Rotavirus

Taxobox
name = Rotavirus
status =
status_ref =


image_width = 180px
image_caption = Electron micrograph of Rotaviruses. The bar = 100 nm


image2_width =
image2_caption =
virus_group = iii
familia = Reoviridae
genus = "Rotavirus"
species = "A, B, C, D, E, F & G"
baltimore Group = III
binomial_authority =
range_map_width =
range_map_caption = DiseaseDisorder infobox|right
Name = Rotaviral Gastroenteritis
ICD10 = ICD10|A|08|0|a|00
ICD9 = ICD9|008.61
ICDO =


Caption =
OMIM =
MedlinePlus = 000252
eMedicineSubj = emerg
eMedicineTopic = 401
eMedicine_mult =
DiseasesDB = 11667
MeshID = D012401|

Rotavirus is a genus of double-stranded RNA virus in the family Reoviridae. It is the leading, single cause of severe diarrhoea among infants and young children. By the age of five, nearly every child in the world has been infected with rotavirus at least once. However, with each infection, immunity develops, subsequent infections are less severe, and adults are rarely affected. There are seven species of this virus, referred to as A, B, C, D, E, F and G. Rotavirus A, the most common, causes more than 90% of infections in humans.

Rotavirus is transmitted by the faecal-oral route. It infects cells that line the small intestine and produces an enterotoxin, which induces gastroenteritis, leading to severe diarrhoea and sometimes death through dehydration. Although rotavirus was discovered in 1973 and accounts for up to 50% of hospitalisations for severe diarrhoea in infants and children, its importance is still not widely known within the public health community, particularly in developing countries. In addition to its impact on human health, rotavirus also infects animals, and is a pathogen of livestock.

More than 500,000 children under five years of age die from rotavirus infection each year, [ [http://www.who.int/wer/2007/wer8232.pdf World Health Organization. Rotavirus vaccines position paper.] ] and almost two million more become severely ill. In the United States, rotavirus causes about 2.7 million cases of severe gastroenteritis in children, almost 60,000 hospitalisations, and around 37 deaths each year. Public health campaigns to combat rotavirus focus on providing oral rehydration therapy for infected children and vaccination to prevent the disease.

History

In 1943, Jacob Light and Horace Hodes proved that a filterable agent, in the faeces of children with infectious diarrhoea, also caused scours (livestock diarrhoea) in cattle.cite journal |author=Light JS, Hodes HL |title=Studies on epidemic diarrhea of the new-born: Isolation of a Filtrable Agent Causing Diarrhea in Calves |journal=Am. J. Public Health Nations Health |volume=33 |issue=12 |pages=1451–1454 |year=1943 |pmid=18015921 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1527675] Three decades later, preserved samples of the agent were shown to be rotavirus.cite journal
author=Mebus CA, Wyatt RG, Sharpee RL, "et al"
title=Diarrhea in gnotobiotic calves caused by the reovirus-like agent of human infantile gastroenteritis
journal=Infect. Immun.
volume=14
issue=2
pages=471–4
year=1976
pmid=184047
url=http://iai.asm.org/cgi/reprint/14/2/471
format=PDF] In the intervening years, a virus in micecite journal
author=Rubenstein D, Milne RG, Buckland R, Tyrrell DA
title=The growth of the virus of epidemic diarrhoea of infant mice (EDIM) in organ cultures of intestinal epithelium
journal=British journal of experimental pathology
volume=52
issue=4
pages=442–45
year=1971
pmid=4998842 ] was shown to be related to the virus causing scours.cite journal
author=Woode GN, Bridger JC, Jones JM, Flewett TH, Davies HA, Davis HA, White GB
title=Morphological and antigenic relationships between viruses (rotaviruses) from acute gastroenteritis in children, calves, piglets, mice, and foals
journal=Infect. Immun.
volume=14
issue=3
pages=804–10
year=1976
pmid=965097
url=http://iai.asm.org/cgi/reprint/14/3/804
format=PDF] In 1973, related viruses were described by Ruth Bishop in children with gastroenteritis, in Australia.cite journal
author=Bishop RF, Davidson GP, Holmes IH, Ruck BJ
title=Virus particles in epithelial cells of duodenal mucosa from children with acute non-bacterial gastroenteritis
journal=Lancet
volume=2
issue=7841
pages=1281–3
year=1973
pmid=4127639
doi=10.1016/S0140-6736(73)92867-5 ] cite journal
author=Bishop RF, Davidson GP, Holmes IH, Ruck BJ |title=Letter: Evidence for viral gastroenteritis
journal=N. Engl. J. Med.
volume=289
issue=20
pages=1096–7
year=1973
pmid=4742237 ]

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);cite journal
author=Flewett TH, Bryden AS, Davies H, Woode GN, Bridger JC, Derrick JM
title=Relation between viruses from acute gastroenteritis of children and newborn calves
journal=Lancet
volume=2
issue=7872
pages=61–3
year=1974
pmid=4137164
doi=10.1016/S0140-6736(74)91631-6] the name was officially recognised by the International Committee on Taxonomy of Viruses four years later.cite journal
author=Matthews RE
title=Third report of the International Committee on Taxonomy of Viruses. Classification and nomenclature of viruses
journal=Intervirology
volume=12
issue=3-5
pages=129–296
year=1979
pmid=43850] In 1976, related viruses were described in several other species of animals.cite journal
author=Woode GN, Bridger JC, Jones JM, Flewett TH, Davies HA, Davis HA, White GB |title=Morphological and antigenic relationships between viruses (rotaviruses) from acute gastroenteritis of children, calves, piglets, mice, and foals
journal=Infect. Immun.
volume=14
issue=3
pages=804–10
year=1976
pmid=965097 ] These viruses, all causing acute gastroenteritis, were recognised as a collective pathogen affecting humans and animals worldwide.cite journal
author=Flewett TH, Woode GN |title=The rotaviruses
journal=Arch. Virol.
volume=57
issue=1
pages=1–23
year=1978
pmid=77663 |doi=10.1007/BF01315633 ] Rotavirus serotypes were first described in 1980,cite journal
author=Beards GM, Pilfold JN, Thouless ME, Flewett TH
title=Rotavirus serotypes by serum neutralisation
journal=J. Med. Virol.
volume=5
issue=3
pages=231–7
year=1980
pmid=6262451
doi=10.1002/jmv.1890050307 ] and in the following year, rotavirus from humans was first grown in cell cultures derived from monkey kidneys, by adding trypsin, (an enzyme found in the duodenum of mammals and is now known to be essential for rotavirus to replicate), to the culture medium. [cite journal
author=Urasawa T, Urasawa S, Taniguchi K
title=Sequential passages of human rotavirus in MA-104 cells
journal=Microbiol. Immunol.
volume=25
issue=10
pages=1025–35
year=1981
pmid=6273696 ] The ability to grow rotavirus in culture accelerated the pace of research, and by the mid-1980s the first candidate vaccines were being evaluated. [cite journal
author=Vesikari T, Isolauri E, Delem A, "et al"
title=Clinical efficacy of the RIT 4237 live attenuated bovine rotavirus vaccine in infants vaccinated before a rotavirus epidemic
journal=J. Pediatr.
volume=107
issue=2
pages=189–94
year=1985
pmid=3894608
doi=10.1016/S0022-3476(85)80123-2 ]

