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Template:Taxobox begin Template:Taxobox image Template:Taxobox begin placement virus Template:Taxobox group iii entry Template:Taxobox familia entry Template:Taxobox genus entry Template:Taxobox end placement Template:Taxobox section subdivision Rotavirus A (RV-A)
Rotavirus B (RV-B)
Rotavirus C (RV-C)
Rotavirus D (RV-D)
Rotavirus E (RV-E)
Rotavirus F (RV-F)
Rotavirus G (RV-G)
Template:Taxobox end Rotavirus is the most common cause of viral gastroenteritis in infants and all children suffer from at least one rotavirus infection before their fifth birthday. Rotavirus is found in all countries of the world. In the developing countries approximately 100 million cases of rotavirus infection occur annually in children under five and around 600,000 die. In America, rotaviruses cause an estimated one million episodes of gastroenteritis and 150 deaths of children every year.

Rotavirus is an RNA virus and seven species have been identified. Rotavirus A is the species that causes over 90% of infections in humans. There are different strains of Rotavirus A and many children suffer from more than one infection during their early years. The infection is spread via the fecal-oral route and huge numbers of rotaviruses are excreted by infected children. The virus has a triple-layered protein coat and is very stable outside the body.

All strains of rotavirus infect the cells of small intestine and produce a powerful enterotoxin that causes diarhoea and spreads the infection rapidly within families and communities.

The virus is also important in veterinary medicine, as it infects the young of many animals. As with Influenza, animals infected by rotavirus may act as a reservoir for new strains of rotavirus that could cause epidemics.

In 2003 the World Health Organization and the US Centers for Disease Control established the Rotavirus Vaccine Program to reduce child morbidity and mortality from diarrhoeal disease by making a vaccine against rotavirus available for use in developing countries.

Etymology

The name rotaviruses was first suggested in 1977 by Thomas Henry Flewett because of the resemblance of rotavirus particles to wheels when they are examined by transmission electron microscopy. The name was later adopted by the International Committee on Taxonomy of Viruses (ICTV) as the official name of the genus. The name is derived from the Latin word for a wheel; rota.

History

In 1943 Light and Hodes described a virus, now known to be a rotavirus, that caused scours in cattle. In the 1960s, a similar virus that infects mice was discovered, which was also subsequently shown to be a rotavirus. In 1973 rotaviruses were first seen in children with gastroenteritis by a research team, lead by Ruth Bishop, in Australia. In the same year, similar discoveries were reported from England by a research group led by Tom Flewett. In 1976 rotaviruses were discovered in several species of animals, and they were soon recognised as a world-wide human and animal pathogen. In the early 1980s rotaviruses were discovered to be a diverse group of viruses. At this time, progress in research was slow because rotaviruses could not be grown artificially in cell cultures. This problem was solved in 1981 by Japanese scientists who successfully grew rotaviruses from humans in monkey kidney cells by adding trypsin to the culture medium. By the mid-1980s the first candidate vaccines were being evaluated.

Microbiology

Types of rotavirus

Rotaviruses are not a single type of virus but are a diverse mixture. There are seven groups which are called rotavirus A, B, C, D, E, F, and G. Groups A, B and C infect humans and all groups can cause disease in animals. Group A rotavirus is by far the commonest cause of infections of humans. Within Group A rotaviruses there is further diversity and different strains, called serotypes, exist. As is the case with Influenza virus, two genes determine rotavirus serotypes and these genes are inherited independently. For group A rotaviruses these genes produce two proteins called VP4 and VP7 which are on the surface of the virion and are antigens. Both of these proteins are important in immunity. Rotavirus A is subdivided into the different serotypes based on the antibody response to VP7 (designated as G types) and to VP4 (P types).

Structure

The genome of rotavirus consists of eleven double helix molecules of RNA which are 18,555 nucleoside base-pairs in total. Each helix, or segment, is a gene and they are 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. The first layer is formed by the protein VP2, with each vertex having a copy of the proteins VP1 and VP3. VP stands for Viral Protein. The second layer is formed by the protein VP6. The outermost protein layer is composed of the structural glycoprotein VP7 and the spike protein VP4. Viral particles are up to 76.5 nm in diameter.

