Reoviruses

The family Reoviridae is divided into 9 genera, 4 of which—Orthoreovirus, Coltivirus, Rotavirus, and Orbivirus —can infect humans and animals. Four other genera infect only plants and insects, and one infects fish. Although almost 100 orbivirus serotypes are known, only 3 serotypes of orthoreovirus and 2 of coltivirus have been identified. The genus Rotavirus contains 3 groups, A, B, and C, with group A causing most outbreaks of disease. Both orthoreoviruses and orbiviruses contain 10 segments of double-stranded RNA. Rotaviruses contain 11 genome segments, and coltiviruses have 12 segments.

Reovirus is used as a therapeutic agent in the treatment of various types of malignancy. Reolysin, a strain of reovirus, has been studied extensively as an anticancer agent in the treatment of head and neck cancers, metastatic melanoma, ovarian cancer, and other solid-organ tumors. ^{[1, 2, 3, 4]}

The virions of Reoviridae family viruses measure 60-80 nm in diameter and possess 2 concentric capsid shells, each of which is icosahedral. No envelope is present. ^[5] The inner capsids of all genera display sharply defined subunits; the outer capsids of rotaviruses and orbiviruses lack well-defined subunit structures. The genome consists of double-stranded RNA in 10-12 discrete segments, with a total genome size of 16-27 kilobase pair (kbp), depending on the genus. The double-shelled particle is the complete infectious form of the virus. The individual RNA segments vary in size from 680 base pair (bp), ie, rotavirus, to 3900 bp, ie, orthoreovirus. The virion core contains several enzymes needed for transcription and capping of viral RNA. ^[5]

Reoviruses are unusually stable to heat, to a pH range of 3.0-9.0, and to lipid solvents, but they are inactivated by 95% ethanol, phenol, and chlorine.

The first human orthoreovirus was isolated in 1953 from a rectal swab collected from a healthy child and was originally the prototype for echovirus type 10 of the Picornaviridae family. Subsequently, 3 serotypes were identified, and these agents, designated as reovirus, were placed into the Reoviridae family. In 1959, Sabin proposed the name reovirus to reflect the fact that viruses of this group had been isolated from the respiratory and enteric tracts and were orphan (reo) viruses without known associated disease. From these early isolation studies, the respiratory and enteric tracts are assumed to represent the natural portals of entry for reoviruses into the host.

The 3 serotypes share a common group antigen as detected with complement fixation.

Reoviruses are ubiquitous in nature, but their role in human disease is vague. Numerous early reports noted their association with human disease; however, during the last 2 decades, few cases of human disease have been reported. These viruses also have been evaluated extensively in studies involving laboratory animals.

Reoviruses (which also are called orthoreoviruses to avoid confusion with the family Reoviridae) are nonenveloped viruses. Reovirus particles are composed of an inner protein shell (ie, core) of a diameter of 60 nm, which is surrounded by an outer protein shell (ie, outer capsid) that measures 81 nm in diameter. The core is composed of 3 major (ie, lambda-1, lambda-2, sigma-2) and several minor proteins that surround 10 segments of double-stranded RNA. The virions also contain 3 nonstructural proteins. Reoviruses are moderately heat-stable, stable through a wide pH range, and stable in aerosols, particularly when the relative humidity is high.

Reoviruses replicate with a cytopathic effect in a large number of tissue culture systems of both primate and other animal origin. For recovery from clinical material, monkey kidney tissue cultures are satisfactory. ^[6] Because of their widespread prevalence in nature and the ease of infection in laboratory animals, reoviruses have been used widely in pathogenicity studies. ^{[7, 8, 9]}

Orbivirus

Orbiviruses commonly infect insects, and many can be transmitted by insects to vertebrates. More than 100 serotypes have been identified. Serious animal pathogens include bluetongue virus of sheep and African horse sickness virus. Antibodies are found in many vertebrates, including humans. The genome consists of 10 segments of double-stranded RNA. ^[10] The replicative cycle is similar to that of reoviruses. In contrast with the general stability of other reoviruses, orbiviruses are inactivated by low pH.