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 rotavirus A, and researchers had detected no statistically significant serious adverse effects.cite journal
author=
title=Rotavirus vaccine for the prevention of rotavirus gastroenteritis among children. Recommendations of the Advisory Committee on Immunization Practices (ACIP)
journal=MMWR Recomm Rep
volume=48
issue=RR-2
pages=1–20
year=1999
pmid=10219046] cite journal
author=Kapikian AZ
title=A rotavirus vaccine for prevention of severe diarrhoea of infants and young children: development, utilization and withdrawal
journal=Novartis Found. Symp.
volume=238
pages=153–71; discussion 171–9
year=2001
pmid=11444025
doi=10.1002/0470846534.ch10] The manufacturer, however, withdrew it from the market in 1999, after it was discovered that the vaccine may have contributed to an increased risk for intussusception, a type of bowel obstruction, in one of every 12,000 vaccinated infants.cite journal
author=Bines JE
title=Rotavirus vaccines and intussusception risk
journal=Curr. Opin. Gastroenterol.
volume=21
issue=1
pages=20–5
year=2005
pmid=15687880
url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0267-1379&volume=21&issue=1&spage=20] The experience provoked intense debate about the relative risks and benefits of a rotavirus vaccine.cite journal |author=Bines J |title=Intussusception and rotavirus vaccines |journal=Vaccine |volume=24 |issue=18 |pages=3772–6 |year=2006 |pmid=16099078 |doi=10.1016/j.vaccine.2005.07.031] In 2006, two new vaccines against nowrap|rotavirus A infection were shown to be safe and effective in children.cite journal
author=Dennehy PH
title=Rotavirus vaccines: an overview
journal=Clin. Microbiol. Rev.
volume=21
issue=1
pages=198–208
year=2008
pmid=18202442
doi=10.1128/CMR.00029-07
url=http://cmr.asm.org/cgi/content/full/21/1/198?view=long&pmid=18202442]

igns and symptoms

Rotavirus gastroenteritis is a mild to severe disease characterised by vomiting, watery diarrhoea, and low-grade fever. Once a child is infected by the virus, there is an incubation period of about two days before symptoms appear.cite journal
author=Hochwald C, Kivela L
title=Rotavirus vaccine, live, oral, tetravalent (RotaShield)
journal=Pediatr. Nurs.
volume=25
issue=2
pages=203–4, 207
year=1999
pmid=10532018] Symptoms often start with vomiting followed by four to eight days of profuse diarrhoea. Dehydration is more common in rotavirus infection than in most of those caused by bacterial pathogens, and is the most common cause of death related to rotavirus infection.cite journal
author=Maldonado YA, Yolken RH
title=Rotavirus
journal=Baillieres Clin. Gastroenterol.
volume=4
issue=3
pages=609–25
year=1990
pmid=1962726
doi=10.1016/0950-3528(90)90052-I ]

Rotavirus A infections can occur throughout life: the first usually produces symptoms, but subsequent infections are typically asymptomatic,cite journal
author=Bishop RF
title=Natural history of human rotavirus infection
journal=Arch. Virol. Suppl.
volume=12
issue=
pages=119–28
year=1996
pmid=9015109] as the immune system provides some protection.cite journal
author=Velázquez FR, Matson DO, Calva JJ, Guerrero L, Morrow AL, Carter-Campbell S, Glass RI, Estes MK, Pickering LK, Ruiz-Palacios GM
title=Rotavirus infections in infants as protection against subsequent infections
journal=N. Engl. J. Med.
volume=335
issue=14
pages=1022–8
year=1996
pmid=8793926
url=http://content.nejm.org/cgi/content/full/335/14/1022
doi=10.1056/NEJM199610033351404] Consequently, symptomatic infection rates are highest in children under two years of age and decrease progressively towards 45 years of age.cite journal
author=Bernstein DI, Sander DS, Smith VE, Schiff GM, Ward RL
title=Protection from rotavirus reinfection: 2-year prospective study
journal=J. Infect. Dis.
volume=164
issue=2
pages=277–83
year=1991
pmid=1649875] cite journal
author=Koopman JS, Monto AS
title=The Tecumseh Study. XV: Rotavirus infection and pathogenicity
journal=Am. J. Epidemiol.
volume=130
issue=4
pages=750–9
year=1989
pmid=2549788] Infection in newborn children, although common, is often associated with mild or asymptomatic disease;cite journal
author=Cameron DJ, Bishop RF, Veenstra AA, Barnes GL
title=Noncultivable viruses and neonatal diarrhea: Fifteen-month survey in a newborn special care nursery
journal=J. Clin. Microbiol.
volume=8
issue=1
pages=93–8
year=1978
pmid=209058
url=http://jcm.asm.org/cgi/reprint/8/1/93
format=PDF] cite journal
author=Grillner L, Broberger U, Chrystie I, Ransjö U
title=Rotavirus infections in newborns: an epidemiological and clinical study
journal=Scand. J. Infect. Dis.
volume=17
issue=4
pages=349–55
year=1985
pmid=3003889] the most severe symptoms tend to occur in children six months to two years of age, the elderly, and those with compromised or absent immune system functions. Due to immunity acquired in childhood, most adults are not susceptible to rotavirus; gastroenteritis in adults usually has a cause other than rotavirus, but asymptomatic infections in adults may maintain the transmission of infection in the community.cite journal
author=Hrdy DB
title=Epidemiology of rotaviral infection in adults
journal=Rev. Infect. Dis.
volume=9
issue=3
pages=461–9
year=1987
pmid=3037675] Symptomatic reinfections are often due to a different rotavirus A serotype.cite journal
author=Linhares AC, Gabbay YB, Mascarenhas JD, Freitas RB, Flewett TH, Beards GM
title=Epidemiology of rotavirus subgroups and serotypes in Belem, Brazil: a three-year study
journal=Ann. Inst. Pasteur Virol.
volume=139
issue=1
pages=89–99
year=1988
pmid=2849961
doi=10.1016/S0769-2617(88)80009-1] cite journal
author=De Champs C, Laveran H, Peigue-Lafeuille H, "et al"
title=Sequential rotavirus infections: characterization of serotypes and electrophoretypes
journal=Res. Virol.
volume=142
issue=1
pages=39–45
year=1991
pmid=1647052
doi=10.1016/0923-2516(91)90026-Y]

