Rotavirus in Animals

Rotaviruses infect and cause diarrhoea in young animals. They have been shown to infect mammals (for example, apes, cattle, pigs, sheep, rats, cats and dogs, mice, horses, rabbits) and birds (chickens and turkeys). These rotaviruses are a potential reservoir for genetic exchange with human rotaviruses. There is evidence that animal rotaviruses can infect humans, either by direct transmission of the virus or by contributing one or several RNA segments to reassortants with human strains. Rotavirus are a pathogen of livestock and cause economic loss to farmers because of costs of treatment associated with high morbidity and mortality rates.

Within rotavirus A there are different strains, called serotypes. As with influenza virus, a dual classification system is used, which is based on two structural proteins on the surface of the virion. The glycoprotein VP7 defines G-types and the protease-sensitive protein VP4 defines P-types. Strains are generally designated by their G serotype specificities (e.g., serotypes G1 to G4 and G9), and the P-type is indicated by a number and a letter for the P-serotype and by a number in square brackets for the corresponding P-genotype. (P-serotypes are difficult to characterize; therefore, molecular methods based on sequence analysis are often used to define the corresponding P-genotype instead. These genotypes correlate well with known P-serotypes). Because the two genes that determine G-types and P-types can be passed on separately to offspring, various combinations occur in any one strain. The Wa strain is classified in full as G1P1Agenome of rotavirus consists of 11 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. 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 ''nonstructural'' 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.

specific for rotavirus protein VP6.|alt=An electron micrograph of many rotavirus particles, two of which have several smaller, black spheres which appear to be attached to them]

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.

VP4 is on the surface of the virion that protrudes as a spike. 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 involved in immunity to infection.

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.

NSP6 is a nucleic acid binding protein, and is encoded by gene 11 from an out of phase open reading frame.

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

Replication

Rotaviruses replicate mainly in the gut, and infect enterocytes of the villi of the small intestine, leading to structural and functional changes of the epithelium. The triple protein coats make them resistant to the acidic pH of the stomach and the digestive enzymes in the gut.

The virus 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 around the cell nucleus as early as two hours after virus infection, and consists of viral factories thought to be made by two viral nonstructural 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.

Further Reading

• Rotavirus
• Rotavirus Symptoms
• Rotavirus Transmission
• Rotavirus Mechanisms
• Rotavirus Diagnosis
• Rotavirus Treatment
• Rotavirus Epidemiology
• Rotavirus Prevention

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