Rotavirus proteins

There are six viral proteins, (VP) which form the virus particle (virion). These are called VP1, VP2, VP3, VP4, VP5, VP6 and VP7 and five non-structural proteins that are only produced in cells infected by rotavirus. These are called NSP1, NSP2, NSP3, NSP4, NSP5 and NSP6. 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 and VP2 forms the core layer of the virion and binds the RNA genome. VP3 is part of the inner core of the virion but it is also 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 a protein 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 also determines how virulent the virus is and along with VP7 determines the serotype of the virus and is important to immunity. VP7 is a glycoprotein that forms the outer surface of the virion. VP6 is the major protein and that forms the bulk of the capsid. It is highly antigenic and can be used to identify rotavirus species as it is conserved within each group. This protein is used in laboratory tests for rotavirus A infections. NSP1 is 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 the end of viral mRNAs in infected cells. NSP4 is a viral enterotoxin to induce diarrhoea and was the first viral enterotoxin discovered. NSP5 is encoded by genome segment 11 of group A rotaviruses and in virus-infected cells NSP5 accumulates in the viroplasms. Gene 11 also 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

Rotaviruses infect the cells that line the small intestine. Their triple protein coats make them very resistant to the acidic pH of the stomach, and also the digestive enzymes (lipases and proteases) in the gut.

They enter cells by 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 Ca concentration. This causes the breakdown of VP7 trimers into single protein subunits, leaving the VP2 and VP6 coats around the viral dsRNA, forming a double-layer particle (DLP).

While the eleven dsRNA strands are still within the protection of the two protein shells, 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 translation and genome replication. Most of the rotavirus proteins accumulate in structures known as viroplasms, where the RNA is replicated and the DLPs are assembled. Viroplasms are electron-dense structures found as early as two hours after virus infection around the cell nucleus. Viroplasms are viral factories and are thought to be formed 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.

Pathogenesis

Rotavirus gastroenteritis is a self-limiting, mild to severe disease characterized by vomiting, watery diarrhoea, and low-grade fever. The infective dose is 10–100 infectious viral particles. Large numbers of virus are in the faeces (10–10 infectious particles per ml), and infection can be readily acquired through contaminated hands, objects, or utensils.

The virus infects enterocytes of the villi of the small intestine, leading to structural changes of the epithelium and diarrhea. The result of this infection is complex, and it is affected by an interaction of host and viral factors. Rotavirus diarrhoea is caused by several mechanisms which include: malabsorption that occurs secondary to the destruction of enterocytes, a reduced supply of blood to the cells that line the small intestine, an activation of the enteric nervous system, and the flow of fluid into the gut from the tissues and blood that is caused by the rotavirus non-structural protein, NSP4, which is an enterotoxin. NSP4 causes an age and dose-dependent diarrhoea in young rodents that is similar to the natural infection. NSP4 also causes cells to become permeable and damages them. Antibody to NSP4 protects mouse pups from diarrhoea induced by different serotypes of rotaviruses. The incubation period ranges from one to three days. Symptoms often start with vomiting followed by four to eight days of diarrhoea. Recovery is usually complete. However, severe diarrhoea without fluid and electrolyte replacement may result in death.

Epidemiology

"Infantile diarrhoea", "winter diarrhoea", "stomach 'flu", "acute nonbacterial infectious gastroenteritis", and "acute viral gastroenteritis" are other names applied to this disease. Humans of all ages are susceptible to rotavirus infection, but children six months to two years of age, the elderly, and the immunocompromised are particularly susceptible to more severe symptoms. Rotaviruses are transmitted by the fecal-oral route. Person-to-person spread through contaminated hands is probably the most important means by which rotaviruses are transmitted in close communities such as pediatric and geriatric wards, day care centers and family homes. Infected food handlers may contaminate foods that require handling and no further cooking, such as salads, fruits, and hors d'oeuvres. Rotaviruses are quite stable in the environment and have been found in estuary samples at levels as high as 1–5 infectious particles per gallon. Sanitary measures adequate for bacteria and parasites seem to be ineffective in endemic control of rotavirus, as similar incidence of rotavirus infection is observed in countries with both high and low health standards.

Group A rotavirus is endemic worldwide. It is the leading cause of severe diarrhoea among infants and children, being responsible for about 20% of cases, and accounts for about half of the cases requiring hospitalization. Boys are twice as likely to be admitted to hospital than girls, but the reason for this is not understood. Almost every child has been infected with rotavirus by age five. Over three million cases of rotavirus gastroenteritis occur annually in the U.S. In temperate areas, it occurs primarily in the winter, but in the tropics it occurs throughout the year. The number attributable to food contamination is unknown.

Group B rotavirus, also called adult diarrhoea rotavirus or ADRV, has caused major epidemics of severe diarrhoea affecting thousands of persons of all ages in China. In a group B epidemic in China in 1982, more than a million people were affected. Group B rotavirus has also been identified after the Chinese epidemics from Calcutta, India in 1998 and this strain was named CAL. Unlike ADRV, the CAL strain is endemic and does not cause known epidemics.

Group C rotavirus has been associated with rare and sporadic cases of diarrhoea in children in many countries. However, the first outbreaks were reported from Japan and England.

About 100 million rotavirus infections occur every year and two million children are admitted to hospital, approximately 600,000 children die from the infection.