Transmission

Rotavirus is transmitted by the faecal-oral route, via contact with contaminated hands, surfaces and objects,cite journal
author=Butz AM, Fosarelli P, Dick J, Cusack T, Yolken R
title=Prevalence of rotavirus on high-risk fomites in day-care facilities
journal=Pediatrics
volume=92
issue=2
pages=202–5
year=1993
pmid=8393172] and possibly by the respiratory route.cite journal
author=Dennehy PH
title=Transmission of rotavirus and other enteric pathogens in the home
journal=Pediatr. Infect. Dis. J.
volume=19
issue=10 Suppl
pages=S103–5
year=2000
pmid=11052397
doi=10.1097/00006454-200010001-00003] The faeces of an infected person can contain more than 10 trillion infectious particles per gram;cite journal
author=Bishop RF
title=Natural history of human rotavirus infection
journal=Arch. Virol. Suppl.
volume=12
issue=
pages=119–28
year=1996
pmid=9015109] only 10–100 of these are required to transmit infection to another person.cite journal
author=Graham DY, Dufour GR, Estes MK
title=Minimal infective dose of rotavirus
journal=Arch. Virol.
volume=92
issue=3–4
pages=261–71
year=1987
pmid=3028333
doi=10.1007/BF01317483]

Rotaviruses are stable in the environment and have been found in estuary samples at levels as high as 1–5 infectious particles per US gallon.cite journal |author=Rao VC, Seidel KM, Goyal SM, Metcalf TG, Melnick JL |title=Isolation of enteroviruses from water, suspended solids, and sediments from Galveston Bay: survival of poliovirus and rotavirus adsorbed to sediments |journal=Appl. Environ. Microbiol. |volume=48 |issue=2 |pages=404–9 |year=1984 |pmid=6091548 |url=http://aem.asm.org/cgi/reprint/48/2/404 |format=PDF] Sanitary measures adequate for eliminating bacteria and parasites seem to be ineffective in control of rotavirus, as the incidence of rotavirus infection in countries with high and low health standards is similar.cite journal |author=Dennehy PH |title=Transmission of rotavirus and other enteric pathogens in the home |journal=Pediatr. Infect. Dis. J. |volume=19 |issue=10 Suppl |pages=S103–5 |year=2000 |pmid=11052397 |doi=10.1097/00006454-200010001-00003]

Disease mechanisms

The diarrhoea is caused by multiple activities of the virus. Malabsorption occurs because of the destruction of gut cells called enterocytes. The toxic rotavirus protein NSP4 induces age- and calcium ion-dependent chloride secretion, disrupts SGLT1 transporter-mediated reabsorption of water, apparently reduces activity of brush-border membrane disaccharidases, and possibly activates the calcium ion-dependent secretory reflexes of the enteric nervous system.cite journal
author=Ball JM, Mitchell DM, Gibbons TF, Parr RD
title=Rotavirus NSP4: a multifunctional viral enterotoxin
journal=Viral Immunol.
volume=18
issue=1
pages=27–40
year=2005
pmid=15802952
doi=10.1089/vim.2005.18.27] cite journal
author=Lorrot M, Vasseur M
title=How do the rotavirus NSP4 and bacterial enterotoxins lead differently to diarrhea?
journal=Virol. J.
volume=4
issue=
pages=31
year=2007
pmid=17376232
doi=10.1186/1743-422X-4-31
url=http://www.virologyj.com/content/4/1/31] Healthy enterocytes secrete lactase into the small intestine; milk intolerance due to lactase deficiency is a particular symptom of rotavirus infection,cite journal
author=Jourdan N, Brunet JP, Sapin C, "et al"
title=Rotavirus infection reduces sucrase-isomaltase expression in human intestinal epithelial cells by perturbing protein targeting and organization of microvillar cytoskeleton
journal=J. Virol.
volume=72
issue=9
pages=7228–36
year=1998
pmid=9696817
url=http://jvi.asm.org/cgi/content/full/72/9/7228] cite journal
author=Davidson GP, Barnes GL
title=Structural and functional abnormalities of the small intestine in infants and young children with rotavirus enteritis
journal=Acta. Paediatr. Scand.
volume=68
issue=2
pages=181–6
year=1979
pmid=217231
doi=10.1111/j.1651-2227.1979.tb04986.x] which can persist for weeks.cite journal
author=Ouwehand A, Vesterlund S
title=Health aspects of probiotics
journal=IDrugs
volume=6
issue=6
pages=573–80
year=2003
pmid=12811680] 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.cite journal
author=Arya SC
title=Rotaviral infection and intestinal lactase level
journal=J. Infect. Dis.
volume=150
issue=5
pages=791
year=1984
pmid=6436397]

Diagnosis and detection

Diagnosis of infection with rotavirus normally follows diagnosis of gastroenteritis as the cause of severe diarrhoea. Most children admitted to hospital with gastroenteritis are tested for nowrap|rotavirus A.cite journal |author=Patel MM, Tate JE, Selvarangan R, "et al" |title=Routine laboratory testing data for surveillance of rotavirus hospitalizations to evaluate the impact of vaccination |journal=Pediatr. Infect. Dis. J. |volume=26 |issue=10 |pages=914–9 |year=2007 |pmid=17901797 |] cite journal |author=The Pediatric ROTavirus European CommitTee (PROTECT) |title=The paediatric burden of rotavirus disease in Europe |journal=Epidemiol. Infect. |volume=134 |issue=5 |pages=908–16 |year=2006 |pmid=16650331 |doi=10.1017/S0950268806006091] Specific diagnosis of infection with nowrap|rotavirus A is made by identification of the virus in the patient's stool by enzyme immunoassay. There are several licensed test kits on the market which are sensitive, specific and detect all serotypes of nowrap|rotavirus A.cite journal
author=Smith TF, Wold AD, Espy MJ, Marshall WF
title=New developments in the diagnosis of viral diseases
journal=Infect. Dis. Clin. North Am.
volume=7
issue=2
pages=183–201
year=1993
pmid=8345165] Other methods, electron microscopy and polyacrylamide gel electrophoresis, are used in research laboratories.cite journal |author=Beards GM |title=Laboratory diagnosis of viral gastroenteritis |journal=Eur. J. Clin. Microbiol. Infect. Dis. |volume=7 |issue=1 |pages=11–3 |year=1988 |pmid=3132369 |doi=10.1007/BF01962164] Reverse transcription-polymerase chain reaction (RT-PCR) can detect and identify all species and serotypes of human rotavirus.cite journal |author=Fischer TK, Gentsch JR |title=Rotavirus typing methods and algorithms |journal=Rev. Med. Virol. |volume=14 |issue=2 |pages=71–82 |year=2004 |pmid=15027000 |doi=10.1002/rmv.411]

