Rotavirus
Overview
Rotavirus is the most common cause of severe diarrhoea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

 among infants and young children, and is one of several viruses that cause infections often called stomach flu, despite having no relation to influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...

. It is a genus
Genus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...

 of double-stranded RNA virus in the family
Family (biology)
In biological classification, family is* a taxonomic rank. Other well-known ranks are life, domain, kingdom, phylum, class, order, genus, and species, with family fitting between order and genus. As for the other well-known ranks, there is the option of an immediately lower rank, indicated by the...

 Reoviridae
Reoviridae
Reoviridae is a family of viruses that can affect the gastrointestinal system and respiratory tract. Viruses in the family Reoviridae have genomes consisting of segmented, double-stranded RNA...

. By the age of five, nearly every child in the world has been infected with rotavirus at least once. However, with each infection, immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...

 develops, and subsequent infections are less severe; adults are rarely affected.
Encyclopedia
Rotavirus is the most common cause of severe diarrhoea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

 among infants and young children, and is one of several viruses that cause infections often called stomach flu, despite having no relation to influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...

. It is a genus
Genus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...

 of double-stranded RNA virus in the family
Family (biology)
In biological classification, family is* a taxonomic rank. Other well-known ranks are life, domain, kingdom, phylum, class, order, genus, and species, with family fitting between order and genus. As for the other well-known ranks, there is the option of an immediately lower rank, indicated by the...

 Reoviridae
Reoviridae
Reoviridae is a family of viruses that can affect the gastrointestinal system and respiratory tract. Viruses in the family Reoviridae have genomes consisting of segmented, double-stranded RNA...

. By the age of five, nearly every child in the world has been infected with rotavirus at least once. However, with each infection, immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...

 develops, and subsequent infections are less severe; adults are rarely affected. There are five species
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...

 of this virus, referred to as A, B, C, D, and E. Rotavirus A, the most common, causes more than 90% of infections in humans.

The virus is transmitted by the faecal-oral route
Fecal-oral route
The fecal-oral route, or alternatively, the oral-fecal route or orofecal route is a route of transmission of diseases, in which they are passed when pathogens in fecal particles from one host are introduced into the oral cavity of another potential host.There are usually intermediate steps,...

. It infects and damages the cells
Enterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal...

 that line the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...

 and causes gastroenteritis
Gastroenteritis
Gastroenteritis is marked by severe inflammation of the gastrointestinal tract involving both the stomach and small intestine resulting in acute diarrhea and vomiting. It can be transferred by contact with contaminated food and water...

. 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
Public health
Public health is "the science and art of preventing disease, prolonging life and promoting health through the organized efforts and informed choices of society, organizations, public and private, communities and individuals" . It is concerned with threats to health based on population health...

 community, particularly in developing countries
Developing country
A developing country, also known as a less-developed country, is a nation with a low level of material well-being. Since no single definition of the term developing country is recognized internationally, the levels of development may vary widely within so-called developing countries...

. In addition to its impact on human health, rotavirus also infects animals, and is a pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

 of livestock.

Rotavirus is usually an easily managed disease of childhood, but worldwide nearly 500,000 children under five years of age still die from rotavirus infection each year and almost two million more become severely ill. In the United States, before initiation of the rotavirus vaccination programme, rotavirus caused 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
Oral rehydration therapy
Oral rehydration therapy is a simple treatment for dehydration associated with diarrhoea, particularly gastroenteritis or gastroenteropathy, such as that caused by cholera or rotavirus. ORT consists of a solution of salts and sugars which is taken by mouth...

 for infected children and vaccination
Vaccination
Vaccination is the administration of antigenic material to stimulate the immune system of an individual to develop adaptive immunity to a disease. Vaccines can prevent or ameliorate the effects of infection by many pathogens...

