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Rotavirus, a leading cause of death among infants and children under the age of five, is a genus of double-stranded RNA virus in the taxonomic family Reoviridae. By the age of five, nearly every child in the world has been infected with rotavirus at least once and is thus less susceptible to it. In susceptible people, rotavirus infects cells that line the small intestine, producing an enterotoxin. This toxin causes gastroenteritis with severe diarrhoea and potentially fatal dehydration. Although rotavirus accounts for 30–50% of infants and children hospitalised with severe diarrhoea, the major role of rotavirus in causing diarrhoea is not widely recognised. Each year, rotavirus causes 2.7 million cases of severe gastroenteritis in the United States alone, almost 60,000 resulting in hospitalisation and 40 resulting in death, and causes 100 million cases in developing countries, almost 2 million resulting in hospitalisation and 500,000 resulting in death. The virus can spread rapidly within families and close communities. Large numbers of rotavirus particles are excreted by infected people, and are spread via the fecal–oral route. Public health campaigns to reduce morbidity and mortality from rotavirus focus on increasing the use of oral rehydration therapy and vaccination.Rotavirus is divided into seven species. Rotavirus A, the most prevalent, causes more than 90% of infections in humans. Rotavirus also infects animals, which may provide a reservoir for new strains of rotavirus that could cause zoonotic epidemics in humans.
History In 1943, Light and Hodes proved that an infectious agent causing scours in cattle was a virus.Light, J.S. and Hodes, H.L. Studies on epidemic diarrhoea in the newborn: isolation of a filterable agent causing diarrhoea in calves. Am. J. Publ. Health. 33, 1451–54, 1943 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 in children with gastroenteritis, in Australia
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.
The name rotavirus was coined in 1974 by Thomas Henry Flewett, who observed that, viewed through an electron microscope, a rotavirus particle looks like a wheel (rota in Latin).
The name was later adopted by the International Committee on Taxonomy of Viruses. 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.
Types of rotavirusThere 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 rotaviruses A there are different strains, called serotypes. Two independently inherited genes determine rotavirus serotypes, and a strain of rotavirus A is classified by its G and P type.
StructureThe 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.
Rotavirus proteinsThere 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 five non-structural proteins (NSPs), that are only produced in cells infected by rotavirus. These are called NSP1, NSP2, NSP3, NSP4, NSP5 and NSP6.
Structural proteinsVP1 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 but it 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
Non-structural viral proteinsNSP1, 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.Desselberger U. Rotavirus: basic facts. In Rotaviruses Methods and Protocols. Ed. Gray, J. and Desselberger U. Humana Press, 2000, pp. 1–8. ISBN 0-89603-736-3Patton JT. Rotavirus RNA replication and gene expression. In Novartis Foundation. Gastroenteritis Viruses, Humana Press, 2001, pp. 64–81. ISBN 0-471-49663-4 RNA-protein coding assignments differ in some strains.
ReplicationRotaviruses infect the cells that line the small intestine. 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.
PathogenesisRotavirus gastroenteritis is a self-limiting, mild to severe disease characterised 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 (108–1010 infectious particles per ml), and infection can be readily acquired through contaminated hands, objects, or utensils. 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. The virus infects enterocytes of the villi of the small intestine, leading to structural and functional changes of the epithelium. The 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. The enterotoxin causes cells to become permeable and damaged. Healthy enterocytes secrete lactase into the small intestine and milk intolerance caused by lactase deficiency is a particular symptom of rotavirus infection and this can persist for weeks. Often this causes a recurrence of mild diarrhoea following the reintroduction of milk into the child's diet. The diarrhoea is caused by bacterial fermentation of lactose in the gut.
ComplicationsRotavirus infections rarely cause other complications in the well managed child. There are reports of 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 rare 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 animalsRotaviruses infect and cause diarhoea in young animals. They have been shown to 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 cause of economic loss to farmers because of costs of treatment associated with high morbidity and mortality rates.
Diagnosis and treatment Diagnosis of infection with rotavirus normally follows diagnosis of gastroenteritis. Most children admitted to hospital with gastroenteritis are tested for rotavirus A.