Treatment and prognosis

Treatment of acute rotavirus infection is nonspecific and involves management of symptoms and, most importantly, maintenance of hydration.cite journal
author=Diggle L
title=Rotavirus diarrhoea and future prospects for prevention
journal=Br. J. Nurs.
volume=16
issue=16
pages=970–4
year=2007
pmid=18026034] If untreated, children can die from the resulting severe dehydration.cite journal
author=Alam NH, Ashraf H
title=Treatment of infectious diarrhea in children
journal=Paediatr. Drugs
volume=5
issue=3
pages=151–65
year=2003
pmid=12608880] Depending on the severity of diarrhoea, treatment consists of oral rehydration with plain water, water plus salts, or water plus salts and sugar.cite journal |author=Sachdev HP |title=Oral rehydration therapy |journal=Journal of the Indian Medical Association |volume=94 |issue=8 |pages=298–305 |year=1996 |pmid=8855579] Some infections are serious enough to warrant hospitalisation where fluids are given by intravenous drip or nasogastric tube, and the child's electrolytes and blood sugar are monitored.cite journal |author=Patel MM, Tate JE, Selvarangan R, Daskalaki I, Jackson MA, Curns AT, Coffin S, Watson B, Hodinka R, Glass RI, Parashar UD |title=Routine laboratory testing data for surveillance of rotavirus hospitalizations to evaluate the impact of vaccination |journal=Pediatr. Infect. Dis. J. |volume=26 |issue=10 |pages=914–9 |year=2007 |pmid=17901797 |doi=10.1097/INF.0b013e31812e52fd |doi_brokendate=2008-06-26]

Rotavirus infections rarely cause other complications and for a well managed child the prognosis is excellent.cite journal
author=Haffejee IE
title=The pathophysiology, clinical features and management of rotavirus diarrhoea
journal=Q. J. Med.
volume=79
issue=288
pages=289–99
year=1991
pmid=1649479
url=http://qjmed.oxfordjournals.org/cgi/reprint/79/1/289] cite journal |author=Ramig RF |title=Systemic rotavirus infection |journal=Expert review of anti-infective therapy |volume=5 |issue=4 |pages=591–612 |year=2007 |pmid=17678424 |doi=10.1586/14787210.5.4.591] There are rare 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,cite journal |author=Goto T, Kimura H, Numazaki K, "et al" |title=A case of meningoencephalitis associated with G1P [8] rotavirus infection in a Japanese child |journal=Scand. J. Infect. Dis. |volume=39 |issue=11 |pages=1067–70 |year=2007 |pmid=17852929 |doi=10.1080/00365540701466249] cite journal |author=Kehle J, Metzger-Boddien C, Tewald F, Wald M, Schüürmann J, Enders G |title=First case of confirmed rotavirus meningoencephalitis in Germany |journal=Pediatr. Infect. Dis. J. |volume=22 |issue=5 |pages=468–70 |year=2003 |pmid=12797316 |doi=10.1097/00006454-200305000-00020] cite journal |author=Pager C, Steele D, Gwamanda P, Driessen M |title=A neonatal death associated with rotavirus infection—detection of rotavirus dsRNA in the cerebrospinal fluid |journal=S. Afr. Med. J. |volume=90 |issue=4 |pages=364–5 |year=2000 |pmid=10957919] and recent studies have confirmed that rotavirus infection is not always confined to the gut, but can cause viremia.cite journal
author=Widdowson MA, Bresee JS, Gentsch JR, Glass RI
title=Rotavirus disease and its prevention
journal=Curr. Opin. Gastroenterol.
volume=21
issue=1
pages=26–31
year=2005
pmid=15687881
url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0267-1379&volume=21&issue=1&spage=26]