Diagnosis

Specific diagnosis of the disease is made by identification of the virus in the patient's stool. Enzyme immunoassay (EIA) is the test most widely used to screen clinical specimens, and several commercial kits are available for group A rotavirus. Electron microscopy and polyacrylamide gel electrophoresis are used in some laboratories in addition or as an alternative to EIA. A reverse transcription-polymerase chain reaction (RT-PCR) has been developed to detect and identify all groups and known serotypes of human rotaviruses.

Treatment

There is no cure for rotavirus, so treatment of the disease is aimed at managing the symptoms. Depending on the severity of these treatment consists of oral rehydration with water, or fluids containing sugars and salts. About one out of every 40 children develops severe enough dehydration to require hospitalisation. In these children fluids are given intravenously or nasogastricly and laboratory tests to monitor the child's electrolyte levels and sugar in the blood are carried out.

Vaccines

In 1998 a rotavirus vaccine was licensed for use in the United States. Clinical trials in the United States, Finland, and Venezuela had found it to be 80 to 100% effective at preventing severe diarrhoea caused by group A rotavirus, and researchers had detected no statistically significant serious adverse effects. The manufacturer of the vaccine, however, withdrew it from the market in 1999, after it was discovered that the vaccine may have contributed to an increased risk for intussusception, or bowel obstruction, in one of every 12,000 vaccinated infants. The experience provoked intense debate about the relative risks and benefits of a rotavirus vaccine. In 2006, two vaccines against Rotavirus infection were shown to be safe and effective in children: Rotarix by GlaxoSmithKline and RotaTeq by Merck. Both are taken orally and contain disabled live virus.

RotaTeq is a live, oral pentavalent vaccine that contains five rotaviruses produced by reassortment. The rotavirus parent strains of the reassortants were isolated from human and bovine hosts. Four reassortant rotaviruses express one of the outer capsid, VP7, proteins (serotypes G1, G2, G3, or G4) from the human rotavirus parent strain and the attachment protein VP4 (type P7) from the bovine rotavirus parent strain. The fifth reassortant virus expresses the attachment protein VP4, (type P1A), from the human rotavirus parent strain and the outer capsid protein VP7 (serotype G6) from the bovine rotavirus parent strain.

In February 2006, the U.S. Food and Drug Administration approved RotaTeq for use in the United States. Merck announced a price of $187.50 for the standard three-dose regimen; this is much more expensive than other standard childhood immunisations and, even allowing for discounts, will probably prevent widespread use of the vaccine in poor countries. However, Merck is selling vaccines at dramatically lower prices in developing world countries and is working with a range of partners including the Rotavirus Vaccine Project, PATH, (Program for Appropriate Technology in Health) and other governmental and non-governmental organisations to develop and implement mechanisms for providing access to this vaccine in the developing world.

Epidemics

Outbreaks of group A rotavirus diarrhea are common among hospitalised infants, young children attending day care centres, and elderly persons in nursing homes. Among adults, multiple foods served in banquets were implicated in two outbreaks. An outbreak due to contaminated municipal water occurred in Colorado, 1981.

Several large epidemics of group B rotavirus involving millions of persons as a result of sewage contamination of drinking water supplies have occurred in China since 1982. Although to date outbreaks caused by group B rotavirus have been confined to mainland China, seroepidemiological surveys have indicated lack of immunity to this group of virus in the US. Recent studies led to the identification of group B rotavirus occurring at a sporadic frequency in Calcutta, India and subsequently from other Asian countries.

Rotavirus C had been previously implicated in rare and isolated cases of gastroenteritis. However, it has caused many epidemics among school children, particularly in Japan.

During 2005 the largest recorded epidemic of diarrhoea occurred in Nicaragua. After a detailed investigation this unusual large and severe outbreak was found to be associated with mutations in the rotavirus A genome, possibly helping the virus escape the prevalent immunity in the population which had no protection against this type. A similar large outbreak occurred in Brazil in 1977.

Complications

Rotavirus infections rarely cause other complications in the well managed child. There are reports in the literature of rare complications involving the central nervous system (CNS) where rotavirus was detected in the fluid of the CNS in cases of encephalitis and meningitis, but these complications are uncommon even in the developing countries. Repeated rotavirus infections may increase the risk of celiac disease in genetically susceptible children. A case-control study of infants with a genetic predisposition for celiac disease observed that the risk of developing the disease increased twofold in children who were infected with rotavirus once and almost fourfold for those who were infected with it multiple times.

Rotavirus infections of animals

Rotaviruses infect and cause diarhoea in the young of many species of animals. They have been shown to commonly infect mammals; apes, cattle, pigs, sheep, rats, cats and dogs, mice, rabbits and birds including 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. Rotaviruses are a major cause of economic loss to farmers because of costs of treatment associated with high morbidity and mortality rates.

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