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 zoonoticepidemics in humans.
In 1943, Light and 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 in children with gastroenteritis, in Australia and England. 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 rotavirus
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 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.
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 proteincapsid. Viral particles are up to 76.5 nm in diameter and are not enveloped.
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 five non-structural proteins (NSPs), 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 polymeraseenzyme. 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* and VP8* before the virus is infectious. It 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 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.
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.
This table is based on the simian rotavirus strain SA11. RNA-protein coding assignments differ in some strains.
Rotaviruses 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.
Rotavirus 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.
Rotavirus 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 animals
Rotaviruses 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.
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.
Outbreaks 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.
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.
^ Velázquez FR, Matson DO, Calva JJ, Guerrero L, Morrow AL, Carter-Campbell S, Glass RI, Estes MK, Pickering LK, Ruiz-Palacios GM (1996). "Rotavirus infections in infants as protection against subsequent infections". N. Engl. J. Med.335 (14): 1022–8. PMID 8793926.
^ ab Simpson E, Wittet S, Bonilla J, Gamazina K, Cooley L, Winkler JL (2007). "Use of formative research in developing a knowledge translation approach to Rotavirus vaccine introduction in developing countries". BMC Public Health7 (1): 281. doi:10.1186/1471-2458-7-281. PMID 17919334.
^ abc Fischer TK, Viboud C, Parashar U, Malek M, Steiner C, Glass R, Simonsen L (2007). "Hospitalizations and deaths from diarrhea and rotavirus among children <5 years of age in the United States, 1993-2003.". J. Infect. Dis.195 (8): 1117–25. doi:10.1086/512863. PMID 17357047.
Stebbins S (2007). "Rotavirus: disease and vaccine update, 2007.". J Fam Pract56 (2 Suppl Vaccines): S6–11. PMID 17270111.
^ abc Holland RE (1990). "Some infectious causes of diarrhea in young farm animals". Clin. Microbiol. Rev.3 (4): 345–75. PMID 2224836.
Saif LJ, Fernandez FM (1996). "Group A rotavirus veterinary vaccines". J. Infect. Dis.174 Suppl 1: S98–106. PMID 8752298.
Cook N, Bridger J, Kendall K, Gomara MI, El-Attar L, Gray J (2004). "The zoonotic potential of rotavirus". J. Infect.48 (4): 289–302. doi:10.1016/j.jinf.2004.01.018. PMID 15066329.
^ 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
^ Mebus CA, Wyatt RG, Sharpee RL, et al (1976). "Diarrhea in gnotobiotic calves caused by the reovirus-like agent of human infantile gastroenteritis". Infect. Immun.14 (2): 471–4. PMID 184047.
Rubenstein D, Milne RG, Buckland R, Tyrrell DA (1971). "The growth of the virus of epidemic diarrhoea of infant mice (EDIM) in organ cultures of intestinal epithelium". British journal of experimental pathology52 (4): 442–45. PMID 4998842.
Woode GN, Bridger JC, Jones JM, Flewett TH, Davies HA, Davis HA, White GB (1976). "Morphological and antigenic relationships between viruses (rotaviruses) from acute gastroenteritis in children, calves, piglets, mice, and foals". Infect. Immun.14 (3): 804–10. PMID 965097.
Bishop RF, Davidson GP, Holmes IH, Ruck BJ (1973). "Letter: Evidence for viral gastroenteritis". N. Engl. J. Med.289 (20): 1096–7. PMID 4742237.
Bishop RF, Davidson GP, Holmes IH, Ruck BJ (1973). "Virus particles in epithelial cells of duodenal mucosa from children with acute non-bacterial gastroenteritis". Lancet2 (7841): 1281–3. PMID 4127639.
Flewett TH, Bryden AS, Davies H (1973). "Letter: Virus particles in gastroenteritis". Lancet2 (7844): 1497. PMID 4129337.
Flewett TH, Woode GN (1978). "The rotaviruses". Arch. Virol.57 (1): 1–23. PMID 77663.
^ Flewett TH, Bryden AS, Davies H, Woode GN, Bridger JC, Derrick JM (1974). "Relation between viruses from acute gastroenteritis of children and newborn calves". Lancet2 (7872): 61–3. PMID 4137164. Retrieved on 2007-12-29.