Epidemiology

Rotavirus A, which accounts for more than 90% of rotavirus gastroenteritis in humans,cite journal
author=Leung AK, Kellner JD, Davies HD
title=Rotavirus gastroenteritis
journal=Adv. Ther.
volume=22
issue=5
pages=476–87
year=2005
pmid=16418157
doi=10.1007/BF02849868] is endemic worldwide. Each year rotavirus causes millions of cases of diarrhoea in developing countries, almost 2 million resulting in hospitalisation and an estimated 611,000 resulting in death.cite journal
author=Parashar UD, Gibson CJ, Bresse JS, Glass RI
title=Rotavirus and severe childhood diarrhea
journal=Emerging Infect. Dis.
volume=12
issue=2
pages=304–6
year=2006
pmid=16494759] In the United States alone, over 2.7 million cases of rotavirus gastroenteritis occur annually, 60,000 children are hospitalised and around 37 die from the results of the infection.cite journal |author=Fischer TK, Viboud C, Parashar U, "et al" |title=Hospitalizations and deaths from diarrhea and rotavirus among children <5 years of age in the United States, 1993–2003 |journal=J. Infect. Dis. |volume=195 |issue=8 |pages=1117–25 |year=2007 |pmid=17357047 |doi=10.1086/512863] The major role of rotavirus in causing diarrhoea is not widely recognised within the public health community, particularly in developing countries.cite journal
author=Simpson E, Wittet S, Bonilla J, Gamazina K, Cooley L, Winkler JL
title=Use of formative research in developing a knowledge translation approach to rotavirus vaccine introduction in developing countries
journal=BMC Public Health
volume=7
issue=
pages=281
year=2007
pmid=17919334
doi=10.1186/1471-2458-7-281
url=http://www.biomedcentral.com/1471-2458/7/281] Almost every child has been infected with rotavirus by age five. 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.cite journal
author=Simpson E, Wittet S, Bonilla J, Gamazina K, Cooley L, Winkler JL
title=Use of formative research in developing a knowledge translation approach to Rotavirus vaccine introduction in developing countries
journal=BMC Public Health
volume=7
issue=1
pages=281
year=2007
pmid=17919334
doi=10.1186/1471-2458-7-281
url=http://www.biomedcentral.com/1471-2458/7/281] Boys are twice as likely to be admitted to hospital as girls.cite journal |author=Rheingans RD, Heylen J, Giaquinto C |title=Economics of rotavirus gastroenteritis and vaccination in Europe: what makes sense? |journal=Pediatr. Infect. Dis. J. |volume=25 |issue=1 Suppl |pages=S48–55 |year=2006 |pmid=16397429 |doi=10.1097/01.inf.0000197566.47750.3d] cite journal |author=Ryan MJ, Ramsay M, Brown D, Gay NJ, Farrington CP, Wall PG |title=Hospital admissions attributable to rotavirus infection in England and Wales |journal=J. Infect. Dis. |volume=174 Suppl 1 |pages=S12–8 |year=1996 |pmid=8752285] In temperate areas, rotavirus infections occur primarily in the winter, but in the tropics they occur throughout the year;cite journal
author=Cook SM, Glass RI, LeBaron CW, Ho MS
title=Global seasonality of rotavirus infections
journal=Bull. World Health Organ.
volume=68
issue=2
pages=171–7
year=1990
pmid=1694734] the difference is partly explained by seasonal changes in temperature and humidity.cite journal
author=Moe K, Harper GJ
title=The effect of relative humidity and temperature on the survival of bovine rotavirus in aerosol
journal=Arch. Virol.
volume=76
issue=3
pages=211–6
year=1983
pmid=6307226
doi=10.1007/BF01311105] cite journal
author=Moe K, Shirley JA
title=The effects of relative humidity and temperature on the survival of human rotavirus in faeces
journal=Arch. Virol.
volume=72
issue=3
pages=179–86
year=1982
pmid=6287970
doi=10.1007/BF01348963] The number attributable to food contamination is unknown.cite journal |author=Koopmans M, Brown D |title=Seasonality and diversity of Group A rotaviruses in Europe |journal=Acta paediatrica (Oslo, Norway : 1992). Supplement |volume=88 |issue=426 |pages=14–9 |year=1999 |pmid=10088906 |doi=10.1111/j.1651-2227.1999.tb14320.x]

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.cite journal |author=Hopkins RS, Gaspard GB, Williams FP, Karlin RJ, Cukor G, Blacklow NR |title=A community waterborne gastroenteritis outbreak: evidence for rotavirus as the agent |journal=American Journal of Public Health |volume=74 |issue=3 |pages=263–5 |year=1984 |pmid=6320684 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6320684] 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.cite journal |author=Bucardo F, Karlsson B, Nordgren J, "et al" |title=Mutated G4P [8] rotavirus associated with a nationwide outbreak of gastroenteritis in Nicaragua in 2005 |journal=J. Clin. Microbiol. |volume=45 |issue=3 |pages=990–7 |year=2007 |pmid=17229854 |doi=10.1128/JCM.01992-06 |url=http://jcm.asm.org/cgi/content/full/45/3/990] A similar large outbreak occurred in Brazil in 1977.cite journal |author=Linhares AC, Pinheiro FP, Freitas RB, Gabbay YB, Shirley JA, Beards GM |title=An outbreak of rotavirus diarrhea among a non-immune, isolated South American Indian community |journal=Am. J. Epidemiol. |volume=113 |issue=6 |pages=703–10 |year=1981 |pmid=6263087]

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.cite journal |author=Hung T, Chen GM, Wang CG, "et al" |title=Waterborne outbreak of rotavirus diarrhea in adults in China caused by a novel rotavirus |journal=Lancet |volume=1 |issue=8387 |pages=1139–42 |year=1984 |pmid=6144874] cite journal |author=Fang ZY, Ye Q, Ho MS, "et al" |title=Investigation of an outbreak of adult diarrhea rotavirus in China |journal=J. Infect. Dis. |volume=160 |issue=6 |pages=948–53 |year=1989 |pmid=2555422] Rotavirus B infections also occurred in India in 1998; the causative strain was named CAL. Unlike ADRV, the CAL strain is endemic.cite journal |author=Kelkar SD, Zade JK |title=Group B rotaviruses similar to strain CAL-1, have been circulating in Western India since 1993 |journal=Epidemiol. Infect. |volume=132 |issue=4 |pages=745–9 |year=2004 |pmid=15310177 |doi=10.1017/S0950268804002171] cite journal |author=Ahmed MU, Kobayashi N, Wakuda M, Sanekata T, Taniguchi K, Kader A, Naik TN, Ishino M, Alam MM, Kojima K, Mise K, Sumi A |title=Genetic analysis of group B human rotaviruses detected in Bangladesh in 2000 and 2001 |journal=J. Med. Virol. |volume=72 |issue=1 |pages=149–55 |year=2004 |pmid=14635024 |doi=10.1002/jmv.10546] To date, epidemics caused by rotavirus B have been confined to mainland China, but surveys indicate a lack of immunity to this species in the United States.cite journal |author=Penaranda ME, Ho MS, Fang ZY, "et al" |title=Seroepidemiology of adult diarrhea rotavirus in China, 1977 to 1987 |journal=J. Clin. Microbiol. |volume=27 |issue=10 |pages=2180–3 |year=1989 |pmid=2479654 |url=http://jcm.asm.org/cgi/reprint/27/10/2180 |format=PDF]

Rotavirus C has been associated with rare and sporadic cases of diarrhoea in children in many countries, and outbreaks have occurred in Japan and England.cite journal |author=Kuzuya M, Fujii R, Hamano M, Nishijima M, Ogura H |title=Detection and molecular characterization of human group C rotaviruses in Okayama Prefecture, Japan, between 1986 and 2005 |journal=J. Med. Virol. |volume=79 |issue=8 |pages=1219–28 |year=2007 |pmid=17596825 |doi=10.1002/jmv.20910] cite journal |author=Brown DW, Campbell L, Tomkins DS, Hambling MH |title=School outbreak of gastroenteritis due to atypical rotavirus |journal=Lancet |volume=2 |issue=8665 |pages=737–8 |year=1989 |pmid=2570978 |doi=10.1016/S0140-6736(89)90794-0]

