viral disease

Bluetongue disease

Bluetongue disease or catarrhal fever is a non-contagious, insect-borne viral disease of ruminants, mainly sheep and less frequently of cattle, goats, buffalo, deer, dromedaries and antelope. It is caused by the Bluetongue virus.

There are no reports of human transmission. Although the tongues of human patients with some types of heart disease may be blue, this sign is not related to bluetongue disease.

Pathogen and vector

Bluetongue is caused by the pathogenic virus, Bluetongue virus (BTV), of the genus Orbivirus, is a member of the Reoviridae family. There are 24 serotypes. It is transmitted by a midge, Culicoides imicola and other culicoids.

Bluetongue virus

Bluetongue virus causes serious disease in livestock (sheep, goats, cattle and deer). Partly due to this BTV has been in the forefront of molecular studies for last three decades and now represents one of the best understood viruses at the molecular and structural levels. BTV, like the other members of the family is a complex non-enveloped virus with seven structural proteins and a RNA genome consisting of 10 double-stranded (ds) RNA segments of different sizes. Data obtained from studies over a number of years have defined the key players in BTV entry, replication, assembly and exit and have increasingly found roles for host proteins at each stage. Specifically, it has been possible to determine the complex nature of the virion through 3D structure reconstructions (diameter ~ 800 Å); the atomic structure of proteins and the internal capsid (~ 700 Å, the first large highly complex structure ever solved); the definition of the virus encoded enzymes required for RNA replication; the ordered assembly of the capsid shell and the protein sequestration required for it; and the role of host proteins in virus entry and virus release. These areas are important for BTV replication but they also indicate the pathways that may be used by related viruses, which include viruses that are pathogenic to man and animals, thus providing the basis for developing strategies for intervention or prevention.

BTV is the type species of the genus Orbivirus within the family Reoviridae. The Reoviridae family is one of the largest families of viruses and includes major human pathogens (e.g., rotavirus) as well as other vertebrate, plant and insect pathogens. Like the other members of the family, Orbiviruses which encompass, besides BTV, the agents causing African horse sickness (AHSV) and epizootic hemorrhagic disease of deer (EHDV), have the characteristic double-stranded and segmented features of their RNA genomes. However, unlike the mammalian reoviruses, Orbiviruses comprising 14 serogroups, are vectored to a variety of vertebrates by arthropod species (e.g., gnats, mosquitoes and ticks) and replicate in both hosts. BTV, the etiological agent of Bluetongue disease of animals, is transmitted by Culicoides species. In sheep BTV causes an acute disease with high morbidity and mortality. BTV also infects goats, cattle and other domestic animals as well as wild ruminants (e.g., blesbuck, white-tailed deer, elk, pronghorn antelope, etc.). The disease was first described in the late 18th century and was believed for many decades to be confined to Africa. However, to date BTV has been isolated in many tropical, subtropical and temperate zones and 24 serotypes have been identified from different parts of the world. Due to its economic significance BTV has been the subject of extensive molecular, genetic and structural studies. As a consequence it now represents one of the best characterised viruses.

Unlike the reovirus and rotavirus particles, the mature BTV particle is relatively fragile and the infectivity of BTV is lost easily in mildly acidic conditions. BTV virions (550S) are architecturally complex structures composed of 7 discrete proteins that are organised into two concentric shells, the outer and inner capsids, and a genome of 10 dsRNA segments. The outer capsid, which is composed of two major structural proteins (VP2 and VP5), is involved in cell attachment and virus penetration during the initial stages of infection. Shortly after infection, BTV is uncoated, i.e. VP2 and VP5 are removed, to yield a transcriptionally active 470S core particle which is composed of two major proteins VP7 and VP3, and the three minor proteins VP1, VP4 and VP6 in addition to the dsRNA genome. There is no evidence that any trace of the outer capsid remains associated with these cores, as has been described for reovirus. The cores may be further uncoated to form 390S subcore particles that lack VP7, also in contrast to reovirus. Subviral particles are probably akin to cores derived in vitro from virions by physical or proteolytic treatments that remove the outer capsid and causes activation of the BTV transcriptase. In addition to the seven structural proteins, three non-structural (NS) proteins, NS1, NS2, NS3 (and a related NS3A) are synthesised in BTV-infected cells. Of these, NS3/NS3A is involved in the egress of the progeny virus. The two remaining non-structural proteins, NS1 and NS2, are produced at high levels in the cytoplasm and are believed to be involved in virus replication, assembly and morphogenesis.