Specific diagnosis of infection with rotavirus A is made by identification of the virus in the patient's stool by enzyme immunoassay. Several licensed test kits are used which are sensitive, specific and detect all serotypes of rotavirus A. These kits are also used to diagnose infections of animals. Other methods, electron microscopy and polyacrylamide gel electrophoresis, are used in research laboratories. Reverse transcription-polymerase chain reaction (RT-PCR) is used to detect and identify all species and serotypes of human rotavirus.Treatment of acute rotavirus infection is nonspecific and involves management of symptoms and, most importantly, maintenance of hydration. Depending on the severity of diarrhoea, treatment consists of oral rehydration with plain water, water plus salts, or water plus salts and sugar. Out of every 40 children diagnosed with acute rotavirus infection, about one child develops dehydration severe enough to necessitate admission to hospital. Once in hospital, fluids are given by intravenous drip or nasogastric tube, and the child's electrolytes and blood sugar are monitored.
Epidemiology 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 paediatric 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 and fruit. Rotaviruses are 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.Rotavirus A infections occur throughout life, but most recurrent infections are mild or asymptomatic. Children six months to two years of age, the elderly, and the immunocompromised are particularly susceptible to more severe symptoms. Symptoms usually accompany primary infection, which is followed by protection against subsequent symptomatic infection. Symptomatic infection rates are highest in children under two years of age, and lowest in those over 45 years of age. Rotavirus infection is common in the newborn but is often associated with mild or asymptomatic disease. Rotavirus infections of adults also occur, and frequent asymptomatic adult infections may be important in maintaining the transmission of infection in the community.Rotavirus A is endemic worldwide. It is the leading single cause of severe diarrhoea among infants and children, being responsible for about 20% of cases, and accounts for 50% of the cases requiring hospitalisation. The other 80% of cases are caused by bacteria, parasites and other viruses. Rotavirus A serotype strains G1 through G4 account for more than 90% of rotavirus gastroenteritis in humans, with G1 being the predominant serotype. Boys are twice as likely to be admitted to hospital than girls, but the reason for this is not understood. Between 1986-1999, approximately 22% of childhood hospitalisations for diarrheal disease were caused by rotavirus, but this increased to approximately 39% during 2000-2004. Almost every child has been infected with rotavirus by age five. Over 2.7 million cases of rotavirus gastroenteritis occur annually in the U.S. and around 37 children die from the results of the infection each year. These death rates are down from 600,000 and 150, respectively, in 1995; the improved survival rate is attributed to better prevention of dehydration, primarily through use of oral rehydration therapy. In some children re-infections by rotavirus occur and these are often, but not always, caused by different serotypes.In temperate areas, rotavirus occurs primarily in the winter, but in the tropics it occurs throughout the year. This is partly explained by seasonal changes in temperature and humidity. The number attributable to food contamination is unknown.Rotavirus B, also called adult diarrhoea rotavirus or ADRV, has caused major epidemics of severe diarrhoea affecting thousands of persons of all ages in China. Rotavirus B caused infections in India in 1998 and this strain was named CAL. Unlike ADRV, the CAL strain is endemic.Rotavirus C has been associated with rare and sporadic cases of diarrhoea in children in many countries but outbreaks were first reported in Japan and England.
EpidemicsOutbreaks of rotavirus A diarrhoea are common among hospitalised infants, young children attending day care centres, and elderly persons in nursing homes. An outbreak caused by contaminated municipal water occurred in Colorado in 1981.During 2005 the largest recorded epidemic of diarrhoea occurred in Nicaragua. This unusually large and severe outbreak was associated with mutations in the rotavirus A genome, possibly helping the virus escape the prevalent immunity in the population which had no protection. A similar large outbreak occurred in Brazil in 1977.Epidemics of rotavirus B involving millions of people have occurred in China as a result of sewage contamination of drinking water. To date, outbreaks caused by rotavirus B have been confined to mainland China, but seroepidemiological surveys have indicated a lack of immunity to rotavirus B in the US. Rotavirus C has caused epidemics among school children in Japan.
Vaccines In 2003 the World Health Organization and the U.S. 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.In 2006, two vaccines against Rotavirus A 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.
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