Orungo virus, isolated in Africa, has been implicated in an acute illness with myalgias and headache. Lebombo virus is another orbivirus isolated from humans in Africa. Kemerovo virus has been implicated in neurologic infections in central Europe and Russia. Serologic evidence of infection with Lipovnik or Tribec virus has been demonstrated in patients with polyradiculitis in the former Czechoslovakia. Changuinola virus has been isolated from humans in Panama.

Coltivirus

Coltiviruses resemble the orbiviruses in size and in having 2 capsids. These viruses contain 12 RNA segments. Colorado tick fever (CTF), Salmon River virus (in Idaho), Eyach virus (in Germany and France), isolate S6-14-03 (in California), Banna virus, Beijing virus, and Gansu virus (in China) either are proved or suspected of causing human disease.

Colorado tick fever

During early investigations of Rocky Mountain spotted fever (RMSF), sporadic cases of an illness that followed a tick bite were recognized. This illness differed from RMSF in that the characteristic skin rash was absent. Because this new illness was thought to occur predominantly in Colorado, it was named CTF to distinguish it from the more severe RMSF. Mountain fever and mountain tick fever are other names for this disease. ^[11] The etiologic agent was recognized as a virus in 1946. CTF virus is the prototype species for the genus Coltivirus of the family Reoviridae. CTF virus has a genome that consists of 12 segments of double-stranded RNA. The virus is transmitted to mammals, including humans, principally by the adult Rocky Mountain wood tick (ie, Dermacentor andersoni), and exposure to the virus is therefore restricted to the vector habitat. Clinical cases peak between May and July. ^[12]

Historically, CTF has been the most frequently reported arboviral disease in the United States. Nevertheless, it is considered an underdiagnosed condition. Viral maintenance is achieved via larval and nymphal stages of D andersoni and various rodent species.

In most cases, a history of tick bite can be obtained, but, occasionally, only body contact with a tick is remembered. In certain instances, the bite has been unnoticed, and only a history of having been in a tick-infested area can be elicited. Occasionally, the tick may be found imbedded in the skin only after very careful examination with particularly close observation of body folds, skin creases, and areas with hair. The illness occurs primarily in spring and summer, with most cases occurring in April and May at lower altitudes and in June and July at higher elevations. The disease may affect persons of any age.

Rotavirus

Infection with human rotavirus (HRV) appears to cause a substantial portion of cases of gastroenteritis in children aged 6 months to 2 years. ^[13] The rotavirus particle consists of an 11 double-stranded RNA genome enclosed in a double-shelled capsid. The outer shell is composed of a major glycoprotein with a molecular weight of 34,000 (ie, viral protein [VP]7) and a minor, trypsin-sensitive protein with a molecular weight of 84,000 (ie, VP4, previously designated VP3). Four proteins (ie, VP1, VP2, VP3, VP6) make up the virus core. Six nonstructural (NS) proteins (ie, NS53, NS34, NS35, NS28, NS26, NS12) are also produced during rotavirus infection.

Trypsin cleavage of VP4, which yields 2 polypeptides, VP8 and VP5, with molecular weights of 27,000 and 58,000, respectively, is required for the activation of infectivity. Originally, serotyping was based solely on differences in the VP7 protein because animals hyperimmunized with rotaviruses develop most neutralizing antibody to this protein. Cross-neutralization studies conducted with these hyperimmune sera readily separated the strains into VP7 serotypes. Later, a dual serotyping scheme was developed when VP4 was discovered to be the dominant neutralization protein in some cases. Rotavirus serotypes include a description of both the VP4 (protease-sensitive protein, P) and the VP7 (glycoprotein, G) types.

HRVs belonging to 11 G serotypes have been isolated, but the vast majority have been identified as G1, G2, G3, or G4, and strains belonging to these G types have commonly been designated as serotype 1, 2, 3, or 4, respectively. The severity of illness caused by viruses that belong to these 4 serotypes varies little, if at all. At least 6 different HRV P types have been identified. P type 1a, the most common, is usually associated with G types 1, 3, or 4; whereas, P type 1b is usually associated with G type 2.