Current Research

Bluetongue virus (BTV) is well characterized both genetically (the sequence was completed in 1989) and structurally. Understanding of the molecular biology of the virus and mapping the role of each protein in virus life cycle has benefited significantly through the availability of recombinant BTV proteins and sub-viral particles. In addition the structure of BTV proteins, core and virionparticles have contributed greatly to understanding the mechanism of protein–protein interaction in the virus assembly pathway of BTV and other orbiviruses. Most importantly, information gained from these studies has laid sound foundation for the generation of safe BTV vaccines with the possibility of use in animals in the near future. Latterly, studies have concentrated on the fundamental mechanisms that are used by the virus to invade, replicate in and escape from susceptible host cells. Progress has been made in understanding the structure and entry of intact virus particles, the role of each enzymatic protein in the transcription complex, the critical interactions that occur between the viral non-structural proteins and viral RNA and the role of cellular proteins in non-enveloped virus egress.

Despite these advances, some critical questions remain unanswered for the BTV life cycle and a more complete understanding of the interactions between the virus and the host cell is required for these to be addressed. For example, although progress has been made in the identification of signals for the recruitment of BTV RNA segments into the virion assembly site in the host cell cytoplasm, it has not been possible yet to determine how exactly each genome segment is packaged into the progeny virus. It is also not apparent when and how these genome segments wrap around the polymerase complex once the RNA has been recruited. One of the major drawbacks of research with BTV and other members of Reoviridae has been the lack of availability of a suitable system for genetic manipulation of the virus. This has been a major obstacle in understanding the replication processes of these viruses. However, one of the recent developments in the field of BTV research has been to rescue live virus from transfection of BTV transcripts. There is no doubt that this will be soon extended to establish in vitro manipulative genetic system and will be utilized to address some of these remaining questions.

Very little is known of the intracellular trafficking of newly generated virions although there are some indications of involvement of the cytoskeleton, intermediate filaments and vimentin during BTV morphogenesis. Host–virus interactions during virus trafficking will be one of the future areas needing intense attention. Recent work has revealed unexpected and striking parallels between the entry and release pathways of BTV and pathways involved in entry and release of enveloped viruses. These parallels may be the result of an enveloped ancestor virus or because there are a limited number of cellular pathways that can be useful for the egress of large protein complexes from cells. It is notable that the NS3 glycoprotein of BTV is an integral membrane protein that is functionally involved in virus egress by bridging between the outer capsid protein VP2 and the cellular export machinery. Although no cell-free enveloped form of BTV has been isolated, budding of BTV particles from infected cells at the plasma membrane are quite apparent. The exact role of NS3 in this process and the role of host proteins (Annexin II and p11, Tsg101 and MVB) and their contribution in the release of non-enveloped viruses, such as BTV, remains to be clarified.

Epidemiology

Bluetongue has been observed in Australia, the USA, Africa, the Middle East, Asia and Europe. Its occurrence is seasonal in the affected Mediterranean countries, subsiding when temperatures drop and hard frosts kill the adult midge vectors. Bluetongue has been spreading northward since October 1998, perhaps as a result of global warming, which may promote viral survival and vector longevity during milder winters. A significant contribution to the northward spread of Bluetongue disease has been the ability of Culicoides obsoletus and C.pulicaris to acquire and transmit the disease, both of which are spread widely throughout Europe. This is in contrast to the original C.imicola vector which is limited to North Africa and the Mediterranean. The relatively recent novel vector has facilitated a far more rapid spread than the simple expansion of habitats North through global warming. In August 2006, cases of bluetongue were found in the Netherlands, then Belgium, Germany, and Luxembourg. In 2007, the first case of bluetongue in the Czech Republic was detected in one bull near Cheb at the Czech-German border. In September 2007, the UK reported its first ever suspected case of the disease, in a Highland cow on a rare breeds farm near Ipswich, Suffolk. Since then the virus has spread from cattle to sheep in Britain. By October 2007 bluetongue had become a serious threat in Scandinavia and Switzerland. In fall of 2008, several cases were reported in the southern Swedish provinces of Småland, Halland, and Skåne. Although the disease is not a threat to humans the most vulnerable common domestic ruminants in the UK are cattle, goats and, especially, sheep.