 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. Three decades later, preserved samples of the agent 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, Ruth Bishop
Ruth Bishop
Dr Ruth Bishop was a leading member of the team that discovered the human rotavirus. In 1973, she, along with G. Davidson , and collaborators I.Holmes & B.Ruck examined cells from the intestines of children with gastroenteritis...

 and colleagues described related viruses found in children with gastroenteritis.

In 1974, Thomas Henry Flewett
Thomas Henry Flewett
Dr Thomas Henry Flewett, MD, FRCPath, FRCP was a founder member of the Royal College of Pathologists and was elected a Fellow of the Royal College of Physicians of London in 1978...

 suggested the name rotavirus after observing that, when viewed through an electron microscope
Electron microscope
An electron microscope is a type of microscope that uses a beam of electrons to illuminate the specimen and produce a magnified image. Electron microscopes have a greater resolving power than a light-powered optical microscope, because electrons have wavelengths about 100,000 times shorter than...

, a rotavirus particle looks like a wheel (rota in Latin); the name was officially recognised by the International Committee on Taxonomy of Viruses
International Committee on Taxonomy of Viruses
The International Committee on Taxonomy of Viruses is a committee which authorizes and organizes the taxonomic classification of viruses. They have developed a universal taxonomic scheme for viruses and aim to describe all the viruses of living organisms. Members of the committee are considered to...

 four years later. In 1976, related viruses were described in several other species of animals. These viruses, all causing acute gastroenteritis, were recognised as a collective pathogen affecting humans and animals worldwide. Rotavirus serotypes were first described in 1980, and in the following year, rotavirus from humans was first grown in cell culture
Cell culture
Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...

s derived from monkey kidneys, by adding trypsin
Trypsin
Trypsin is a serine protease found in the digestive system of many vertebrates, where it hydrolyses proteins. Trypsin is produced in the pancreas as the inactive proenzyme trypsinogen. Trypsin cleaves peptide chains mainly at the carboxyl side of the amino acids lysine or arginine, except when...

 (an enzyme found in the duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...

 of mammals and now known to be essential for rotavirus to replicate) 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.

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
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....

 serious adverse effects
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

. 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
Intussusception (medical disorder)
An intussusception is a medical condition in which a part of the intestine has invaginated into another section of intestine, similar to the way in which the parts of a collapsible telescope slide into one another. This can often result in an obstruction...

, a type of bowel obstruction
Bowel obstruction
Bowel obstruction is a mechanical or functional obstruction of the intestines, preventing the normal transit of the products of digestion. It can occur at any level distal to the duodenum of the small intestine and is a medical emergency...

, in one of every 12,000 vaccinated infants. The experience provoked intense debate about the relative risks and benefits of a rotavirus vaccine.
In 2006, two new vaccines against infection were shown to be safe and effective in children, and in June 2009 the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 recommended that rotavirus vaccination be included in all national immunisation programmes to provide protection against this virus.

Signs and symptoms

Rotavirus gastroenteritis is a mild to severe disease characterised by vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

, watery diarrhoea, and low-grade fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

. Once a child is infected by the virus, there is an incubation period
Incubation period
Incubation period is the time elapsed between exposure to a pathogenic organism, a chemical or radiation, and when symptoms and signs are first apparent...

 of about two days before symptoms appear. Symptoms often start with vomiting followed by four to eight days of profuse diarrhoea. Dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...

 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.

Rotavirus A infections can occur throughout life: the first usually produces symptoms, but subsequent infections are typically asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...

, as the immune system provides some protection. Consequently, symptomatic infection rates are highest in children under two years of age and decrease progressively towards 45 years of age. Infection in newborn children, although common, is often associated with mild or asymptomatic disease; 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
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...

. 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. Symptomatic reinfections are often due to a different rotavirus A serotype.

Transmission

Rotavirus is transmitted by the faecal-oral route
Fecal-oral route
The fecal-oral route, or alternatively, the oral-fecal route or orofecal route is a route of transmission of diseases, in which they are passed when pathogens in fecal particles from one host are introduced into the oral cavity of another potential host.There are usually intermediate steps,...