Urasawa T, Urasawa S, Taniguchi K (1981). "Sequential passages of human rotavirus in MA-104 cells". Microbiol. Immunol.25 (10): 1025–35. PMID 6273696.
Vesikari T, Isolauri E, Delem A, et al (1985). "Clinical efficacy of the RIT 4237 live attenuated bovine rotavirus vaccine in infants vaccinated before a rotavirus epidemic". J. Pediatr.107 (2): 189–94. PMID 3894608.
^ Beards GM, Brown DW (1988). "The antigenic diversity of rotaviruses: significance to epidemiology and vaccine strategies". Eur. J. Epidemiol.4 (1): 1–11. PMID 2833405.
^ Santos N, Hoshino Y (2005). "Global distribution of rotavirus serotypes/genotypes and its implication for the development and implementation of an effective rotavirus vaccine". Rev. Med. Virol.15 (1): 29–56. doi:10.1002/rmv.448. PMID 15484186.
^ Desselberger U, Iturriza-Gómara M, Gray JJ (2001). "Rotavirus epidemiology and surveillance". Novartis Found. Symp.238: 125–47; discussion 147–52. PMID 11444024.
^ Chan WK, Penaranda ME, Crawford SE, Estes MK (1986). "Two glycoproteins are produced from the rotavirus neutralization gene". Virology151 (2): 243–52. PMID 3010552.
^ ab Pesavento JB, Crawford SE, Estes MK, Prasad BV (2006). "Rotavirus proteins: structure and assembly". Curr. Top. Microbiol. Immunol.309: 189–219. PMID 16913048.
^ Prasad BV, Chiu W (1994). "Structure of rotavirus". Curr. Top. Microbiol. Immunol.185: 9–29. PMID 8050286.
^ Vásquez-del Carpió R, Morales JL, Barro M, Ricardo A, Spencer E (2006). "Bioinformatic prediction of polymerase elements in the rotavirus VP1 protein". Biol. Res.39 (4): 649–59. doi:/S0716-97602006000500008. PMID 17657346.
^ Arnoldi F, Campagna M, Eichwald C, Desselberger U, Burrone OR (2007). "Interaction of rotavirus polymerase VP1 with nonstructural protein NSP5 is stronger than that with NSP2". J. Virol.81 (5): 2128–37. doi:10.1128/JVI.01494-06. PMID 17182692.
^ Fresco LD, Buratowski S (1994). "Active site of the mRNA-capping enzyme guanylyltransferase from Saccharomyces cerevisiae: similarity to the nucleotidyl attachment motif of DNA and RNA ligases". Proc. Natl. Acad. Sci. U.S.A.91 (14): 6624–8. PMID 8022828.
^ Gardet A, Breton M, Fontanges P, Trugnan G, Chwetzoff S (2006). "Rotavirus spike protein VP4 binds to and remodels actin bundles of the epithelial brush border into actin bodies". J. Virol.80 (8): 3947–56. doi:10.1128/JVI.80.8.3947-3956.2006. PMID 16571811.
^ Arias CF, Isa P, Guerrero CA, Méndez E, Zárate S, López T, Espinosa R, Romero P, López S (2002). "Molecular biology of rotavirus cell entry". Arch. Med. Res.33 (4): 356–61. PMID 12234525.
^ Konno T, Suzuki H, Kitaoka S, Sato T, Fukuhara N, Yoshie O, Fukudome K, Numazaki Y (1993). "Proteolytic enhancement of human rotavirus infectivity". Clin. Infect. Dis.16 Suppl 2: S92–7. PMID 8384014.
^ Hoshino Y, Jones RW, Kapikian AZ (2002). "Characterization of neutralization specificities of outer capsid spike protein VP4 of selected murine, lapine, and human rotavirus strains". Virology299 (1): 64–71. PMID 12167342.
^ abc Bishop RF (1996). "Natural history of human rotavirus infection". Arch. Virol. Suppl.12: 119–28. PMID 9015109.
^ ab Beards GM, Campbell AD, Cottrell NR, Peiris JS, Rees N, Sanders RC, Shirley JA, Wood HC, Flewett TH (1984). "Enzyme-linked immunosorbent assays based on polyclonal and monoclonal antibodies for rotavirus detection". J. Clin. Microbiol.19 (2): 248–54. PMID 6321549.
