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The family name Reoviridae is derived from the prototype “reovirus” strain of the genus Orthoreovirus, the first genus of this family to be identified. The name reovirus was proposed in 1959 to describe a group of viruses previously classified as enteric cytopathic human orphan (ECHO) virus type 10, but which was found to differ from the other echoviruses in several important aspects (e.g., size). In addition, the acronym “reo” was suggested to denote that these agents were isolated from the respiratory and enteric tracts and had not been associated with any disease (orphan virus). Important features of the orthoreoviruses (or “reoviruses”) include a diameter of 70 nm; a double capsid; ether and acid stability; a genome of 10 segments of double-stranded RNA; three serotypes designated types 1, 2, and 3; and the ability to infect humans as well as various other animals. The three serotypes share a common complement fixation antigen but can be distinguished by hemagglutination inhibition and neutralization techniques. Reoviruses grow efficiently from clinical specimens in various cell cultures, including monkey kidney cells.
Reoviruses are ubiquitous agents. Strains identical serologically to the human reovirus serotypes have been recovered from a wide variety of animals, including mice, chimpanzees, dogs, cats, cattle, sheep, swine, horses, and monkeys. Avian reoviruses also have been isolated; however, with one possible exception, these are antigenically distinct from the three reovirus serotypes described previously. In addition, a reovirus possessing certain characteristics of the mammalian and avian reoviruses has been recovered from a bat.
Reovirus infections occur often in humans, but most are mild or subclinical. The virus is detected efficiently in feces. It may also be recovered from nasal or pharyngeal secretions, urine, blood, cerebrospinal fluid, and various organs obtained at autopsy. Despite the ease with which reoviruses are detected in clinical specimens, their role in human disease remains uncertain. Reovirus infections have been observed in patients with various conditions such as fever, exanthema, upper and lower respiratory tract illnesses, gastrointestinal illness (including steatorrhea), hepatitis, pneumonitis, keratoconjunctivitis, neonatal cholestasis, meningitis, encephalitis, myocarditis, and Burkitt's lymphoma. Their role as agents of such illnesses remains unclear since convincing evidence of an etiologic association remains elusive. Thus, it is generally considered that although reoviruses can readily infect humans, they are not important agents of human diseas
The dsRNA Viruses. .
This family is ubiquitous in nature - infecting invertebrates, vertebrates and plants. Abs have been found in all species of mammals tested (except whales), implying wide cell tropism/ubiquitous receptor (see below).
All are similar: Non-enveloped, icosahedral capsids (T=13) composed of double protein shell: Outer shell ~80nm diameter; Inner shell ~60nm diameter. The various genera are
serologically unrelated. Proteins:
The family Reoviridae is composed of eight genera: Orthoreovirus, Orbivirus, Coltivirus, Rotavirus, Aquareovirus, Cypovirus, Phytoreovirus, and Fijivirus. Certain Orthoreovirus, Orbivirus, Coltivirus, and Rotavirus species infect humans; Phytoreovirus and Fijivirus species infect plants and insects; the cypoviruses (the cytoplasmic polyhidrosis viruses) infect insects, and aquareoviruses infect fish. This paper concerns only the members of the Reoviridae known to infect humans.
Although the orthoreoviruses (referred to commonly as reoviruses), orbiviruses,coltiviruses, and rotaviruses are similar in morphology, diameter (about 70 nm), and possession of a segmented, double-stranded RNA genome, they differ in epidemiology, association with disease, and ability to be cultured. In addition, the four groups are distinct antigenically.
Rotaviruses are major agents of severe diarrhea in infants and young children in developed and developing countries. Such diarrhea can lead to dehydration that may be fatal if rehydration fluids are not available. Reovirus infections are quite common in humans, although they tend to be mild or subclinical. The extent of their role as agents of illness in humans is unclear. Four human orbiviruses or coltiviruses have been associated with human disease. The most serious of these diseases is Colorado tick fever, characterized by diphasic fever, headache, muscle pain, anorexia, leukopenia, and weakness; some cases are complicated by encephalitis, hemorrhage, thrombocytopenia, or pericarditis; death is rare.