, via contact with contaminated hands, surfaces and objects, and possibly by the respiratory route. The faeces of an infected person can contain more than 10 trillion infectious particles per gram; only 10–100 of these are required to transmit infection to another person.

Rotaviruses are stable in the environment and have been found in estuary
Estuary
An estuary is a partly enclosed coastal body of water with one or more rivers or streams flowing into it, and with a free connection to the open sea....

 samples at levels as high as 1–5 infectious particles per US gallon. Sanitary measures adequate for eliminating bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

 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.

Disease mechanisms

The diarrhoea is caused by multiple activities of the virus. Malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...

 occurs because of the destruction of gut cells called enterocyte
Enterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal...

s. The toxic
Enterotoxin
An enterotoxin is a protein toxin released by a microorganism in the intestine. Enterotoxins are chromosomally encoded exotoxins that are produced and secreted from several bacterial organisms. They are often heat-stable, and are of low molecular weight and water-soluble...

 rotavirus protein NSP4
NSP4 (rotavirus)
The rotavirus nonstructural protein NSP4 was the first viral enterotoxin discovered. It induces diarrhea and causes Ca2+-dependent transepithelial secretion.-References:...

 induces age- and calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

 ion-dependent chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...

 secretion, disrupts SGLT1
Sodium-glucose transport proteins
Sodium-dependent glucose cotransporters are a family of glucose transporter found in the intestinal mucosa of the small intestine and the proximal tubule of the nephron . They contribute to renal glucose reabsorption...

 transporter-mediated reabsorption of water, apparently reduces activity of brush-border membrane
Brush border
A brush border is the name for the microvilli-covered surface of simple cuboidal epithelium and simple columnar epithelium cells found in certain locations of the body. Microvilli are approximately 100 nanometers in diameter and their length varies from approximately 100 to 2,000 nanometers in...

 disaccharidase
Disaccharidase
Disaccharidases are a type of glycoside hydrolases, enzymes that break down disaccharides into monosaccharides.-Examples of disaccharidases:* Lactase * Maltase...

s, and possibly activates the calcium ion-dependent secretory
Secretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...

 reflex
Reflex
A reflex action, also known as a reflex, is an involuntary and nearly instantaneous movement in response to a stimulus. A true reflex is a behavior which is mediated via the reflex arc; this does not apply to casual uses of the term 'reflex'.-See also:...

es of the enteric nervous system
Enteric nervous system
The enteric nervous system is a subdivision of the autonomic nervous system that directly controls the gastrointestinal system in vertebrates.It is derived from neural crest.-Function:...

. Healthy enterocytes secrete lactase
Lactase
Lactase , a part of the β-galactosidase family of enzymes, is a glycoside hydrolase involved in the hydrolysis of the disaccharide lactose into constituent galactose and glucose monomers...

 into the small intestine; milk intolerance due to lactase deficiency is a particular symptom of rotavirus infection, which can persist for weeks. A recurrence of mild diarrhoea often follows the reintroduction of milk into the child's diet, due to bacterial fermentation of the disaccharide
Disaccharide
A disaccharide or biose is the carbohydrate formed when two monosaccharides undergo a condensation reaction which involves the elimination of a small molecule, such as water, from the functional groups only. Like monosaccharides, disaccharides form an aqueous solution when dissolved in water...

 lactose
Lactose
Lactose is a disaccharide sugar that is found most notably in milk and is formed from galactose and glucose. Lactose makes up around 2~8% of milk , although the amount varies among species and individuals. It is extracted from sweet or sour whey. The name comes from or , the Latin word for milk,...

 in the gut.