^ Hua J, Mansell EA, Patton JT (1993). "Comparative analysis of the rotavirus NS53 gene: conservation of basic and cysteine-rich regions in the protein and possible stem-loop structures in the RNA". Virology196 (1): 372–8. doi:10.1006/viro.1993.1492. PMID 8395125.
^ Kattoura MD, Chen X, Patton JT (1994). "The rotavirus RNA-binding protein NS35 (NSP2) forms 10S multimers and interacts with the viral RNA polymerase". Virology202 (2): 803–13. doi:10.1006/viro.1994.1402. PMID 8030243.
^ Taraporewala ZF, Patton JT (2004). "Nonstructural proteins involved in genome packaging and replication of rotaviruses and other members of the Reoviridae". Virus Res.101 (1): 57–66. doi:10.1016/j.virusres.2003.12.006. PMID 15010217.
^ Poncet D, Aponte C, Cohen J (1993). "Rotavirus protein NSP3 (NS34) is bound to the 3' end consensus sequence of viral mRNAs in infected cells". J. Virol.67 (6): 3159–65. PMID 8388495.
^ Dong Y, Zeng CQ, Ball JM, Estes MK, Morris AP (1997). "The rotavirus enterotoxin NSP4 mobilizes intracellular calcium in human intestinal cells by stimulating phospholipase C-mediated inositol 1,4,5-trisphosphate production". Proc. Natl. Acad. Sci. U.S.A.94 (8): 3960–5. PMID 9108087.
^ Afrikanova I, Miozzo MC, Giambiagi S, Burrone O (1996). "Phosphorylation generates different forms of rotavirus NSP5". J. Gen. Virol.77 ( Pt 9): 2059–65. PMID 8811003.
^ Mohan KV, Atreya CD (2001). "Nucleotide sequence analysis of rotavirus gene 11 from two tissue culture-adapted ATCC strains, RRV and Wa". Virus Genes23 (3): 321–9. PMID 11778700.
^ Rainsford EW, McCrae MA (2007). "Characterization of the NSP6 protein product of rotavirus gene 11". doi:10.1016/j.virusres.2007.06.011. PMID 17658646.
^ Desselberger U. Rotavirus: basic facts. In Rotaviruses Methods and Protocols. Ed. Gray, J. and Desselberger U. Humana Press, 2000, pp. 1–8. ISBN 0-89603-736-3
^ Patton JT. Rotavirus RNA replication and gene expression. In Novartis Foundation. Gastroenteritis Viruses, Humana Press, 2001, pp. 64–81. ISBN 0-471-49663-4
^ Jayaram H, Estes MK, Prasad BV (2004). "Emerging themes in rotavirus cell entry, genome organization, transcription and replication". Virus Res.101 (1): 67–81. doi:10.1016/j.virusres.2003.12.007. PMID 15010218.
^ Patton JT, Vasquez-Del Carpio R, Spencer E (2004). "Replication and transcription of the rotavirus genome". Curr. Pharm. Des.10 (30): 3769–77. PMID 15579070.
^ Graham DY, Dufour GR, Estes MK (1987). "Minimal infective dose of rotavirus". Arch. Virol.92 (3-4): 261–71. PMID 3028333.
^ Jourdan N, Brunet JP, Sapin C, et al (1998). "Rotavirus infection reduces sucrase-isomaltase expression in human intestinal epithelial cells by perturbing protein targeting and organization of microvillar cytoskeleton". J. Virol.72 (9): 7228–36. PMID 9696817.
^ Davidson GP, Barnes GL (1979). "Structural and functional abnormalities of the small intestine in infants and young children with rotavirus enteritis". Acta Paediatr Scand68 (2): 181–6. PMID 217231.
^ Ouwehand A, Vesterlund S (2003). "Health aspects of probiotics". IDrugs6 (6): 573–80. PMID 12811680.
^ Arya SC (1984). "Rotaviral infection and intestinal lactase level". J. Infect. Dis.150 (5): 791. PMID 6436397.
^ ab Ramig RF (2007). "Systemic rotavirus infection". Expert review of anti-infective therapy5 (4): 591–612. doi:10.1586/14787220.127.116.111. PMID 17678424.