Prevention

In 2006, two vaccines against Rotavirus A infection were shown to be safe and effective in children: Rotarix by GlaxoSmithKlinecite journal |author=O'Ryan M |title=Rotarix (RIX4414): an oral human rotavirus vaccine |journal=Expert review of vaccines |volume=6 |issue=1 |pages=11–9 |year=2007 |pmid=17280473 |doi=10.1586/14760584.6.1.11] and RotaTeq by Merck.cite journal |author=Matson DO |title=The pentavalent rotavirus vaccine, RotaTeq |journal=Seminars in paediatric infectious diseases |volume=17 |issue=4 |pages=195–9 |year=2006 |pmid=17055370 |doi=10.1053/j.spid.2006.08.005] Both are taken orally and contain disabled live virus. Rotavirus vaccines are available in Australia, [cite press release|url=http://www.gsk.com.au/media-centre_detail.aspx?view=54|title=Rotarix vaccine launched in Australia |publisher=GlaxoSmithKline|date=2006-05-14|accessdate=2008-08-18] Europe, Canada, [cite press release|url= http://www.merckfrosst.ca/assets/en/pdf/press/product_info/rotateq/press_releases/Release_NATIONAL_CNW.pdf|title=RotaTeq Is Approved In Canada|publisher=Merck Frosst Canada|date=2006-08-23|accessdate=2008-08-18] Brazil, [cite press release|url= http://portalweb05.saude.gov.br/portal/aplicacoes/noticias/noticias_detalhe.cfm?co_seq_noticia=24336|title=Rotavírus: vacina começa a ser aplicada no SUS|publisher=Ministério da Saúde|date=2006-06-03|accessdate=2008-08-18] Israel, South Africa, [cite journal|url=http://www.safpj.co.za/index.php/safpj/article/viewFile/616/548|title=The Introduction of Rotavirus Vaccines in South Africa|publisher=National Center for Communicable Disease, Johannesburg, South Africa|year=2006] Panama, Argentina and the United States. [cite journal |author=Tom-Revzon C |title=Rotavirus live, oral, pentavalent vaccine |journal=Clin. Ther. |volume=29 |issue=12 |pages=2724–37 |year=2007 |pmid=18201590 |doi=10.1016/j.clinthera.2007.12.018]

The Rotavirus Vaccine Program is a collaboration between PATH, the World Health Organization, and the U.S. Centers for Disease Control and Prevention, and is funded by the GAVI Alliance. The Program aims to reduce child morbidity and mortality from diarrhoeal disease by making a vaccine against rotavirus available for use in developing countries. [ [http://www.path.org/projects/rvp.php "Accelerating access to rotavirus vaccines" PATH, access date July 22 2008] ]

Infections of animals

Rotaviruses infect and cause diarrhoea in young animals. They have been shown to infect mammals (for example, apes,cite journal |author=Ashley CR, Caul EO, Clarke SK, Corner BD, Dunn S |title=Rotavirus infections of apes |journal=Lancet |volume=2 |issue=8087 |pages=477 |year=1978 |pmid=79844 |doi=10.1016/S0140-6736(78)91485-X] cattle,cite journal |author=Wani SA, Bhat MA, Ishaq SM, Ashrafi MA |title=Determination of bovine rotavirus G genotypes in Kashmir, India |journal=Rev. - Off. Int. Epizoot. |volume=23 |issue=3 |pages=931–6 |year=2004 |pmid=15861888] pigs,cite journal |author=Saif LJ |title=Enteric viral infections of pigs and strategies for induction of mucosal immunity |journal=Advances in veterinary medicine |volume=41 |pages=429–46 |year=1999 |pmid=9890034 |doi=10.1016/S0065-3519(99)80033-0] sheep,cite journal |author=Holland RE |title=Some infectious causes of diarrhea in young farm animals |journal=Clin. Microbiol. Rev. |volume=3 |issue=4 |pages=345–75 |year=1990 |pmid=2224836|url=http://cmr.asm.org/cgi/reprint/3/4/345 |format=PDF] rats,cite journal |author=Pérez-Cano FJ, Castell M, Castellote C, Franch A |title=Characterization of Clinical and Immune Response in a Rotavirus Diarrhea Model in Suckling Lewis Rats |journal=Pediatr Res |year=2007 |pmid=17957154 |doi=] cats and dogs,cite journal |author=Enriquez C, Nwachuku N, Gerba CP |title=Direct exposure to animal enteric pathogens |journal=Reviews on environmental health |volume=16 |issue=2 |pages=117–31 |year=2001 |pmid=11512628] mice,cite journal |author=Feng N, Franco MA, Greenberg HB |title=Murine model of rotavirus infection |journal=Adv. Exp. Med. Biol. |volume=412 |pages=233–40 |year=1997 |pmid=9192019] horses,cite journal |author=Hardy ME, Woode GN, Xu ZC, "et al" |title=Analysis of serotypes and electropherotypes of equine rotaviruses isolated in the United States |journal=J. Clin. Microbiol. |volume=29 |issue=5 |pages=889–93 |year=1991 |month=May |pmid=1647407 |pmc=269902 |doi= |url=http://jcm.asm.org/cgi/reprint/29/5/889?view=long&pmid=1647407] rabbits)cite journal |author=Thouless ME, DiGiacomo RF, Deeb BJ, Howard H |title=Pathogenicity of rotavirus in rabbits |journal=J. Clin. Microbiol. |volume=26 |issue=5 |pages=943–7 |year=1988 |pmid=2838507 |url=http://jcm.asm.org/cgi/reprint/26/5/943 |format=PDF] and birds (chickens and turkeys).cite journal |author=Guy JS |title=Virus infections of the gastrointestinal tract of poultry |journal=Poult. Sci. |volume=77 |issue=8 |pages=1166–75 |year=1998 |pmid=9706084|url=http://ps.fass.org/cgi/reprint/77/8/1166 | format=PDF] 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.cite journal |author=Müller H, Johne R |title=Rotaviruses: diversity and zoonotic potential—a brief review |journal=Berl. Munch. Tierarztl. Wochenschr. |volume=120 |issue=3–4 |pages=108–12 |year=2007 |pmid=17416132] cite journal |author=Cook N, Bridger J, Kendall K, Gomara MI, El-Attar L, Gray J |title=The zoonotic potential of rotavirus |journal=J. Infect. |volume=48 |issue=4 |pages=289–302 |year=2004 |pmid=15066329 |doi=10.1016/j.jinf.2004.01.018] Rotavirus are a pathogen of livestock and cause economic loss to farmers because of costs of treatment associated with high morbidity and mortality rates.cite journal |author=Holland RE |title=Some infectious causes of diarrhea in young farm animals |journal=Clin. Microbiol. Rev. |volume=3 |issue=4 |pages=345–75 |year=1990 |pmid=2224836]

