syncytia, while other members of this genus are fusogenic, such as avian orthoreoviruses (ARV), baboon orthoreoviruses (BRV), reptilian orhtoreoviruses (RRV).Mammalian Orthoreovirus virions are non-enveloped with icosahedral symmetry created by a double-layered capsid reaching about 80 nm wide. Each capsid contains 10 segments of double stranded RNA (dsRNA) genome. The inner capsid or core particle (T=2) contains five different proteins: σ2, λ1, λ2, λ3, and μ2 and is approximately 70 nm in diameter. One hundred and twenty copies of the λ1 protein arranged in 12 decameric units make up the shell of the inner capsid structure. This shell is stabilized by one hundred and fifty copies of the σ2 protein that 'clamp' adjacent λ1 monomers together. At the 12 five-fold axes of symmetry, pentamers of the λ2 protein form turret-like structures that protrudes from the surface of the shell. In the center of the λ2 turret a channel allows viral mRNAs to be extruded during transcription. The channel is 70Å at its base and 15Å at its narrowest point. The core also contains within it twelve copies of λ3, the RNA-dependent RNA polymerase. One λ3 protein is found slightly offset from each of the twelve pentameric λ2 turrets. Closely associated with λ3 are one or two copies of μ2, a transcriptase cofactor. μ2 has been found to have some enzymatic functions, such as NTPase activity. The λ3 protein is responsible for transcription of the double-stranded RNA genome segments. Each transcript is threaded through the λ2 pentameric turret as it is being extruded. Guanylyltransferase enzmatic activity in the λ2 turret adds a 5' guanosine cap to the extruded mRNA. In addition, two methyltransferase domains found in the λ2 structure act to methylate the 7N position of the added guanosine and the 2' O of the first templated nucleotide, which in all cases is also a guanosine. The outer capsid (T=13) is composed of μ1 and σ3 proteins with λ2, in compound with σ1, interspersed around the capsid. It has been proposed that λ2 is involved in replication due to its placement at the fivefold axes and its ability to interact with λ3 in solution. σ1, a filamentous trimer extruding from the outer capsid, is responsible for cell attachment by interacting with sialic acid and other entry receptors. μ1 and σ3 are both involved in the attachment and thus entry of the virus via receptor-mediated endocytosis involving the formation of clathrin-coated pits.The only orthoreovirus to not produce syncytia, mammalian orthoreoviruses have the capability of infecting all mammals, but do not cause disease, except in young populations enabling them to be studied frequently as a model for viral replication and pathogenesis.Transmission of the virus is either through the fecal–oral route or through respiratory droplets. The virus is transmitted horizontally and only known to cause disease in vertebrates. Different levels of virulence may be observed depending on the strain of orthoreovirus. Species that are known to become infected with the virus include: humans, birds, cattle, monkeys, sheep, swine, baboons, and batsReplication occurs in the cytoplasm of the host cell. The following lists the replication cycle of the virus from attachment to egress of the new virus particle ready to infect next host cell. Mammalian orthoreovirus does not really cause a significant disease in humans. Even though the virus is fairly common, the infection produced is either asymptomatic or causes a mild disease which is self-limiting in the gastrointestinal tract and respiratory region for children and infants. Symptoms are similar to what a person might have when they have the common cold, such as a low-grade fever and pharyngitits. However, in other animals such as baboons and reptiles, other known orthoreoviruses fusogenic strains can cause more serious illness. In baboons it can cause neurological illness while in reptiles it can be the cause of pneumonia. In birds this virus may even cause death.Members of the Orthoreovirus genus have been known to cause apoptosis in host cells, and have thus been studied fairly extensively for this very purpose. Mammalian orthoreoviruses induce apoptosis via the activation of several death receptors—TNFR, TRAIL, and Fas—while avian orthoreovirus has been found to use the up-regulation of p53 to induce apoptosis. Both of these strains have also been found to be involved in G2/M cell cycle arrest. The avian orthoreovirus has also been proven to promote autophagy of the host which could contribute to disease in a similar manner as apoptosis. The inhibition of the innate immune response has also been seen in mammalian and avian orthoreoviruses. Other strains of the orthoreoviruses have not been studied as frequently as mammalian and avian strains resulting in a lack of understanding in the pathophysiology of those strains, though it can be assumed they act in similar ways.One of the most relevant uses for the mammalian orthoreoviruses are the manipulation of their oncolytic properties for their use in cancer treatments. This particular use of reoviruses was discovered in 1995 by Dr Patrick Lee who discovered these viruses could kill those cells that contained an over-activated Ras pathway, often a hallmark of cancerous cells. These viruses are particularly ideal for these sort of therapies because they are self-limiting while simultaneously harnessing the ability to induce apoptosis in tumor cells exclusively. One of the more widely used strains for these anti-cancer clinical trials is the serotype 3 dearing strain, Resolysin, used in phase I-III trials. A variety of cancers have been treated with this therapy, either alone or in tandem with others, including multiple myeloma, ovarian epithelial, and pancreatic cancers. A recent clinical trial demonstrated that mammalian orthoreovirus was effective in inducing apoptosis in hypoxic prostate tumor cells with hopes of success in clinical trials.To be able to perform a proper diagnosis of this pathogen is it important to take samples from the suspected infected individuals such as a stool, throat, or nasopharyngeal sample. There are various tests that can be done on these samples to see if a person is infected. Viral antigen can be detected by performing an assay. A serological assay can also be performed on the sample to look for virus-specific antibodies present in the sample, thus showing that the person is trying to combat the virus. The virus can be isolated in culture through the use of mouse-L fibroblasts, green monkey kidney cells, as well as HeLa cells.