Diagnosis and detection

Diagnosis of infection with rotavirus normally follows diagnosis of gastroenteritis
Gastroenteritis
Gastroenteritis is marked by severe inflammation of the gastrointestinal tract involving both the stomach and small intestine resulting in acute diarrhea and vomiting. It can be transferred by contact with contaminated food and water...

 as the cause of severe diarrhoea. Most children admitted to hospital with gastroenteritis are tested for
Specific diagnosis
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...

 of infection with is made by finding the virus in the child's stool
Human feces
Human feces , also known as a stool, is the waste product of the human digestive system including bacteria. It varies significantly in appearance, according to the state of the digestive system, diet and general health....

 by enzyme immunoassay. There are several licensed test kits on the market which are sensitive, specific and detect all serotypes of . Other methods, electron microscopy and polyacrylamide gel electrophoresis, are used in research laboratories. Reverse transcription-polymerase chain reaction (RT-PCR) can detect and identify all species and serotypes of human rotavirus.

Treatment and prognosis

Treatment of acute rotavirus infection is nonspecific and involves management of symptoms and, most importantly, maintenance of hydration. If untreated, children can die from the resulting severe dehydration. Depending on the severity of diarrhoea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

, treatment consists of oral rehydration
Oral rehydration therapy
Oral rehydration therapy is a simple treatment for dehydration associated with diarrhoea, particularly gastroenteritis or gastroenteropathy, such as that caused by cholera or rotavirus. ORT consists of a solution of salts and sugars which is taken by mouth...

, during which the child is given extra water to drink that contains small amounts of salt and sugar. Some infections are serious enough to warrant hospitalisation where fluids are given by intravenous drip or nasogastric tube, and the child's electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....

s and blood sugar
Blood sugar
The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally in mammals, the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM , or 64.8 and 104.4 mg/dL...

 are monitored.

Rotavirus infections rarely cause other complications and for a well managed child the prognosis is excellent. There are rare reports of complications involving the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 (CNS) where rotavirus was detected in the fluid of the CNS in cases of encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...

 and meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...

, and recent studies have confirmed that rotavirus infection is not always confined to the gut, but can cause viremia
Viremia
Viremia is a medical condition where viruses enter the bloodstream and hence have access to the rest of the body. It is similar to bacteremia, a condition where bacteria enter the bloodstream.- Primary versus Secondary :...

.

Epidemiology

Rotavirus A, which accounts for more than 90% of rotavirus gastroenteritis in humans, is endemic
Endemic (epidemiology)
In epidemiology, an infection is said to be endemic in a population when that infection is maintained in the population without the need for external inputs. For example, chickenpox is endemic in the UK, but malaria is not...

 worldwide. Each year rotavirus causes millions of cases of diarrhoea in developing countries, almost 2 million resulting in hospitalisation and an estimated 453,000 resulting in the death of a child younger than five. In the United States alone—before initiation of the rotavirus vaccination programme—over 2.7 million cases of rotavirus gastroenteritis occurred annually, 60,000 children were hospitalised and around 37 died from the results of the infection. The major role of rotavirus in causing diarrhoea is not widely recognised within the public health community, particularly in developing countries. 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. Rotavirus causes 37% of deaths attributable to diarrhoea and 5% of all deaths in children younger than five. Boys are twice as likely as girls to be admitted to hospital.
In temperate areas, rotavirus infections occur primarily in the winter, but in the tropics they occur throughout the year; the difference is partly explained by seasonal changes in temperature and humidity. The number attributable to food contamination is unknown.
Outbreaks of rotavirus A diarrhoea are common among hospitalised infants, young children attending day care centres, and elderly people in nursing homes. An outbreak caused by contaminated municipal water occurred in Colorado in 1981.
During 2005, the largest recorded epidemic of diarrhoea occurred in Nicaragua. This unusually large and severe outbreak was associated with mutations in the rotavirus A genome, possibly helping the virus escape the prevalent immunity in the population. A similar large outbreak occurred in Brazil in 1977.

