Bluetongue disease
Encyclopedia
Bluetongue disease or catarrhal fever is a non-contagious
Infectious disease
Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...

, non-zoonotic
Zoonosis
A zoonosis or zoonoseis any infectious disease that can be transmitted from non-human animals to humans or from humans to non-human animals . In a study of 1415 pathogens known to affect humans, 61% were zoonotic...

, insect-borne, viral
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

 disease of ruminant
Ruminant
A ruminant is a mammal of the order Artiodactyla that digests plant-based food by initially softening it within the animal's first compartment of the stomach, principally through bacterial actions, then regurgitating the semi-digested mass, now known as cud, and chewing it again...

s, mainly sheep
Domestic sheep
Sheep are quadrupedal, ruminant mammals typically kept as livestock. Like all ruminants, sheep are members of the order Artiodactyla, the even-toed ungulates. Although the name "sheep" applies to many species in the genus Ovis, in everyday usage it almost always refers to Ovis aries...

 and less frequently cattle, goats, buffalo
Bovinae
The biological subfamily Bovinae includes a diverse group of 10 genera of medium to large sized ungulates, including domestic cattle, the bison, African buffalo, the water buffalo, the yak, and the four-horned and spiral-horned antelopes...

, deer
Deer
Deer are the ruminant mammals forming the family Cervidae. Species in the Cervidae family include white-tailed deer, elk, moose, red deer, reindeer, fallow deer, roe deer and chital. Male deer of all species and female reindeer grow and shed new antlers each year...

, dromedaries
Dromedary
The dromedary or Arabian camel is a large, even-toed ungulate with one hump on its back. Its native range is unclear, but it was probably the Arabian Peninsula. The domesticated form occurs widely in North Africa and the Middle East...

 and antelope
Antelope
Antelope is a term referring to many even-toed ungulate species indigenous to various regions in Africa and Eurasia. Antelopes comprise a miscellaneous group within the family Bovidae, encompassing those old-world species that are neither cattle, sheep, buffalo, bison, nor goats...

. It is caused by the Bluetongue virus (BTV).

Pathogen and vector

Bluetongue is caused by the 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...

ic virus, Bluetongue virus (BTV), of the genus Orbivirus
Orbivirus
The genus Orbivirus is a member of the Reoviridae family. This genus currently contains 22 species and at least 130 different serotypes. Orbiviruses can infect and replicate within a wide range of arthropod and vertebrate hosts...

, is a member of 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...

 family. There are 25 serotype
Serotype
Serotype or serovar refers to distinct variations within a subspecies of bacteria or viruses. These microorganisms, viruses, or cells are classified together based on their cell surface antigens...

s. It is transmitted by a midge
Midge
A midge is a very small, two-winged flying insect. "Midge" may also refer to:-Real:* Midge Costanza , American politician* Mildred Gillars , aka "Midge", American broadcaster of Nazi propaganda during World War II...

, Culicoides imicola
Culicoides imicola
Culicoides imicola is a midge which transmits the bluetongue virus. Other suspected BTV vectors areCulicoides pulicaris and species in the Culicoides obsoletus complex....

and other culicoid
Culicoides
Culicoides is a genus of biting midges in the subfamily Ceratopogonidae. Around 500 species of Ceratopogonidae are at present placed in the genus and this is split into many subgenera. Several species are known to be vectors of various diseases and parasites which can affect animals.-Notable...

s.

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 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...

s and a RNA 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....

 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 (such as rotavirus
Rotavirus
Rotavirus is the most common cause of severe diarrhoea among infants and young children, and is one of several viruses that cause infections often called stomach flu, despite having no relation to influenza. It is a genus of double-stranded RNA virus in the family Reoviridae. By the age of five,...

) 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
Epizootic Hemorrhagic Disease
Epizootic Hemorrhagic Disease is an orbivirus that infects White-tailed Deer in the northeastern and midwestern United States. The virus is transmitted by the Culicoides biting midge. The EHD virus is closely related to the Bluetongue virus and crossreacts with it on many blood tests...

 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 (for example, 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 (for example,, blesbuck, white-tailed deer, elk, pronghorn antelope, and so on.). 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.