^ Goto T, Kimura H, Numazaki K, Akiyama M, Kato M, Noda M, Nozaki Y, Tanaka-Taya K, Taniguchi K, Yamagata T, Nishio O, Oogane T, Momoi MY, Okabe N (2007). "A case of meningoencephalitis associated with G1P rotavirus infection in a Japanese child": 1–4. doi:10.1080/00365540701466249. PMID 17852929.
^ Kehle J, Metzger-Boddien C, Tewald F, Wald M, Schüürmann J, Enders G (2003). "First case of confirmed rotavirus meningoencephalitis in Germany". Pediatr. Infect. Dis. J.22 (5): 468–70. PMID 12797316.
^ Pager C, Steele D, Gwamanda P, Driessen M (2000). "A neonatal death associated with rotavirus infection--detection of rotavirus dsRNA in the cerebrospinal fluid". S. Afr. Med. J.90 (4): 364–5. PMID 10957919.
^ Stene LC, Honeyman MC, Hoffenberg EJ, Haas JE, Sokol RJ, Emery L, Taki I, Norris JM, Erlich HA, Eisenbarth GS, Rewers M (2006). "Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study". Am. J. Gastroenterol.101 (10): 2333–40. doi:10.1111/j.1572-0241.2006.00741.x. PMID 17032199.
^ Ashley CR, Caul EO, Clarke SK, Corner BD, Dunn S (1978). "Rotavirus infections of apes". Lancet2 (8087): 477. PMID 79844.
^ Wani SA, Bhat MA, Ishaq SM, Ashrafi MA (2004). "Determination of bovine rotavirus G genotypes in Kashmir, India". Rev. - Off. Int. Epizoot.23 (3): 931–6. PMID 15861888.
^ Saif LJ (1999). "Enteric viral infections of pigs and strategies for induction of mucosal immunity". Advances in veterinary medicine41: 429–46. PMID 9890034.
^ Pérez-Cano FJ, Castell M, Castellote C, Franch A (2007). "Characterization of Clinical and Immune Response in a Rotavirus Diarrhea Model in Suckling Lewis Rats". Pediatr Res. doi:10.1203/PDR.0b013e318159a273. PMID 17957154.
^ Enriquez C, Nwachuku N, Gerba CP (2001). "Direct exposure to animal enteric pathogens". Reviews on environmental health16 (2): 117–31. PMID 11512628.
^ Feng N, Franco MA, Greenberg HB (1997). "Murine model of rotavirus infection". Adv. Exp. Med. Biol.412: 233–40. PMID 9192019.
^ Thouless ME, DiGiacomo RF, Deeb BJ, Howard H (1988). "Pathogenicity of rotavirus in rabbits". J. Clin. Microbiol.26 (5): 943–7. PMID 2838507.
^ Guy JS (1998). "Virus infections of the gastrointestinal tract of poultry". Poult. Sci.77 (8): 1166–75. PMID 9706084.
^ abc Patel MM, Tate JE, Selvarangan R, et al (2007). "Routine laboratory testing data for surveillance of rotavirus hospitalizations to evaluate the impact of vaccination". Pediatr. Infect. Dis. J.26 (10): 914–9. doi:10.1097/INF.0b013e31812e52fd. PMID 17901797.
^ (2006) "The paediatric burden of rotavirus disease in Europe". Epidemiol. Infect.134 (5): 908–16. doi:10.1017/S0950268806006091. PMID 16650331.
^ Lipson SM, Svenssen L, Goodwin L, Porti D, Danzi S, Pergolizzi R (2001). "Evaluation of two current generation enzyme immunoassays and an improved isolation-based assay for the rapid detection and isolation of rotavirus from stool". J. Clin. Virol.21 (1): 17–27. PMID 11255094.
^ Eing BR, May G, Baumeister HG, Kühn JE (2001). "Evaluation of two enzyme immunoassays for detection of human rotaviruses in fecal specimens". J. Clin. Microbiol.39 (12): 4532–4. doi:10.1128/JCM.39.12.4532-4534.2001. PMID 11724877.
^ Dennehy PH, Hartin M, Nelson SM, Reising SF (1999). "Evaluation of the ImmunoCardSTAT! rotavirus assay for detection of group A rotavirus in fecal specimens". J. Clin. Microbiol.37 (6): 1977–9. PMID 10325358.
^ Maes RK, Grooms DL, Wise AG, et al (2003). "Evaluation of a human group a rotavirus assay for on-site detection of bovine rotavirus". J. Clin. Microbiol.41 (1): 290–4. PMID 12517863.