Rotavirus B, also called adult diarrhoea rotavirus or ADRV, has caused major epidemics of severe diarrhoea affecting thousands of people of all ages in China. These epidemics occurred as a result of sewage contamination of drinking water. Rotavirus B infections also occurred in India in 1998; the causative strain was named CAL. Unlike ADRV, the CAL strain is endemic. To date, epidemics caused by rotavirus B have been confined to mainland China
Mainland China
Mainland China, the Chinese mainland or simply the mainland, is a geopolitical term that refers to the area under the jurisdiction of the People's Republic of China . According to the Taipei-based Mainland Affairs Council, the term excludes the PRC Special Administrative Regions of Hong Kong and...

, and surveys indicate a lack of immunity to this species in the United States.

Rotavirus C has been associated with rare and sporadic cases of diarrhoea in children in many countries, and outbreaks have occurred in Japan and England.

Prevention

Because improved sanitation does not decrease the prevalence of rotaviral disease, and the rate of hospitalisations remains high, despite the use of oral rehydrating medicines, the primary public health intervention is vaccination.
In 2006, two vaccines against Rotavirus A infection were shown to be safe and effective in children: Rotarix by GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...

 and RotaTeq by Merck. Both are taken orally and contain attenuated live virus. Rotavirus vaccines are licensed in more than 100 countries, but only 17 countries have introduced routine rotavirus vaccination. Following the introduction of routine rotavirus vaccination in the US in 2006, the health burden of rotavirus gastroenteritis "rapidly and dramatically reduced" despite lower coverage levels compared to other routine infant immunizations.

The Rotavirus Vaccine Program is a collaboration between PATH
Program for Appropriate Technology in Health
The Program for Appropriate Technology in Health is an international, nonprofit global health organization based in Seattle, Washington , with 900+ employees in more than 30 offices around the world. Its president and CEO is Dr...

, the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

, and the U.S. Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...

, and is funded by the GAVI Alliance
Global Alliance for Vaccines and Immunization
The GAVI Alliance is a public-private global health partnership committed to saving children’s lives and protecting people’s health by increasing access to immunisation in poor countries...

. The Program aims to reduce child morbidity and mortality
Mortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...

 from diarrhoeal disease by making a vaccine against rotavirus available for use in developing countries.

On June 5, 2009, WHO announced that clinical trials of Rotarix vaccine “in high-mortality, low-socioeconomic settings of South Africa and Malawi, found that the vaccine significantly reduced severe diarrhoea episodes due to rotavirus.” WHO now recommends that rotavirus vaccine be included in all national immunisation programmes.

A 2010 Cochrane
Cochrane Collaboration
The Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...

 review of 34 clinical trials that included 175,994 participants concluded Rotarix and RotaTeq are effective vaccines, but direct comparisons of the two were still needed. Additional rotavirus vaccines are under development.

Infections of animals

Rotaviruses infect and cause diarrhoea in the young of many species of animals. They infect mammals (for example, apes, cattle, pigs, sheep, rats, cats and dogs, mice, horses, rabbits) and birds (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
Reassortment
Reassortment is the mixing of the genetic material of a species into new combinations in different individuals. Several different processes contribute to reassortment, including assortment of chromosomes, and chromosomal crossover. It is particularly used when two similar viruses that are infecting...

 with human strains. Rotavirus are a pathogen of livestock and cause economic loss to farmers because of costs of treatment associated with high morbidity and mortality rates.

Types of rotavirus

There are five species of rotavirus, referred to as A, B, C, D and E. Humans are primarily infected by species A, B and C, most commonly by species A. All five species cause disease in other animals.
Within rotavirus A there are different strains, called serotypes. As with influenza virus
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...

, a dual classification system is used, which is based on two structural proteins on the surface of the virion. The glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...

 VP7 defines G-types and the protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....

-sensitive protein VP4 defines P-types. Strains are generally designated by their G serotype specificities (e.g., serotypes G1 to G4 and G9), and the P-type is indicated by a number and a letter for the P-serotype and by a number in square brackets for the corresponding P-genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...

. (P-serotypes are difficult to characterize; therefore, molecular methods based on sequence analysis are often used to define the corresponding P-genotype instead. These genotypes correlate well with known P-serotypes). 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. The Wa strain is classified in full as G1P1A[8].

