User:Colin/Rotavirus

Rotavirus is a genus of double-stranded RNA virus in the taxonomic family Reoviridae. It is the leading cause of severe diarrhoea among infants and young children; by the age of five, nearly every child in the world has been infected with rotavirus at least once. Rotavirus was discovered in 1973, and is now known to account for up to 50% of infants and children being hospitalised with severe diarrhoea.

There are seven species of rotavirus, referred to as A, B, C, D, E, F, and G. Rotavirus A, the most prevalent, causes more than 90% of infections in humans. Within Rotavirus A there are different strains called serotypes. Rotavirus also infects animals and is an important pathogen of livestock.



Classification
There are seven species of rotavirus, referred to as A, B, C, D, E, F, and G. Humans are primarily infected by species A, B and C, most commonly by species A. All seven species cause disease in animals. Within rotavirus A there are different strains, called serotypes. Two genes determine these serotypes, and a strain of rotavirus A is classified both by its G and P type. Serotyping of rotavirus A is thus complex; each virus has a P-type and a G-type. P-type is indicated by a number for the P-serotype and by a number in square brackets for the coresponding P-genotype. G-serotypes and are similarly numbered but the G-genotype number is the same as the G-serotype. For example, the rotavirus strain Wa is defined as P1A [8] G1. This dual classification system is similar to that used for influenza virus. Because the genes that determine G-types and P-types can be passed on separately to offspring various, combinations occur in any one strain.

Structure
The genome of rotavirus consists of eleven unique double helix molecules of RNA which are 18,555 nucleoside base-pairs in total. Each helix, or segment, is a gene, numbered 1 to 11 by decreasing size. Each gene codes for one protein, except genes 9 and 11, which each code for two proteins. The RNA is surrounded by a three-layered icosahedral protein capsid. Viral particles are up to 76.5 nm in diameter and are not enveloped.

Proteins
There are six viral proteins (VPs), that form the virus particle (virion). These structural proteins are called VP1, VP2, VP3, VP4, VP6 and VP7. In addition to the VPs, there are six non-structural proteins (NSPs), that are only produced in cells infected by rotavirus. These are called NSP1, NSP2, NSP3, NSP4, NSP5 and NSP6.

At least six of the twelve proteins encoded by the rotavirus genome bind RNA. The role of these proteins play in rotavirus replication is not entirely understood, their functions are thought to be related to RNA synthesis and packaging in the virion, mRNA transport to the site of genome replication, and mRNA translation and regulation of gene expression.

Structural proteins
VP1 is located in the core of the virus particle and is an RNA polymerase enzyme. In an infected cell this enzyme produces mRNA transcripts for the synthesis of viral proteins and produces copies of the rotavirus genome RNA segments for newly produced virus particles.

VP2 forms the core layer of the virion and binds the RNA genome.

VP3 is part of the inner core of the virion and is an enzyme called guanylyl transferase. This is a capping enzyme that catalyses the formation of the 5' cap in the post-transcriptional modification of mRNA. The cap stabilises viral mRNA by protecting it from nucleic acid degrading enzymes called nucleases, and is required for mRNA export to the cytoplasm.

VP4 is on the surface of the virion that protrudes as a spike. VP4 has many functions. It binds to molecules on the surface of cells called receptors and drives the entry of the virus into the cell. VP4 has to be modified by a protease enzyme, (found in the gut), into VP5* and VP8* before the virus is infectious. It determines how virulent the virus is and it determines the P-type of the virus.

VP6 forms the bulk of the capsid. It is highly antigenic and can be used to identify rotavirus species. This protein is used in laboratory tests for rotavirus A infections.

VP7 is a glycoprotein that forms the outer surface of the virion. Apart from its structural functions, it determines the G-type of the strain and, along with VP4, is important in immunity to infection.

Non-structural viral proteins
NSP1, the product of gene 5, is a nonstructural RNA-binding protein.

NSP2 is an RNA-binding protein that accumulates in cytoplasmic inclusions (viroplasms) and is required for genome replication.

NSP3 is bound to viral mRNAs in infected cells and it is responsible for the shutdown of cellular protein synthesis.

NSP4 is a viral enterotoxin to induce diarrhoea and was the first viral enterotoxin discovered.

NSP5 is encoded by genome segment 11 of rotavirus A and in virus-infected cells NSP5 accumulates in the viroplasm.

Gene 11 encodes NSP6, from an out of phase open reading frame. NSP6 is a nucleic acid binding protein.

This table is based on the simian rotavirus strain SA11. RNA-protein coding assignments differ in some strains.

Replication
Rotavirus infects enterocytes of the villi of the small intestine, leading to structural and functional changes of the epithelium. Their triple protein coats make them resistant to the acidic pH of the stomach, and the digestive enzymes in the gut.

They enter cells by receptor mediated endocytosis and form a vesicle known as an endosome. Proteins in the third layer (VP7 and the VP4 spike) disrupt the membrane of the endosome, creating a difference in the calcium concentration. This causes the breakdown of VP7 trimers into single protein subunits, leaving the VP2 and VP6 protein coats around the viral dsRNA, forming a double-layered particle (DLP).

The eleven dsRNA strands remain within the protection of the two protein shells and the viral RNA-dependent RNA polymerase creates mRNA transcripts of the double-stranded viral genome. By remaining in the core the viral RNA evades innate host immune responses called RNA interference that are triggered by the presence of double-stranded RNA.

During the infection, rotavirus produces mRNA for both protein biosynthesis and gene replication. Most of the rotavirus proteins accumulate in viroplasm, where the RNA is replicated and the DLPs are assembled. Viroplasm is formed as early as two hours after virus infection around the cell nucleus and, are viral factories and are thought to be made by two viral non-structural proteins, NSP5 and NSP2. Inhibition of NSP5 by RNA interference results in a sharp decrease in rotavirus replication. The DLPs migrate to the endoplasmic reticulum where they obtain their third, outer layer (formed by VP7 and VP4). The progeny viruses are released from the cell by lysis.

History
In 1943, Jacob Light and Horace Hodes proved that an infectious agent causing scours in cattle was a virus. Three decades later, preserved samples of that virus were shown to be rotavirus. In the intervening years, a virus in mice was shown to be related to the virus causing scours. In 1973, related viruses were described by Ruth Bishop in children with gastroenteritis, in Australia.

In 1974, Thomas Henry Flewett suggested the name rotavirus after observing that, viewed through an electron microscope, a rotavirus particle looks like a wheel (rota in Latin). This name was later adopted by the International Committee on Taxonomy of Viruses. In 1976, related viruses were described in several other species of animals, these viruses causing acute gastroenteritis were recognised as a collective pathogen affecting humans and animals world-wide. Rotavirus serotypes were first described in 1980. In 1981, rotavirus from humans was first grown in cell cultures derived from monkey kidneys, by adding trypsin to the culture medium. The ability to grow rotavirus in culture accelerated the pace of research, and by the mid-1980s the first candidate vaccines were being evaluated.