Infection of the foetus

A puzzling aspect of the spread of serotype 8 BTV in northern Europe is the overwintering of the disease. Animals will recover between the end of the midge season in fall and the beginning in spring, so it is believed that the virus somehow survives in overwintering midges. Researchers at the Institute for Animal Health (UK) has however offered an alternative hypothesis. Three cows that had recovered from bluetongue last Autumn, were exported from Holland to Northern Ireland in January 2008. In February, these cows gave birth to calves that were found to be carriers of the disease. If BTV is capable of transplacental infection of the ruminant foetus, this would be a plausible way for it to overwinter. Midges will then spread the disease from the calves to other animals, starting a new season of infection. Based on this finding, it is advised to pay special attention to newborn animals in an effort to eradicate the disease.

It was previously believed that only special lab-raised BTV were capable of transplacental infection. Experiments on sheep in the 1970s showed that such infection would result in abortion or weak or deformed offspring, with some offspring carrying the virus in their bloodstream. Such damage to the offspring was also seen for the calves born in Northern Ireland.

Symptoms

Major signs are high fever, excessive salivation, swelling of the face and tongue and cyanosis of the tongue. Swelling of the lips and tongue gives the tongue its typical blue appearance, though this sign is confined to a minority of the animals.

Nasal symptoms may be prominent, with nasal discharge and stertorous respiration.

Some animals also develop foot lesions, beginning with coronitis, with consequent lameness. In sheep, this can lead to knee-walking. In cattle, constant changing of position of the feet gives bluetongue the nickname "The Dancing Disease".

Torsion of the neck (opisthotonos or torticollis) is observed in severely affected animals.

Not all animals develop symptoms, but all those that do lose condition rapidly, and the sickest die within a week. For affected animals which do not die, recovery is very slow, lasting several months.

The incubation period is 5–20 days, and all symptoms usually develop within a month. The mortality rate is normally low, but it is high in susceptible breeds of sheep. In Africa, local breeds of sheep may have no mortality, but in imported breeds it may be up to 90 percent.

In cattle, goats and wild ruminants infection is usually asymptomatic despite high virus levels in blood. Red deer are an exception, and in them the disease may be as acute as in sheep.

Treatment and prevention

There is no efficient treatment. Prevention is effected via quarantine, inoculation with live modified virus vaccine and control of the midge vector, including inspection of aircraft.

However, simple husbandry changes and practical midge control measures may help break the livestock infection cycle. Housing livestock during times of maximum midge activity (from dusk to dawn) may lead to significantly reduced biting rates. Similarly, protecting livestock shelters with fine mesh netting or coarser material impregnated with insecticide will reduce contact with the midges. The Culicoides midges that carry the virus usually breed on animal dung and moist soils, either bare or covered in short grass. Identifying breeding grounds and breaking the breeding cycle will significantly reduce the local midge population. Turning off taps, mending leaks and filling in or draining damp areas will also help dry up breeding sites. Dung heaps and straw bedding should be removed at least weekly to break the midge breeding cycle.

Vaccine

Outbreaks in southern Europe have been caused by serotypes 2 and 4, and vaccines are available against these serotypes. However, the disease found in northern Europe (including the UK) in 2006 and 2007 has been caused by serotype 8. Vaccine companies Fort Dodge Animal Health (Wyeth), Merial and Intervet were developing vaccines against serotype 8 (Fort Dodge Animal Health has serotype 4 for sheep, serotype 1 for sheep and cattle and serotype 8 for sheep and cattle) and the associated production facilities. A vaccine for this is now available in the UK, produced by Intervet. Fort Dodge Animal Health has their vaccines available for multiple European Countries (vaccination will start in 2008 in Germany, Belgium, Switzerland, Spain and Italy).

Related diseases

African horse sickness is related to Bluetongue and is spread by the same midges (Culicoides species). It can kill up to 90% of the horses it infects.

References

See also

External links

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