Structure

The genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....

 of rotavirus consists of 11 unique double helix molecules of RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

 which are 18,555 nucleotides in total. Each helix, or segment, is a gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

, numbered 1 to 11 by decreasing size. Each gene codes for one protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

, except genes 9 and 11, which each code for two. The RNA is surrounded by a three-layered icosahedral
Truncated icosahedron
In geometry, the truncated icosahedron is an Archimedean solid, one of thirteen convex isogonal nonprismatic solids whose faces are two or more types of regular polygons.It has 12 regular pentagonal faces, 20 regular hexagonal faces, 60 vertices and 90 edges....

 protein capsid
Capsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...

. Viral particles are up to 76.5 nm in diameter and are not enveloped
Viral envelope
Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...

.

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
Nonstructural protein
In virology, a nonstructural protein is a protein encoded by a virus but it is not part of the viral particle....

 (NSPs), that are only produced in cells infected by rotavirus. These are called NSP1
NSP1 (rotavirus)
NSP1, the product of rotavirus gene 5, is an nonstructural RNA-binding protein that contains a cysteine-rich region and is a component of early replication intermediates...

, NSP2
NSP2 (rotavirus)
NSP2, is a rotavirus nonstructural RNA-binding protein that accumulates in cytoplasmic inclusions and is required for genome replication. NSP2 is closely associated in vivo with the viral replicase. The non-structural protein NSP5 plays a role in the structure of viroplasms mediated by its...

, NSP3
NSP3 (rotavirus)
Rotavirus protein NSP3 is bound to the 3' end consensus sequence of viral mRNAs in infected cells.Four nucleotides are the minimal requirement for RNA recognition by rotavirus non-structural protein NSP3: using short oligoribonucleotides, it was established that the minimal RNA sequence required...

, NSP4
NSP4 (rotavirus)
The rotavirus nonstructural protein NSP4 was the first viral enterotoxin discovered. It induces diarrhea and causes Ca2+-dependent transepithelial secretion.-References:...

, NSP5
NSP5 (rotavirus)
NSP5 encoded by genome segment 11 of group A rotaviruses. In virus-infected cells NSP5 accumulates in the viroplasms. NSP5 has been shown to be autophosphorylated.Interaction of NSP5 with NSP2 was also demonstrated...

 and NSP6
NSP6 (rotavirus)
Gene 11 of Rotavirus encodes a nonstructural protein, NSP5 and also encodes NSP6, from an out of phase open reading frame. In contrast to the other rotavirus non-structural proteins, NSP6 was found to have a high rate of turnover, being completely degraded within 2h of synthesis...

.
At least six of the twelve proteins encoded
Coding region
The coding region of a gene, also known as the coding sequence or CDS, is that portion of a gene's DNA or RNA, composed of exons, that codes for protein. The region is bounded nearer the 5' end by a start codon and nearer the 3' end with a stop codon...

 by the rotavirus genome bind RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

. 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
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...

 translation and regulation of gene expression.

Structural proteins

VP1 is located in the core of the virus particle and is an RNA polymerase
RNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...

 enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

. 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 and is an enzyme called guanylyl transferase
Guanylyl transferase
Guanylyl transferases are enzymes that transfer a guanosine monophosphate group, usually from GTP to another molecule, releasing pyrophosphate. Many eukaryotic guanylyl transferases are capping enzymes that catalyze the formation of the 5' cap in the co-transcriptional modification of messenger RNA...