Rotaviruses are closely related to reoviruses in terms of morphology and strategy of replication. ^[13]

Reovirus

Reoviruses cause many inapparent infections because most people have serum antibodies by early adulthood. Antibodies also are present in other species. All 3 types have been recovered from healthy children, from young children during outbreaks of minor febrile illness, and from children with diarrhea or enteritis. Human volunteer studies have failed to demonstrate a clear cause-and-effect relationship between reoviruses and human illness. The method of transmission of reoviruses is unknown. However, because these viruses are recovered most frequently from the feces, primary spread seems most likely to be by the fecal-oral route. Because the reoviruses are stable in aerosols and because respiratory illness has been associated with reovirus infections, this route is an additional possibility.

Colorado tick fever

CTF is the most common arboviral disease among humans in the United States. It has been reported from at least 11 Western states in the United States and from Alberta and British Columbia in Canada. In a 2015 study of 75 cases of CTF from 2002 to 2012, Wyoming had the highest annual incidence, followed by Montana and Utah. ^[14] CTF is transmitted to people by the adult hard-shelled wood tick D andersoni. The virus has been found in as many as 14% of these ticks harvested in endemic areas and is maintained in rather complex cycles between the tick vector and the host animals.

Both male and female adult ticks can transmit infection to humans, and the period of attachment required for transmission of the virus may be very brief. In rare cases, CTF has developed in persons who did not travel to areas of known risk; for example, in persons exposed to ticks brought home on clothing of family members and by transfusion. Most cases occur in May and June, when adult ticks are most active, but infections occurring from March to November have been reported. CTF affects young and old persons who, through occupational or recreational activities, come into contact with D andersoni. Because the disease is relatively benign, the true incidence cannot be assessed. Many cases are never recognized by a physician, or, if cases are recognized, the illness may not be recognized as CTF.

A 1974 ecologic study in Rocky Mountain National Park in north central Colorado identified the primary vertebrate host species for the CTF virus as the least chipmunk (ie, Tamias minimus) and the golden-mantled ground squirrel (ie, Spermophilus lateralis). Secondary hosts were the Uinta chipmunk (ie, Tamias umbrinus), Richardson ground squirrels (ie, Spermophilus richardsonii), and the deer mouse (Peromyscus maniculatus). Larval and nymphal stages of D andersoni ticks were responsible for transmission of CTF virus among rodents, and overwintering of the virus occurred in nymphal and adult D andersoni. Only adult ticks transmit CTF virus to humans.

Rotavirus

The disease has been found on all continents and in all races, but its worldwide prevalence is not known. Since its discovery in 1973, rotavirus has been well documented as an important cause of diarrheal disease in infants and young children. Estimates of the global disease burden of rotavirus diarrhea have been refined and suggest that mortality rates have not declined and that, among hospitalized patients with diarrhea, the fraction of cases associated with rotavirus has increased in many countries. In the United States, the estimated number of hospitalizations attributed to rotavirus has increased.

Although rotaviruses are found in high concentrations in the stools of children with diarrhea and are found less often in children without diarrhea, the presence of rotavirus in the feces is not always associated with symptomatic disease. While asymptomatic endemic rotavirus infections have been observed in newborns, isolation rates of rotavirus infection in asymptomatic infants and children have been reported to be very low.

Morbidity and mortality data from selected studies conducted in the last 3 decades in Africa, Latin America, and Asia show that morbidity rates are highest in infants aged 6-11 months, while the mortality rates are highest in infants and children aged 1 year. In children younger than 5 years, the median incidence of diarrhea is 2.2 episodes per child per year for all studies.

Asymptomatic infections are common in infants younger than 6 months, the time during which protective maternal antibody acquired passively by newborns should be present. Such neonatal infection does not prevent reinfection, but it may protect against the development of severe disease during reinfection.

In temperate climates, rotaviruses are responsible for a large number of cases of diarrheal disease in the winter. The seasonality of rotavirus disease is less apparent in tropical climates but is still more prevalent in the drier, cooler months.

The transmission of rotavirus infections is believed to be fecal-oral, with little evidence of airborne transmission. Adult contacts may be infected, as evidenced by seroconversion, but they rarely exhibit symptoms, and the virus is detected infrequently in their stools. A common source of infection is contact with children who are infected. However, epidemics of severe disease have occurred in adults, especially in closed populations, as in a geriatric ward.