Virology

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 other animals.cite journal |author=Beards GM, Brown DW |title=The antigenic diversity of rotaviruses: Significance to epidemiology and vaccine strategies |journal=Eur. J. Epidemiol. |volume=4 |issue=1 |pages=1–11 |year=1988 |pmid=2833405 |doi=10.1007/BF00152685]

Within rotavirus A there are different strains, called serotypes.cite journal |author=Santos N, Hoshino Y |title=Global distribution of rotavirus serotypes/genotypes and its implication for the development and implementation of an effective rotavirus vaccine |journal=Rev. Med. Virol. |volume=15 |issue=1 |pages=29–56 |year=2005 |pmid=15484186 |doi=10.1002/rmv.448] 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 (see below for details on these proteins). The P-type is indicated by a number for the P-serotype and by a number in square brackets for the corresponding P-genotype. G-serotypes are similarly numbered but the G-genotype number is the same as the G-serotype. For example, the rotavirus strain Wa is defined as P1A [8] G1.cite journal |author=Desselberger U, Iturriza-Gómara M, Gray JJ |title=Rotavirus epidemiology and surveillance |journal=Novartis Found. Symp. |volume=238 |pages=125–47; discussion 147–52 |year=2001 |pmid=11444024 |doi=10.1002/0470846534.ch9] 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.cite journal
author=Desselberger U, Wolleswinkel-van den Bosch J, Mrukowicz J, Rodrigo C, Giaquinto C, Vesikari T
title=Rotavirus types in Europe and their significance for vaccination
journal=Pediatr. Infect. Dis. J.
volume=25
issue=1 Suppl.
pages=S30–41
year=2006
pmid=16397427
url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00006454-200601001-00005
doi=10.1097/01.inf.0000197707.70835.f3]

tructure

The genome 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.cite journal |author=Chan WK, Penaranda ME, Crawford SE, Estes MK |title=Two glycoproteins are produced from the rotavirus neutralization gene |journal=Virology |volume=151 |issue=2 |pages=243–52 |year=1986 |pmid=3010552 |doi=10.1016/0042-6822(86)90046-2] The RNA is surrounded by a three-layered icosahedral protein capsid. Viral particles are up to 76.5 nm in diametercite journal |author=Pesavento JB, Crawford SE, Estes MK, Prasad BV |title=Rotavirus proteins: structure and assembly |journal=Curr. Top. Microbiol. Immunol. |volume=309 |pages=189–219 |year=2006 |pmid=16913048 |doi=10.1007/3-540-30773-7_7] cite journal |author=Prasad BV, Chiu W |title=Structure of rotavirus |journal=Curr. Top. Microbiol. Immunol. |volume=185 |pages=9–29 |year=1994 |pmid=8050286] 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.cite journal
author=Patton JT
title=Structure and function of the rotavirus RNA-binding proteins
journal=J. Gen. Virol.
volume=76 (Pt 11)
pages=2633–44
year=1995
pmid=7595370
url=http://vir.sgmjournals.org/cgi/reprint/76/11/2633
format=PDF
doi=10.1099/0022-1317-76-11-2633] 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.cite journal
author=Patton JT
title=Rotavirus RNA replication and gene expression
journal=Novartis Found. Symp.
volume=238
pages=64–77; discussion 77–81
year=2001
pmid=11444036
doi=10.1002/0470846534.ch5]

tructural proteins

VP1 is located in the core of the virus particle and is an RNA polymerase enzyme.cite journal |author=Vásquez-del Carpió R, Morales JL, Barro M, Ricardo A, Spencer E |title=Bioinformatic prediction of polymerase elements in the rotavirus VP1 protein |journal=Biol. Res. |volume=39 |issue=4 |pages=649–59 |year=2006 |pmid=17657346 |doi= |url=http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602006000500008&tlng=en&lng=en&nrm=iso ] 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.
[

Electron micrograph of gold nanoparticles attached to rotavirus. The small dark circular objects are gold nanoparticles coated with a monoclonal antibody specific for rotavirus protein VP6.]

VP2 forms the core layer of the virion and binds the RNA genome.cite journal |author=Arnoldi F, Campagna M, Eichwald C, Desselberger U, Burrone OR |title=Interaction of rotavirus polymerase VP1 with nonstructural protein NSP5 is stronger than that with NSP2 |journal=J. Virol. |volume=81 |issue=5 |pages=2128–37 |year=2007 |pmid=17182692 |doi=10.1128/JVI.01494-06 |url=http://jvi.asm.org/cgi/content/full/81/5/2128]

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. [cite journal |author=Fresco LD, Buratowski S |title=Active site of the mRNA-capping enzyme guanylyltransferase from Saccharomyces cerevisiae: similarity to the nucleotidyl attachment motif of DNA and RNA ligases |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue=14 |pages=6624–8 |year=1994 |pmid=8022828 |url=http://www.pnas.org/content/91/14/6624.full.pdf+html |format=PDF |doi=10.1073/pnas.91.14.6624] 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.cite journal |author=Gardet A, Breton M, Fontanges P, Trugnan G, Chwetzoff S |title=Rotavirus spike protein VP4 binds to and remodels actin bundles of the epithelial brush border into actin bodies |journal=J. Virol. |volume=80 |issue=8 |pages=3947–56 |year=2006 |pmid=16571811 |doi=10.1128/JVI.80.8.3947-3956.2006 |url=http://jvi.asm.org/cgi/content/full/80/8/3947] It binds to molecules on the surface of cells called receptors and drives the entry of the virus into the cell.cite journal |author=Arias CF, Isa P, Guerrero CA, Méndez E, Zárate S, López T, Espinosa R, Romero P, López S |title=Molecular biology of rotavirus cell entry |journal=Arch. Med. Res. |volume=33 |issue=4 |pages=356–61 |year=2002 |pmid=12234525 |doi=10.1016/S0188-4409(02)00374-0] VP4 has to be modified by a protease enzyme (found in the gut) into VP5* and VP8* before the virus is infectious.cite journal |author=Konno T, Suzuki H, Kitaoka S, Sato T, Fukuhara N, Yoshie O, Fukudome K, Numazaki Y |title=Proteolytic enhancement of human rotavirus infectivity |journal=Clin. Infect. Dis. |volume=16 Suppl 2 |pages=S92–7 |year=1993 |pmid=8384014] It determines how virulent the virus is and it determines the P-type of the virus.cite journal |author=Hoshino Y, Jones RW, Kapikian AZ |title=Characterization of neutralization specificities of outer capsid spike protein VP4 of selected murine, lapine, and human rotavirus strains |journal=Virology |volume=299 |issue=1 |pages=64–71 |year=2002 |pmid=12167342 |doi=10.1006/viro.2002.1474]