. This is a capping enzyme
Capping enzyme
A capping enzyme is a guanylyl transferase enzyme that catalyzes the attachment of the 5' cap to messenger RNA molecules that are in the process of being synthesized in the cell nucleus during the first stages of gene expression. The addition of the cap occurs co-transcriptionally, after the...

 that catalyses the formation of the 5' cap
5' cap
The 5' cap is a specially altered nucleotide on the 5' end of precursor messenger RNA and some other primary RNA transcripts as found in eukaryotes. The process of 5' capping is vital to creating mature messenger RNA, which is then able to undergo translation...

 in the post-transcriptional modification
Post-transcriptional modification
Post-transcriptional modification is a process in cell biology by which, in eukaryotic cells, primary transcript RNA is converted into mature RNA. A notable example is the conversion of precursor messenger RNA into mature messenger RNA , which includes splicing and occurs prior to protein synthesis...

 of mRNA. The cap stabilises viral mRNA by protecting it from nucleic acid
Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...

 degrading enzymes called nucleases.

VP4 is on the surface of the virion that protrudes as a spike. It binds to molecules on the surface of cells called receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

 and drives the entry of the virus into the cell. VP4 has to be modified by a protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....

 enzyme (found in the gut) into VP5* and VP8* before the virus is infectious. It determines how virulent the virus is and it determines the P-type of the virus.

VP6 forms the bulk of the capsid. It is highly antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

ic and can be used to identify rotavirus species. This protein is used in laboratory tests for rotavirus A infections.

VP7 is a glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...

 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
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...

 to infection.

Nonstructural viral proteins

NSP1, the product of gene 5, is a nonstructural
Nonstructural protein
In virology, a nonstructural protein is a protein encoded by a virus but it is not part of the viral particle....

 RNA-binding protein.

NSP2 is an RNA-binding protein
RNA-binding protein
RNA-binding proteins are proteins that bind to RNA. They bind to either double-strand or single-strand RNAs through RNA recognition motif . RNA-binding proteins may regulate the translation of RNA, and post-transcriptional events, such as RNA splicing, editing.They are cytoplasmic and nuclear...

 that accumulates in cytoplasmic inclusions (viroplasm
Viroplasm
A viroplasm is an inclusion body in a cell where viral replication/assembly occurs. They may be thought of as viral factories in the cell. Very little is understood about the mechanism of viroplasm formation...

s) 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
Enterotoxin
An enterotoxin is a protein toxin released by a microorganism in the intestine. Enterotoxins are chromosomally encoded exotoxins that are produced and secreted from several bacterial organisms. They are often heat-stable, and are of low molecular weight and water-soluble...

 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.

NSP6 is a nucleic acid binding protein, and is encoded by gene 11 from an out of phase open reading frame
Open reading frame
In molecular genetics, an open reading frame is a DNA sequence that does not contain a stop codon in a given reading frame.Normally, inserts which interrupt the reading frame of a subsequent region after the start codon cause frameshift mutation of the sequence and dislocate the sequences for stop...

.
Rotavirus genes and proteins
RNA Segment (Gene) Size (base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...

s)
Protein Molecular weight kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...

 
LocationCopies per particle Function
1 3302 VP1 125 At the vertices of the core <25 RNA-dependent RNA polymerase
2 2690 VP2 102 Forms inner shell of the core 120 Stimulates viral RNA replicase
3 2591 VP3 88 At the vertices of the core <25 Guanylyl transferase mRNA capping enzyme
4 2362 VP4 87 Surface spike 120 Cell attachment, virulence
5 1611 NSP1
NSP1 (rotavirus)
NSP1, the product of rotavirus gene 5, is an nonstructural RNA-binding protein that contains a cysteine-rich region and is a component of early replication intermediates...

59 Nonstructural 0 5'RNA binding
6 1356 VP6 45 Inner Capsid 780 Structural and species-specific antigen
7 1104 NSP3
NSP3 (rotavirus)
Rotavirus protein NSP3 is bound to the 3' end consensus sequence of viral mRNAs in infected cells.Four nucleotides are the minimal requirement for RNA recognition by rotavirus non-structural protein NSP3: using short oligoribonucleotides, it was established that the minimal RNA sequence required...