^ Beards GM (1988). "Laboratory diagnosis of viral gastroenteritis". Eur. J. Clin. Microbiol. Infect. Dis.7 (1): 11–3. PMID 3132369.
^ Fischer TK, Gentsch JR (2004). "Rotavirus typing methods and algorithms". Rev. Med. Virol.14 (2): 71–82. doi:10.1002/rmv.411. PMID 15027000.
^ Sachdev HP (1996). "Oral rehydration therapy". Journal of the Indian Medical Association94 (8): 298–305. PMID 8855579.
^ Parashar UD, Chung MA, Holman RC, Ryder RW, Hadler JL, Glass RI (1999). "Use of state hospital discharge data to assess the morbidity from rotavirus diarrhea and to monitor the impact of a rotavirus immunization program: A pilot study in Connecticut". Pediatrics104 (3 Pt 1): 489–94. PMID 10469774.
^ Rao VC, Seidel KM, Goyal SM, Metcalf TG, Melnick JL (1984). "Isolation of enteroviruses from water, suspended solids, and sediments from Galveston Bay: survival of poliovirus and rotavirus adsorbed to sediments". Appl. Environ. Microbiol.48 (2): 404–9. PMID 6091548.
^ Dennehy PH (2000). "Transmission of rotavirus and other enteric pathogens in the home". Pediatr. Infect. Dis. J.19 (10 Suppl): S103–5. PMID 11052397.
^ Ward RL (1996). "Mechanisms of protection against rotavirus in humans and mice". J. Infect. Dis.174 Suppl 1: S51–8. PMID 8752291.
^ Bernstein DI, Sander DS, Smith VE, Schiff GM, Ward RL (1991). "Protection from rotavirus reinfection: 2-year prospective study". J. Infect. Dis.164 (2): 277–83. PMID 1649875.
^ Koopman JS, Monto AS (1989). "The Tecumseh Study. XV: Rotavirus infection and pathogenicity". Am. J. Epidemiol.130 (4): 750–9. PMID 2549788.
^ Cameron DJ, Bishop RF, Veenstra AA, Barnes GL (1978). "Noncultivable viruses and neonatal diarrhea: fifteen-month survey in a newborn special care nursery". J. Clin. Microbiol.8 (1): 93–8. PMID 209058.
^ Grillner L, Broberger U, Chrystie I, Ransjö U (1985). "Rotavirus infections in newborns: an epidemiological and clinical study". Scand. J. Infect. Dis.17 (4): 349–55. PMID 3003889.
^ Hrdy DB (1987). "Epidemiology of rotaviral infection in adults". Rev. Infect. Dis.9 (3): 461–9. PMID 3037675.
^ Rheingans RD, Heylen J, Giaquinto C (2006). "Economics of rotavirus gastroenteritis and vaccination in Europe: what makes sense?". Pediatr. Infect. Dis. J.25 (1 Suppl): S48–55. PMID 16397429.
^ Cheng AC, McDonald JR, Thielman NM (2005). "Infectious diarrhea in developed and developing countries". J. Clin. Gastroenterol.39 (9): 757–73. PMID 16145337.
^ ab Beards GM, Desselberger U, Flewett TH (1989). "Temporal and geographical distributions of human rotavirus serotypes, 1983 to 1988". J. Clin. Microbiol.27 (12): 2827–33. PMID 2556435.
^ ab Beards G, Graham C (1995). "Temporal distribution of rotavirus G-serotypes in the West Midlands region of the United Kingdom, 1983-1994". J Diarrhoeal Dis Res13 (4): 235–7. PMID 8838827.
^ Rodriguez WJ, Kim HW, Brandt CD, et al (1987). "Longitudinal study of rotavirus infection and gastroenteritis in families served by a pediatric medical practice: clinical and epidemiologic observations". Pediatr. Infect. Dis. J.6 (2): 170–6. PMID 3031575.
^ Ho MS, Glass RI, Pinsky PF, Anderson LJ (1988). "Rotavirus as a cause of diarrheal morbidity and mortality in the United States". J. Infect. Dis.158 (5): 1112–6. PMID 3183422.
