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Rotaviruses are the most common cause of diarrhea among infants and young children. Nearly every child in the world is infected with a rotavirus at least once by the age of five. Immunity develops with each infection, so subsequent infections are less severe. Adults are rarely affected.
The virus is transmitted by the faecal–oral route. It infects and damages the enterocyte that line the small intestine and causes gastroenteritis (which is often called "stomach flu" despite having no relation to influenza). Although rotavirus was discovered in 1973 by Ruth Bishop and her colleagues by electron micrograph images and accounts for approximately one third of hospitalisations for severe diarrhoea in infants and children, its importance has historically been underestimated within the public health community, particularly in developing countries. In addition to its impact on human health, rotavirus also infects other animals, and is a pathogen of livestock.
Rotaviral enteritis is usually an easily managed disease of childhood, but among children under 5 years of age rotavirus caused an estimated 151,714 deaths from diarrhoea in 2019. In the United States, before initiation of the rotavirus vaccination programme in the 2000s, rotavirus caused about 2.7million cases of severe gastroenteritis in children, almost 60,000 hospitalisations, and around 37 deaths each year. Following rotavirus vaccine introduction in the United States, hospitalisation rates have fallen significantly. Public health campaigns to combat rotavirus focus on providing oral rehydration therapy for infected children and vaccination to prevent the disease. The incidence and severity of rotavirus infections has declined significantly in countries that have added rotavirus vaccine to their routine childhood immunisation policies.
Rotavirus is a genus of double-stranded RNA viruses in the family Reoviridae. There are 11 species of the genus, usually referred to as RVA, RVB, RVC, RVD, RVF, RVG, RVH, RVI, RVJ, RVK and RVL. The most common is RVA, and these rotaviruses cause more than 90% of rotavirus infections in humans.
Within group A rotaviruses there are different strains, called serovar. As with influenza virus, a dual classification system is used based on two proteins on the surface of the virus. The glycoprotein VP7 defines the G serotypes and the protease-sensitive protein VP4 defines P serotypes. Because the two genes that determine G-types and P-types can be passed on separately to progeny viruses, different combinations are found. A whole genome genotyping system has been established for group A rotaviruses, which has been used to determine the origin of atypical strains. The prevalence of the individual G-types and P-types varies between, and within, countries and years. There are at least 36 G types and 51 P types but in infections of humans only a few combinations of G and P types predominate. They are G1P8, G2P4, G3P8, G4P8, G9P8 and G12P8.
At least six of the twelve proteins coding region by the rotavirus genome bind RNA. The role of these proteins 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 messenger RNA translation and regulation of gene expression.
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.
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 the protease enzyme trypsin, which is found in the gut, into VP5* and VP8* before the virus is infectious. VP4 determines how virulent the virus is and it determines the P-type of the virus. In humans there is an association between the blood group (Lewis antigen system, ABO blood group system and secretor status) and susceptibility to infection. Non-secretors seem resistant to infection by types P4 and P8, indicating that blood group antigens are the receptors for these genotypes. This resistance is dependent on the rotavirus genotype.
VP6 forms the bulk of the capsid. It is highly and can be used to identify rotavirus species. This protein is used in laboratory tests for rotavirus 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.
Targets for degradation include several IRF transcription factors required for interferon gene transcription.
NSP2 is an RNA-binding protein that accumulates in cytoplasmic inclusions () 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. NSP3 inactivates two translation initiation factors essential for synthesis of proteins from host mRNA.
First, NSP3 ejects poly(A)-binding protein (PABP) from the translation initiation factor eIF4F. PABP is required for efficient translation of transcripts with a 3' poly(A) tail, which is found on most host cell transcripts. Second, NSP3 inactivates eIF2 by stimulating its phosphorylation. Efficient translation of rotavirus mRNA, which lacks the 3' poly(A) tail, does not require either of these factors.
NSP4 is a viral enterotoxin that induces diarrhoea and was the first viral enterotoxin discovered. It is a viroporin that elevates cytosolic Ca2+ in mammalian cells.
NSP5 is encoded by genome segment 11 of rotavirus A. 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.
| + Rotavirus genes and proteins ! RNA Segment (Gene) !! Size () !! Protein !! UniProt !! Molecular weight kDa !! Location !! Copies per particle !! Function |
The eleven dsRNA strands remain within the protection of the two protein shells and the viral RNA replicase creates mRNA transcripts of the double-stranded viral genome. By remaining in the core, the viral RNA evades innate host immune responses including RNA interference that are triggered by the presence of double-stranded RNA.
During the infection, rotaviruses produce 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. In the viroplasm the positive sense viral RNAs that are used as templates for the synthesis of viral genomic dsRNA are protected from siRNA-induced RNase degradation. 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 in vitro 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 Offspring viruses are released from the cell by cell lysis.
Rotaviruses are stable in the environment and have been found in estuary samples at levels up to 1–5 infectious particles per USgallon. The viruses survive between 9 and 19 days. Sanitary measures adequate for eliminating bacteria and seem to be ineffective in control of rotavirus, as the incidence of rotavirus infection in countries with high and low health standards is similar.