37 Nonstructural 0 Enhances viral mRNA activity and shut-offs cellular protein synthesis
8 1059 NSP2
NSP2 (rotavirus)
NSP2, is a rotavirus nonstructural RNA-binding protein that accumulates in cytoplasmic inclusions and is required for genome replication. NSP2 is closely associated in vivo with the viral replicase. The non-structural protein NSP5 plays a role in the structure of viroplasms mediated by its...

35 Nonstructural 0 NTPase involved in RNA packaging
9 1062 VP71 VP72 38 and 34 Surface 780 Structural and neutralisation antigen
10 751 NSP4
NSP4 (rotavirus)
The rotavirus nonstructural protein NSP4 was the first viral enterotoxin discovered. It induces diarrhea and causes Ca2+-dependent transepithelial secretion.-References:...

20 Nonstructural 0 Enterotoxin
11 667 NSP5
NSP5 (rotavirus)
NSP5 encoded by genome segment 11 of group A rotaviruses. In virus-infected cells NSP5 accumulates in the viroplasms. NSP5 has been shown to be autophosphorylated.Interaction of NSP5 with NSP2 was also demonstrated...

 NSP6
NSP6 (rotavirus)
Gene 11 of Rotavirus encodes a nonstructural protein, NSP5 and also encodes NSP6, from an out of phase open reading frame. In contrast to the other rotavirus non-structural proteins, NSP6 was found to have a high rate of turnover, being completely degraded within 2h of synthesis...

22 Nonstructural 0 ssRNA and dsRNA binding modulator of NSP2
NSP2 (rotavirus)
NSP2, is a rotavirus nonstructural RNA-binding protein that accumulates in cytoplasmic inclusions and is required for genome replication. NSP2 is closely associated in vivo with the viral replicase. The non-structural protein NSP5 plays a role in the structure of viroplasms mediated by its...


This table is based on the simian
Simian
The simians are the "higher primates" familiar to most people: the Old World monkeys and apes, including humans, , and the New World monkeys or platyrrhines. Simians tend to be larger than the "lower primates" or prosimians.- Classification and evolution :The simians are split into three groups...

 rotavirus strain SA11. RNA-protein coding assignments differ in some strains.

Replication

Rotaviruses replicate mainly in the gut
Gut (zoology)
In zoology, the gut, also known as the alimentary canal or alimentary tract, is a tube by which bilaterian animals transfer food to the digestion organs. In large bilaterians the gut generally also has an exit, the anus, by which the animal disposes of solid wastes...

, and infect enterocytes of the villi of the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...

, leading to structural and functional changes of the epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...

. The triple protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 coats make them resistant to the acidic pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...

 of the stomach and the digestive enzyme
Digestive enzyme
'Digestive enzymes' are enzymes that break down polymeric macromolecules into their smaller building blocks, in order to facilitate their absorption by the body. Digestive enzymes are found in the digestive tract of animals where they aid in the digestion of food as well as inside the cells,...

s in the gut.

The virus enter cells by receptor mediated endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...

 and form a vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...

 known as an endosome
Endosome
In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for...

. Proteins in the third layer (VP7 and the VP4 spike) disrupt the membrane of the endosome, creating a difference in the calcium
Calcium in biology
Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...

 concentration. This causes the breakdown of VP7 trimer
Trimer (biochemistry)
In biochemistry, a trimer is a macromolecular complex formed by three, usually non-covalently bound, macromolecules like proteins or nucleic acids. A homo-trimer would be formed by three identical molecules. A hetero-trimer would be formed by three different macromolecules. Collagen is an example...

s 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
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...

 that are triggered by the presence of double-stranded RNA.

During the infection, rotavirus produces mRNA for both protein biosynthesis
Protein biosynthesis
Protein biosynthesis is the process in which cells build or manufacture proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then...

 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
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...

 where they obtain their third, outer layer (formed by VP7 and VP4). The progeny
Offspring
In biology, offspring is the product of reproduction, of a new organism produced by one or more parents.Collective offspring may be known as a brood or progeny in a more general way...

 viruses are released from the cell by lysis.

External links

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
x
OK