^ Visser LE, Cano Portero R, Gay NJ, Martínez Navarro JF (1999). "Impact of rotavirus disease in Spain: an estimate of hospital admissions due to rotavirus". Acta Paediatr Suppl88 (426): 72–6. PMID 10088916.
^ Van Man N, Luan le T, Trach DD, et al (2005). "Epidemiological profile and burden of rotavirus diarrhea in Vietnam: 5 years of sentinel hospital surveillance, 1998-2003". J. Infect. Dis.192 Suppl 1: S127–32. doi:10.1086/431501. PMID 16088796.
^ Ryan MJ, Ramsay M, Brown D, Gay NJ, Farrington CP, Wall PG (1996). "Hospital admissions attributable to rotavirus infection in England and Wales". J. Infect. Dis.174 Suppl 1: S12–8. PMID 8752285.
^ Parashar UD, Gibson CJ, Bresse JS, Glass RI (2006). "Rotavirus and severe childhood diarrhea". Emerging Infect. Dis.12 (2): 304–6. PMID 16494759. Retrieved on 2007-12-29.
^ Grimwood K, Huang QS, Cohet C, et al (2006). "Rotavirus hospitalisation in New Zealand children under 3 years of age". J Paediatr Child Health42 (4): 196–203. doi:10.1111/j.1440-1754.2006.00829.x. PMID 16630321.
^ Haffejee IE (1995). "The epidemiology of rotavirus infections: a global perspective". J. Pediatr. Gastroenterol. Nutr.20 (3): 275–86. PMID 7608822.
^ Malek MA, Curns AT, Holman RC, et al (2006). "Diarrhea- and rotavirus-associated hospitalizations among children less than 5 years of age: United States, 1997 and 2000". Pediatrics117 (6): 1887–92. doi:10.1542/peds.2005-2351. PMID 16740827.
^ Linhares AC, Gabbay YB, Mascarenhas JD, Freitas RB, Flewett TH, Beards GM (1988). "Epidemiology of rotavirus subgroups and serotypes in Belem, Brazil: a three-year study". Ann. Inst. Pasteur Virol.139 (1): 89–99. PMID 2849961. Retrieved on 2007-12-27.
^ De Champs C, Laveran H, Peigue-Lafeuille H, et al (1991). "Sequential rotavirus infections: characterization of serotypes and electrophoretypes". Res. Virol.142 (1): 39–45. PMID 1647052. Retrieved on 2007-12-27.
^ Moe K, Harper GJ (1983). "The effect of relative humidity and temperature on the survival of bovine rotavirus in aerosol". Arch. Virol.76 (3): 211–6. PMID 6307226.
^ Moe K, Shirley JA (1982). "The effects of relative humidity and temperature on the survival of human rotavirus in faeces". Arch. Virol.72 (3): 179–86. PMID 6287970.
^ Koopmans M, Brown D (1999). "Seasonality and diversity of Group A rotaviruses in Europe". Acta paediatrica (Oslo, Norway : 1992). Supplement88 (426): 14–9. PMID 10088906.
^ Anh DD, Thiem VD, Fischer TK, Canh DG, Minh TT, Tho le H, Van Man N, Luan le T, Kilgore P, von Seidlein L, Glass RI (2006). "The burden of rotavirus diarrhea in Khanh Hoa Province, Vietnam: baseline assessment for a rotavirus vaccine trial". Pediatr. Infect. Dis. J.25 (1): 37–40. PMID 16395100.
^ Tanaka G, Faruque AS, Luby SP, Malek MA, Glass RI, Parashar UD (2007). "Deaths from rotavirus disease in Bangladeshi children: estimates from hospital-based surveillance". Pediatr. Infect. Dis. J.26 (11): 1014–8. doi:10.1097/INF.0b013e318125721c. PMID 17984808.
^ Pérez-Schael I, Salinas B, González R, Salas H, Ludert JE, Escalona M, Alcalá A, Rosas MA, Materán M (2007). "Rotavirus mortality confirmed by etiologic identification in Venezuelan children with diarrhea". Pediatr. Infect. Dis. J.26 (5): 393–7. doi:10.1097/01.inf.0000260252.48129.86. PMID 17468648.
^ Soriano-Gabarró M, Mrukowicz J, Vesikari T, Verstraeten T (2006). "Burden of rotavirus disease in European Union countries". Pediatr. Infect. Dis. J.25 (1 Suppl): S7–S11. PMID 16397431.