Twenty six serotypes are now recognised for this virus.

Current research

Bluetongue virus (BTV) is well characterized both genetically (the sequence was completed in 1989) and structurally. Understanding of the molecular biology
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...

 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 virion particles have contributed greatly to understanding the mechanism of protein–protein interaction in the virus assembly pathway of BTV and other orbivirus
Orbivirus
The genus Orbivirus is a member of the Reoviridae family. This genus currently contains 22 species and at least 130 different serotypes. Orbiviruses can infect and replicate within a wide range of arthropod and vertebrate hosts...

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

 segments into the virion assembly site in the host cell cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

, it has not been possible yet to determine how exactly each 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....

 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
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...

 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
Transfection
Transfection is the process of deliberately introducing nucleic acids into cells. The term is used notably for non-viral methods in eukaryotic cells...

 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
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic 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
Global warming
Global warming refers to the rising average temperature of Earth's atmosphere and oceans and its projected continuation. In the last 100 years, Earth's average surface temperature increased by about with about two thirds of the increase occurring over just the last three decades...

, 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
Cheb
Cheb is a city in the Karlovy Vary Region of the Czech Republic, with about 33,000 inhabitants. It is situated on the river Ohře , at the foot of one of the spurs of the Smrčiny and near the border with Germany...

 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 and the first outbreak in Denmark was reported. In autumn 2008, several cases were reported in the southern Swedish provinces of Småland, Halland, and Skåne,

as well as in areas of the Netherlands bordering Germany, prompting veterinary authorities in Germany to intensify controls.

Norway saw its first finding in February 2009, when cows at two farms in Vest-Agder
Vest-Agder
In the 16th century, Dutch merchant vessels began to visit ports in southern Norway to purchase salmon and other goods. Soon thereafter the export of timber began, as oak from southern Norway was exceptionally well suited for shipbuilding...

 in the south of Norway showed an immune response to bluetongue. Norway have since been declared free of the disease in 2011.

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 fetus

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 autumn 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 the previous autumn were exported from the Netherlands to Northern Ireland
Northern Ireland
Northern Ireland is one of the four countries of the United Kingdom. Situated in the north-east of the island of Ireland, it shares a border with the Republic of Ireland to the south and west...

 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 saliva
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...

tion, swelling
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...

 of the face and tongue and cyanosis
Cyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...

 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
Torticollis
Torticollis, or wryneck, is a stiff neck associated with muscle spasm, classically causing lateral flexion contracture of the cervical spine musculature...

) 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
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...

 is 5–20 days, and all symptoms usually develop within a month. The mortality rate
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...

 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
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

 is usually 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...

 despite high virus levels in blood. Red deer
Red Deer
The red deer is one of the largest deer species. Depending on taxonomy, the red deer inhabits most of Europe, the Caucasus Mountains region, Asia Minor, parts of western Asia, and central Asia. It also inhabits the Atlas Mountains region between Morocco and Tunisia in northwestern Africa, being...

 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
Quarantine
Quarantine is compulsory isolation, typically to contain the spread of something considered dangerous, often but not always disease. The word comes from the Italian quarantena, meaning forty-day period....

, inoculation
Inoculation
Inoculation is the placement of something that will grow or reproduce, and is most commonly used in respect of the introduction of a serum, vaccine, or antigenic substance into the body of a human or animal, especially to produce or boost immunity to a specific disease...

 with live modified virus vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

 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. Control by trapping midges and removing their breeding grounds may reduce vector numbers. Dung heaps or slurry pits should be covered or removed, and their perimeters (where most larvae are found) regularly scraped.

Vaccine

Outbreaks in southern Europe have been caused by serotypes 2 and 4, and vaccines are available against these serotypes (ATCvet codes: for sheep, for cattle). 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
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...

), 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
African Horse sickness
African horse sickness is a highly infectious, and deadly disease. It commonly affects horses, mules, and donkeys. It is caused by a virus of the genus Orbivirus belonging to the family Reoviridae. This disease can be caused by any of the nine serotypes of this virus...

 is related to Bluetongue and is spread by the same midges (Culicoides species). It can kill the horses it infects and mortality may go as high as 90% of the infected horses during an epidemic.

External links

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