Diarrheal diseases are a major cause of morbidity in infants and young children in developed countries and a major cause of morbidity and mortality in developing countries. For example, in a family study of some 25,000 illnesses in the United States, infectious gastroenteritis was the second most common disease and accounted for 16 percent of all illnesses. The impact of diarrheal illnesses on infants and young children in developing countries is staggering. An estimate of the number of diarrheal episodes in children younger than 5 years of age in Asia, Africa, and Latin America for a 1-year period indicated that more than 450 million cases of diarrhea occurred and that 1 to 4 percent were fatal, resulting in the deaths of 5 to 18 million children. A later study in the same areas estimated 3 to 5 billion cases of diarrhea and 5 to 10 million diarrhea-associated deaths in 1 year, ranking diarrhea first among infectious diseases in the categories of both frequency and mortality, with the burden greatest in infants and young children. Despite the importance of this disease, the agents of a large proportion of diarrheal illnesses of infants and young children were not known until relatively recently. It was assumed that viruses were important because the bacterial agents known at that time, could be recovered from only a small proportion of cases during nonepidemic periods. In 1973, rotaviruses were discovered in duodenal biopsies obtained from hospitalized infants and young children with acute gastroenteritis. Subsequently, the agent was detected in stools by electron microscopy, and laboratories all over the world soon began to detect the virus in stools of a large proportion of pediatric patients with gastroenteritis. Efficient and practical tests were developed to detect rotavirus from clinical specimens, thus facilitating the study of this agent which replicated inefficiently in cell cultures. Soon, the major role of rotavirus in diarrheal disease was established. The other major pathogens associated with diarrheal disease in infants and young children
Rotavirus infection was previously thought to be localized to the intestine but new data indicates that infectious virus is present systemically. (Credit: Image courtesy of Public Library of Science)
Rotaviruses induce a clinical illness characterized by vomiting, diarrhea, abdominal discomfort, fever, and dehydration (or a combination of some of these symptoms) that occurs primarily in infants and young children and may lead to hospitalization for rehydration therapy. Fever and vomiting frequently precede the onset of diarrhea. Although milder gastroenteric illnesses that do not require hospitalization are also common, most studies of clinical manifestations of rotavirus-induced gastroenteritis rely on data from hospitalized patients. The duration of hospitalization ranges from 2 to 14 days with a mean of 4 days. The highest attack rate is usually among infants and young children 6 to 24 months old, and the next highest in infants less than 6 months old. Normal neonates infected with rotavirus do not usually develop clinical manifestations. Deaths from rotavirus gastroenteritis may occur from dehydration and electrolyte imbalance. In older children and adults, rotavirus gastroenteritis occurs infrequently, although subclinical infections are common.
Rotaviruses also induce chronic symptomatic diarrhea in immunodeficient children, with an occasional fatal outcome. In addition, rotavirus infections can be especially severe and sometimes fatal in individuals of any age who are immunosuppressed for bone marrow transplantation. Rotavirus infections have also been associated with necrotizing enterocolitis and hemorrhagic gastroenteritis in neonates in special-care units. Rotaviruses have also been found in stools of patients with a variety of other conditions, but the association appears to be temporal rather than etiologic.
otaviruses have a distinctive wheel-like shape Complete particles have a double-layered capsid and measure about 70 nm in diameter. When the outer layer is absent, they measure about 55 nm. Within the inner capsid is the 37-nm core, which contains the RNA genome. The term rotavirus is derived from the Latin word "rota," meaning wheel, and was suggested because the sharply defined circular outline of the outer capsid resembles the rim of a wheel placed on short spokes radiating from a wide hub. Morphologically, rotaviruses resemble the reoviruses, coltiviruses and orbiviruses. However, the sharply defined circular outline of the outer capsid of rotavirus differs from the amorphous outer capsid of orbiviruses and coltiviruses. Reoviruses also have a distinct outer capsid, although it is not characteristically as sharply defined as that of the rotaviruses
FIGURE Human rotavirus particles from a stool filtrate. Particles appear to have a double-shelled capsid. Occasional "empty" particles are seen. (Adapted from Kapikian AZ, Kim HW, Wyatt RG et al: Reovirus-like agent in stools: association with infantile diarrhea and development of serologic tests. Science 15:1049, 1974, with permission.)
The rotavirus genome contains 11 segments of double-stranded RNA, in contrast to the reoviruses and orbiviruses, both of which contain 10 segments and the coltiviruses which contain 12 segments of double-stranded RNA. The segmented genome of rotavirus readily under goes genetic reassortment during coinfection. Rotavirus RNA segments 1, 2, 3, and 6 encode inner capsid polypeptides VP1, VP2, VP3, and VP6, respectively, whereas RNA segments 4 and 7, 8, or 9 encode the major outer capsid polypeptides VP4 and VP7, respectively.
The biochemical properties of human rotaviruses have not been studied extensively because these agents were initially difficult to propagate in cell culture. Rotaviruses, coltiviruses and orbiviruses are ether stable, but acid labile, whereas reoviruses are acid and ether stable. Studies of the effect of various disinfectants on simian rotavirus infectivity demonstrated that 95 percent (vol/vol) ethanol was most effective for rotavirus inactivation in the laboratory setting, where disinfection may be necessary.