Rotavirus infections can occur throughout life: the first usually produces symptoms, but subsequent infections are typically mild or asymptomatic,
The diarrhoea is caused by multiple activities of the virus. Malabsorption occurs because of the destruction of gut cells called . The enterotoxin rotavirus protein NSP4 induces age- and calcium ion-dependent chloride secretion, disrupts SGLT1 (sodium/glucose cotransporter 2) transporter-mediated reabsorption of water, apparently reduces activity of Brush border , and activates the calcium ion-dependent secretion of the enteric nervous system. The elevated concentrations of calcium ions in the cytosol (which are required for the assembly of the progeny viruses) is achieved by NSP4 acting as a viroporin. This increase in calcium ions leads to autophagy (self destruction) of the infected enterocytes.
NSP4 is also secreted. This extracellular form, which is modified by protease enzymes in the gut, is an enterotoxin which acts on uninfected cells via integrin receptors, which in turn cause and increase in intracellular calcium ion concentrations, secretory diarrhoea and autophagy.
The vomiting, which is a characteristic of rotaviral enteritis, is caused by the virus infecting the enterochromaffin cells on the lining of the digestive tract. The infection stimulates the production of 5' hydroxytryptamine (serotonin). This activates vagal afferent nerves, which in turn activates the cells of the brain stem that control the vomiting reflex.
Healthy enterocytes secrete lactase into the small intestine; milk intolerance due to lactase deficiency is a symptom of rotavirus infection, which can persist for weeks. A recurrence of mild diarrhoea often follows the reintroduction of milk into the child's diet, due to bacterial fermentation of the disaccharide lactose in the gut.
Specific diagnosis of infection with rotavirus is made by finding the virus in the child's Human feces by enzyme immunoassay. There are several licensed test kits on the market which are sensitive, specific and detect all serotypes of rotavirus.
In 2006, two new vaccines against infection were shown to be safe and effective in children, and in 2009, the WHO recommended that rotavirus vaccine be included in all national immunisation programmes.
The incidence and severity of rotavirus infections has declined significantly in countries that have acted on this recommendation. A 2014 review of available clinical trial data from countries routinely using rotavirus vaccines in their national immunisation programs found that rotavirus vaccines have reduced rotavirus hospitalisations by 49–92% and all cause diarrhoea hospitalisations by 17–55%. In Mexico, which in 2006 was among the first countries in the world to introduce rotavirus vaccine, diarrhoeal disease death rates dropped during the 2009 rotavirus season by more than 65 percent among children age two and under. In Nicaragua, which in 2006 became the first developing country to introduce a rotavirus vaccine, severe rotavirus infections were reduced by 40 percent and emergency room visits by a half. In the United States, rotavirus vaccination since 2006 has led to drops in rotavirus-related hospitalisations by as much as 86 percent. The vaccines may also have prevented illness in non-vaccinated children by limiting the number of circulating infections. In developing countries in Africa and Asia, where the majority of rotavirus deaths occur, a large number of safety and efficacy trials as well as recent post-introduction impact and effectiveness studies of Rotarix and RotaTeq have found that vaccines dramatically reduced severe disease among infants. In September 2013, the vaccine was offered to all children in the UK, aged between two and three months. A 2022 study found that the number of rotavirus cases in infants in England under one year of age was reduced by 77–88%. In all age groups, the number of laboratory-confirmed rotavirus infections was reduced by 69–83%. In Europe, hospitalisation rates following infection by rotaviruses have decreased by 65% to 84% following the introduction of the vaccine. Globally, vaccination has reduced hospital admissions and emergency department visits by a median of 67%.
Rotavirus vaccines are licensed in over 100 countries, and more than 80 countries have introduced routine rotavirus vaccination, almost half with the support of the GAVI vaccine alliance. To make rotavirus vaccines available, accessible, and affordable in all countries—particularly low- and middle-income countries in Africa and Asia where the majority of rotavirus deaths occur, PATH (formerly Program for Appropriate Technology in Health), the WHO, the U.S. Centers for Disease Control and Prevention, and GAVI have partnered with research institutions and governments to generate and disseminate evidence, lower prices, and accelerate introduction.
The vaccine may prevent type 1 diabetes.
Outbreaks of rotavirus A diarrhoea are common among hospitalised infants, young children attending day care centres, and elderly people 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. A similar large outbreak occurred in Brazil in 1977.
Rotavirus B, also called adult diarrhoea rotavirus or ADRV, has caused major epidemics of severe diarrhoea affecting thousands of people of all ages in China. These epidemics occurred as a result of sewage contamination of drinking water. Rotavirus B infections also occurred in India in 1998; the causative strain was named CAL. Unlike ADRV, the CAL strain is endemic. To date, epidemics caused by rotavirus B have been confined to mainland China, and surveys indicate a lack of immunity to this species in the United States. Rotavirus C has been associated with rare and sporadic cases of diarrhoea in children, and small outbreaks have occurred in families.
In 1974, Thomas Henry Flewett suggested the name rotavirus after observing that, when viewed through an electron microscope, a rotavirus particle looks like a wheel (rota in Latin) the name was officially recognised by the International Committee on Taxonomy of Viruses four years later. In 1976, related viruses were described in several other species of animals. These viruses, all causing acute gastroenteritis, were recognised as a collective pathogen affecting humans and other animals worldwide. Rotavirus serotypes were first described in 1980, and in the following year, rotaviruses from humans were first grown in derived from monkey kidneys, by adding trypsin (an enzyme found in the duodenum of mammals and now known to be essential for rotavirus to replicate) to the culture medium. The ability to grow rotaviruses in culture accelerated the pace of research, and by the mid-1980s the first candidate vaccines were being evaluated.
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