VP6 forms the bulk of the capsid. It is highly antigenic and can be used to identify rotavirus species.cite journal |author=Bishop RF |title=Natural history of human rotavirus infection |journal=Arch. Virol. Suppl. |volume=12 |pages=119–28 |year=1996 |pmid=9015109] This protein is used in laboratory tests for rotavirus A infections.cite journal |author=Beards GM, Campbell AD, Cottrell NR, Peiris JS, Rees N, Sanders RC, Shirley JA, Wood HC, Flewett TH |title=Enzyme-linked immunosorbent assays based on polyclonal and monoclonal antibodies for rotavirus detection |journal=J. Clin. Microbiol. |volume=19 |issue=2 |pages=248–54 |year=1984 |pmid=6321549 |url=http://jcm.asm.org/cgi/reprint/19/2/248 |format=PDF]

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.cite journal |author=Pesavento JB, Crawford SE, Estes MK, Prasad BV |title=Rotavirus proteins: structure and assembly |journal=Curr. Top. Microbiol. Immunol. |volume=309 |pages=189–219 |year=2006 |pmid=16913048 |doi=10.1007/3-540-30773-7_7]

Nonstructural viral proteins

NSP1, the product of gene 5, is a nonstructural RNA-binding protein. [cite journal |author=Hua J, Mansell EA, Patton JT |title=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 |journal=Virology |volume=196 |issue=1 |pages=372–8 |year=1993 |pmid=8395125 |doi=10.1006/viro.1993.1492]

NSP2 is an RNA-binding protein that accumulates in cytoplasmic inclusions (viroplasms) and is required for genome replication. [cite journal |author=Kattoura MD, Chen X, Patton JT |title=The rotavirus RNA-binding protein NS35 (NSP2) forms 10S multimers and interacts with the viral RNA polymerase |journal=Virology |volume=202 |issue=2 |pages=803–13 |year=1994 |pmid=8030243 |doi=10.1006/viro.1994.1402] cite journal |author=Taraporewala ZF, Patton JT |title=Nonstructural proteins involved in genome packaging and replication of rotaviruses and other members of the Reoviridae |journal=Virus Res. |volume=101 |issue=1 |pages=57–66 |year=2004 |pmid=15010217 |doi=10.1016/j.virusres.2003.12.006]

NSP3 is bound to viral mRNAs in infected cells and it is responsible for the shutdown of cellular protein synthesis. [cite journal |author=Poncet D, Aponte C, Cohen J |title=Rotavirus protein NSP3 (NS34) is bound to the 3' end consensus sequence of viral mRNAs in infected cells
journal=J. Virol. |volume=67 |issue=6 |pages=3159–65 |year=1993 |pmid=8388495 |url=http://jvi.asm.org/cgi/reprint/67/6/3159 |format=PDF]

NSP4 is a viral enterotoxin to induce diarrhoea and was the first viral enterotoxin discovered.cite journal |author=Dong Y, Zeng CQ, Ball JM, Estes MK, Morris AP |title=The rotavirus enterotoxin NSP4 mobilizes intracellular calcium in human intestinal cells by stimulating phospholipase C-mediated inositol 1,4,5-trisphosphate production |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue=8 |pages=3960–5 |year=1997 |pmid=9108087 |url=http://www.pnas.org/content/94/8/3960.full |doi=10.1073/pnas.94.8.3960]

NSP5 is encoded by genome segment 11 of rotavirus A and in virus-infected cells NSP5 accumulates in the viroplasm. [cite journal |author=Afrikanova I, Miozzo MC, Giambiagi S, Burrone O |title=Phosphorylation generates different forms of rotavirus NSP5 |journal=J. Gen. Virol. |volume=77 ( Pt 9) |pages=2059–65 |year=1996 |pmid=8811003 |url=http://vir.sgmjournals.org/cgi/reprint/77/9/2059 |doi=10.1099/0022-1317-77-9-2059]

NSP6 is a nucleic acid binding protein, [cite journal |author=Rainsford EW, McCrae MA |title=Characterization of the NSP6 protein product of rotavirus gene 11 |journal=Virus Res. |volume=130 |issue=1–2 |pages=193–201 |year=2007 |pmid=17658646 |doi=10.1016/j.virusres.2007.06.011] and is encoded by gene 11 from an out of phase open reading frame. [cite journal |author=Mohan KV, Atreya CD |title=Nucleotide sequence analysis of rotavirus gene 11 from two tissue culture-adapted ATCC strains, RRV and Wa |journal=Virus Genes |volume=23 |issue=3 |pages=321–9 |year=2001 |pmid=11778700 |doi=10.1023/A:1012577407824]

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 0-89603-736-3] [Patton JT. Rotavirus RNA replication and gene expression. In Novartis Foundation. "Gastroenteritis Viruses", Humana Press, 2001, pp. 64–81. ISBN 0-471-49663-4] RNA-protein coding assignments differ in some strains.

Replication

Rotavirus infects enterocytes of the villi of the small intestine, leading to structural and functional changes of the epithelium.cite journal
author=Greenberg HB, Clark HF, Offit PA
title=Rotavirus pathology and pathophysiology
journal=Curr. Top. Microbiol. Immunol.
volume=185
pages=255–83
year=1994
pmid=8050281] 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.cite journal |author=Jayaram H, Estes MK, Prasad BV |title=Emerging themes in rotavirus cell entry, genome organization, transcription and replication |journal=Virus Res. |volume=101 |issue=1 |pages=67–81 |year=2004 |pmid=15010218 |doi=10.1016/j.virusres.2003.12.007] cite journal
author=Patton JT, Vasquez-Del Carpio R, Spencer E
title=Replication and transcription of the rotavirus genome
journal=Curr. Pharm. Des.
volume=10
issue=30
pages=3769–77
year=2004
pmid=15579070
doi=10.2174/1381612043382620]

See also

*Bacterial gastroenteritis
*Infant mortality

References

External links

* [http://www.cdc.gov/rotavirus/about_rotavirus.htm CDC About Rotavirus]