^ Kelkar SD, Zade JK (2004). "Group B rotaviruses similar to strain CAL-1, have been circulating in Western India since 1993". Epidemiol. Infect.132 (4): 745–9. PMID 15310177.
^ Ahmed MU, Kobayashi N, Wakuda M, Sanekata T, Taniguchi K, Kader A, Naik TN, Ishino M, Alam MM, Kojima K, Mise K, Sumi A (2004). "Genetic analysis of group B human rotaviruses detected in Bangladesh in 2000 and 2001". J. Med. Virol.72 (1): 149–55. doi:10.1002/jmv.10546. PMID 14635024.
^ Brown DW, Campbell L, Tomkins DS, Hambling MH (1989). "School outbreak of gastroenteritis due to atypical rotavirus". Lancet2 (8665): 737–8. PMID 2570978.
^ Kuzuya M, Fujii R, Hamano M, Nishijima M, Ogura H (2007). "Detection and molecular characterization of human group C rotaviruses in Okayama Prefecture, Japan, between 1986 and 2005". J. Med. Virol.79 (8): 1219–28. doi:10.1002/jmv.20910. PMID 17596825.
^ Hopkins RS, Gaspard GB, Williams FP, Karlin RJ, Cukor G, Blacklow NR (1984). "A community waterborne gastroenteritis outbreak: evidence for rotavirus as the agent". American journal of public health74 (3): 263–5. PMID 6320684.
^ Bucardo F, Karlsson B, Nordgren J, et al (2007). "Mutated G4P rotavirus associated with a nationwide outbreak of gastroenteritis in Nicaragua in 2005". J. Clin. Microbiol.45 (3): 990–7. doi:10.1128/JCM.01992-06. PMID 17229854.
^ Linhares AC, Pinheiro FP, Freitas RB, Gabbay YB, Shirley JA, Beards GM (1981). "An outbreak of rotavirus diarrhea among a non-immune, isolated South American Indian community". Am. J. Epidemiol.113 (6): 703–10. PMID 6263087.
^ Hung T, Chen GM, Wang CG, et al (1984). "Waterborne outbreak of rotavirus diarrhea in adults in China caused by a novel rotavirus". Lancet1 (8387): 1139–42. PMID 6144874.
^ Fang ZY, Ye Q, Ho MS, et al (1989). "Investigation of an outbreak of adult diarrhea rotavirus in China". J. Infect. Dis.160 (6): 948–53. PMID 2555422.
^ Penaranda ME, Ho MS, Fang ZY, et al (1989). "Seroepidemiology of adult diarrhea rotavirus in China, 1977 to 1987". J. Clin. Microbiol.27 (10): 2180–3. PMID 2479654.
^ Iizuka S, Tabara K, Kawamukai A, Itogawa H, Hoshina K (2006). "An outbreak of group C rotavirus infection in an elementary school in Shimane prefecture, Japan, February 2006". Jpn. J. Infect. Dis.59 (5): 350–1. PMID 17060710.
^ Kuzuya M, Fujii R, Hamano M, Ogura H (2003). "[Outbreak of acute gastroenteritis caused by human group C rotavirus in a youth educational center in Okayama Prefecture]" (in Japanese). Kansenshogaku Zasshi77 (2): 53–9. PMID 12661079.
^ Hamano M, Kuzuya M, Fujii R, Ogura H, Mori T, Nakayama T, Yuen E, Katayama K, Mitsunobu Y, Inoue K (1999). "Outbreak of acute gastroenteritis caused by human group C rotavirus in a primary school". Jpn. J. Infect. Dis.52 (4): 170–1. PMID 10592901.
^ Glass RI, Parashar UD, Bresee JS, et al (2006). "Rotavirus vaccines: current prospects and future challenges". Lancet368 (9532): 323–32. doi:10.1016/S0140-6736(06)68815-6. PMID 16860702.
^ O'Ryan M (2007). "Rotarix (RIX4414): an oral human rotavirus vaccine". Expert review of vaccines6 (1): 11–9. doi:10.1586/14760518.104.22.168. PMID 17280473.
^ Matson DO (2006). "The pentavalent rotavirus vaccine, RotaTeq". Seminars in paediatric infectious diseases17 (4): 195–9. doi:10.1053/j.spid.2006.08.005. PMID 17055370.