In one study, cases of asymptomatic infection and cases with mild symptoms were characteristic of rotavirus infections among pediatric nurses, indicating that poor handwashing practices by the nursing staff may contribute to the spread of rotavirus gastroenteritis in pediatric wards. ^[15]

Reovirus

Human volunteer studies have failed to demonstrate a clear cause-and-effect relationship between reoviruses and human illness. Reoviruses have been associated with upper respiratory infections, fever, enteritis, and febrile exanthema in childhood.

Colorado tick fever

CTF virus can infect and replicate within both the KG-1a human progenitor cell line and human bone marrow progenitor cells. ^[16] The finding of viral replication 16-48 hours after infection both with plaque assay and with electron microscopy followed by pronounced cytopathic effects at 72-96 hours suggests that the virus is taken up by progenitor cells and diminishes both the numbers and the functions of these cells. While progenitor cells may provide a hospitable environment for viral replication, the in vitro data do not suggest that the cells serve as a long-term reservoir of virus. The CTF virus infects the bone marrow in the initial phases of infection but does not persist. Viral replication occurs in the bone marrow, lymph nodes, spleen, heart, and liver of rhesus monkeys but without histological abnormalities.

Human erythrocytes are known to carry the virus, and the virus has been shown to replicate in erythroblasts and reticulocytes of infected mice. The viral presence in mature erythrocytes is postulated to be a result of replication of the virus in hematopoietic erythrocyte precursor cells and simultaneous maturation of the infected immature cells rather than a result of direct entry and replication of CTF virus in mature erythrocytes.

Rotavirus

After fecal-oral transmission of rotavirus, infection is initiated in the upper intestine and typically leads to a series of histologic and physiologic changes. The incubation period is brief. Rotaviruses infect cells in the villi of the small intestine (gastric and colonic mucosa are spared). They multiply in the cytoplasm of enterocytes and damage their transport mechanism.

One of the rotavirus-encoded proteins, NSP4, is a viral enterotoxin that induces secretion by triggering a signal transduction pathway. Damaged cells may slough into the lumen of the intestine and release large quantities of viruses, which appear in stool. Viral excretion usually lasts 2-12 days in healthy patients but may be prolonged in those with poor nutrition. Diarrhea caused by rotaviruses may be due to impaired sodium and glucose absorption as damaged cells on villi are replaced by nonabsorbing immature crypt cells. Three to 8 weeks may be necessary for normal function to be restored. Antibodies present in the intestinal lumen have been shown to play a role in the passive protection of young animals. Recent studies demonstrate positive in vivo responses to certain compounds such as Loureirin C from Resina Draconis in reducing the intensity of rotavirus disease with decreased fecal water content, intestinal peristalsis rate, and smooth muscle contraction. ^[17]

Frequency

United States

Reoviruses cause many inapparent infections; thus, estimating the true frequency of the infection is difficult. CTF is the most common arboviral disease among people in the United States. It has been reported in at least 11 Western states in the United States. Rotavirus infections account for 3.5 million cases of diarrhea each year and for 20 deaths that occur among children younger than 5 years.

International

CTF has been reported from Alberta and British Colombia in Canada. In developing countries, 3-5 billion cases of gastroenteritis occur each year. A significant proportion is believed to be caused by rotaviruses.

Mortality/Morbidity

Reovirus infection usually has a benign course. Little mortality is associated with reovirus infection.

CTF has a benign course, with an excellent prognosis. Rarely, CTF results in death, usually from hemorrhagic complications.

In developing countries, rotavirus accounts for 10-20% of gastroenteritis-associated deaths (ie, 5-10 million deaths each year).

Race

No clear racial predilection exists for reovirus, CTF virus, or rotavirus infection.

Sex

No clear sexual predilection exists for rotavirus, CTF virus, or rotavirus infection.

Age

A lower rate of acute or symptomatic infections is observed with reoviruses and rotaviruses with increasing age, which is a consequence of the development of antibodies to these viruses. A single attack of CTF produces lifelong immunity.