Classification and Antigenic Types
Rotaviruses are distinct serologically from the three reovirus serotypes and from all orbiviruses with which they have been tested. Most human rotaviruses share a common group antigen and are designated group A rotaviruses, but other antigens separate the group A rotaviruses into serotypes and subgroups. Ten human rotavirus serotypes have been defined by neutralization of one of the outer capsid proteins, VP7. Group A rotaviruses can also be separated into two distinct subgroups by various assays. The neutralization and subgroup specificities are encoded by different genes. Rotaviruses also have been detected in stools of the young of numerous animals with diarrhea. Rotaviruses of humans and animals characteristically share a common group antigen, but strains may differ in serotype specificity by neutralization. However, many animal rotavirus strains (simian, canine, feline, equine, murine, porcine, and lapine strains) share serotype specificity with human rotavirus.
In addition, a few human and animal rotavirus strains have been detected (by electron microscopy) that do not share the common group antigen; these have been designated as non-group A rotaviruses. The non-group A viruses are divided into groups B, C, D, E, F, and G on the basis of distinct group antigens. The group A rotaviruses are the most important agents of severe diarrhea in infants and young children and are prevalent worldwide. The group B and C rotaviruses have a more limited distribution and are not considered to be an important cause of infantile diarrhea. Group B rotavirus has been responsible for large outbreaks of severe gastroenteritis in China, which predominantly involved adults, but the importance of the group B rotaviruses outside China has not been defined. Groups D, E, F, and G have not been detected in humans. Unless otherwise noted, the description of rotaviruses in this paper deals with the group A rotaviruses exclusively.
Human rotaviruses are rather fastidious agents, and for many years they could not be efficiently cultivated from clinical specimens. However, efficient cell culture propagation of human rotavirus strains directly from clinical material became possible by altering the conditions of propagation.
Rotaviruses replicate exclusively in the cytoplasm. The virion enters the cell by endocytosis (or direct membrane penetration if activated by protease), and the outer shell of the double capsid is removed in lysosomes with the liberation of 50-nm subviral particles, thus activating the viral RNA polymerase (transcriptase). RNA positive-sense transcripts induce the production of proteins and are also a template for the production of antisense strands, which remain associated with the positive-sense strand. About 8 hours after infection, viroplasmic inclusions of dense granular material, representing newly synthesized proteins and RNA, accumulate in the cytoplasm. Viral RNA is packaged into core particles, and viral capsid proteins assemble around the cores.
These particles accumulate in vesicles of the endoplasmic reticulum and leave the viroplasm by budding through the membrane of the endoplasmic reticulum, where they acquire the outer capsid protein. The budding process (plus transient acquisition of an envelope) is unique to rotaviruses among members of the family Reoviridae. Particles are released by cell lysis.
The mechanisms of rotavirus pathogenesis and immunity are not completely understood and vary depending on the animal species studied3, 10. A summary of the potential mechanisms of rotavirus pathogenesis and immunity, mostly (steps 3 to 5 in particular) derived from observations in rodents is shown. In step 1, neutralizing antibodies directed against VP4 and/or VP7 can prevent viral binding and penetration, inducing viral exclusion. If this mechanism fails, as shown in step 2, rotavirus replication inside enterocytes causes altered metabolism of enterocyte membrane proteins inducing malabsorptive or osmotic diarrhoea.
Rotavirus also increases the concentration of intracellular calcium, which disrupts the cytoskeleton and the tight junctions, raising the paracellular permeability. During step 3, intracellular viral replication can be inhibited by secretory anti-VP6 immunoglobulin A (IgA) during transcytosis across enterocytes. In step 4, cytokine-secreting rotavirus-specific T cells can also inhibit viral replication. If viral replication is not stopped, as shown in step 5, replicating rotavirus produces non-structural protein 4 (NSP4), a toxin which induces a secretory non-cystic fibrosis transmembrane conductance regulator (CFTR)-mediated diarrhoea. By an unknown mechanism (suggested by some investigators to be dependent on NSP4) rotavirus can also stimulate the enteric nervous system (ENS) (as shown in step 6), inducing secretory diarrhoea and increasing intestinal motility. Drugs that inhibit the ENS are useful in treating rotavirus diarrhoea in children. Antibodies against NSP4 could potentially have an effect against the last two mechanisms. Late in the infectious process, rotavirus kills the host cell (as shown in step 7), further contributing to malabsorptive or osmotic diarrhoea. Despite its 'enteric nature', rotavirus antigens, double-stranded RNA and infectious particles have been found in the blood of children and systemic organs in animals31. The role of these systemic antigens and/or virus in the pathogenesis of rotavirus-induced disease is currently unknown. slgA, secretory lgA.
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