AFRICAN HORSE SICKNESS VIRUSES
INTRODUCTION
African horse sickness virus (AHSV) causes a noncontagious, infectious, insect-borne disease of equids (African horse sickness – AHS) that was first recognized in Africa in the sixteenth century. The effects of the disease, particularly in susceptible populations of horses, can be devastating with mortality rates often in excess of 90%. Although AHS is normally restricted to Africa (and possibly north Yemen), the disease has a much wider significance as a result of the ability of AHSV to spread, without apparent warning,beyond the borders of that continent. For these reasons the virus has been allocated OIE ‘serious notifiable disease’status (i.e., communicable diseases which have the potential
for very rapid spread, irrespective of national borders, which are of serious socioeconomic or public health consequence and which are of major importance in the international trade of livestock or livestock products).
TAXONOMY, POPERTIES OF THE VIRION AND GENOME
Africa borsesickness virus is a species of the genus Orbivirus within the family. The virus is nonenveloped, approximately 90 nm in diameter and has an icosahedral capsid that is made up of three distinct concentric protein layers (Figure 1), and which is very similar to the structure of bluetongue virus (the prototype orbivirus). Nine distinct serotypes of AHSV have been identified by the specificity of interactions between the more variable viral proteins that make up the outermost layer of the virus capsid (VP2 and VP5), and neutralizing antibodies that are normally generated during infection of a mammalian host. The outer capsid layer surrounds the AHSV core particle ( 70 nm diameter), which has a surface layer composed of 260 trimers of VP7 attached to the virus subcore. These VP7 trimers form a closed icosahedral lattice, which is made up of five- and six-membered rings that are visible by electron microscopy, giving rise to the genus Orbivirus (from the Latin ‘orbis ’ meaning ring or cycle – Figure 2). The VP7 trimers synthesized in infected cells sometimes form into large hexagonal crystals, composed entirely of six membered rings, which can be observed by both electron and light microscopy.
The VP7 lattice on the core surface helps to stabilize the thinner and more fragile subcore layer, which is composed of 120 copies of VP3 arranged as 12 dish-shaped decamers that interact, edge to edge, to form the complete innermost capsid layer. This subcore shell also contains the three minor viral proteins (VP1, VP4, and VP6) that formapproximately 10 transcriptase complexes, associated with the 10 linear segments of dsRNA that make up the virus genome. The five viral proteins present in the AHSV core particle and two of the nonstructural proteins (NS1 and NS2) that are also synthesized within the cytoplasm of infected cells are relatively more conserved than the outer capsid proteins. NS1 forms long tubules within the infected cell cytoplasm that are characteristic of orbivirus
infections. NS2 is a major component of the granular matrices (viral inclusion bodies or VIBs) that represent the major site of viral RNA synthesis and particle assembly during the replication of AHSV and other orbiviruses (Figure 3). These more conserved AHSV proteins contain serogroup-specific epitopes, which cross-react between different AHSV serotypes and can therefore be used as a basis for serological assays to distinguish AHSV from the members of other species Orbivirus species (e.g., Equine encephalosis virus (EEV)).
AHSV genome segment 10 encodes two small but largely similar proteins, NS3 and NS3a, that are translated from two in-frame start codons near the upstream end of the genome segment (see Figure 4). These proteins, which (by analogy with bluetongue virus) are thought to be involved in the release of virus particles from infected cells, are also highly variable in their amino acid sequence, forming into three distinct major clades. The biological significance of sequence variation in NS3/3a is uncertain, although it is clearly independent of virus serotype. AHSV serotypes 1–8 are typically found only in restricted areas of sub-Saharan Africa while serotype 9 is more widespread and has been responsible for virtually all epizootics of AHS outside Africa. The only exception is the 1987–90 Spanish–Portuguese outbreak that was due to AHSV serotype 4. AHSV is relatively heat resistant; it is stable at 4 and –70 C but is labile between –20 and –30 C. It is partially resistant to lipid solvents. At pH levels below 6.0 the virus loses its outer capsid proteins, reducing its infectivity for mammalian cell systems, although the core particle retains a lower level of infectivity until it is disrupted at pH 3.0.
VERTEBRATE HOSTS
Equids are by far the most important vertebrate hosts of AHSV and the horse is the species most susceptible to disease, with mules and European donkeys somewhat less so. African donkeys are fairly resistant to clinical AHS, while zebra are usually only affected subclinically. Occasionally, dogs or wild carnivores may become infected with AHSV by ingesting virus-contaminated equid meat and can die from the disease. Some reports also suggest that they can be infected by insect bite but most authorities believe that they play little or no part in the epidemiology of AHS and are merely dead-end hosts. AHS is not a zoonosis. Although at least four human cases of severe disease have been documented, these were all infections acquired in an AHSV vaccine plant under conditions unlikely to be duplicated elsewhere.
CLINICAL SIGNS
AHSV can cause four forms of disease in equids and these are discussed in ascending order of severity. Horse sickness fever is the mildest form of disease involving only a rise in temperature and possibly, edema of the supraorbital fossae; there is no mortality. It occurs following the infection of horses with less virulent strains of virus, or when some degree of immunity exists. It is usually the only form of disease exhibited by the African donkey and zebra. The cardiac or subacute form of disease has an incubation period of about 7–14 days and then the first clinical sign is fever. This is followed by edema, first of the supraorbital fossae and surrounding ocular tissues (which may also exhibit hemorrhage), then extending to other areas of the head, neck, and chest. Petechial hemorrhages may appear in the conjunctivae and ecchymotic hemorrhages on the ventral surface of the tongue. Colic is also a feature of the disease. The mortality rate in horses from this form of disease may be as high as 50%and death usually occurs within 4–8 days of the onset of fever. The next most severe is the mixed form of AHS which is a combination of the cardiac and pulmonary forms with mortality rates in horses as high as 80%. The pulmonary form is peracute and may develop so rapidly that an animal can die without prior indication of disease. Usually, there will be marked depression and fever (39–41 C) followed by onset of respiratory distress. Coughing spasms may also occur, the head and neck tend to be extended, and severe sweating develops. There may be periods of recumbence and terminally, frothy fluid or foam may be discharged from the nostrils. Death is from congestive heart failure or asphyxia and the mortality rate in horses is frequently over 90%. During epizootics in naive populations of horses all forms of disease can occur but the mixed and pulmonary forms usually predominate, so mortality rates well in excess of 80% are likely, making AHS one of the most lethal of all horse diseases.
PATHOGENESIS
On entry into the vertebrate host, initial multiplication of AHSV occurs in the regional lymph nodes. This is followed by dissemination throughout the body via the blood (primary viremia) and subsequent infection of the lungs, spleen, and other lymphoid tissues, and certain endothelial cells. Virus multiplication in these tissues and organs gives rise to secondary viremia, which is of variable duration and titer dependent upon a number of factors including host species. Under natural conditions, the incubation period to the commencement of secondary viremia is less than 9 days, although experimentally it has been shown to vary between 2 and 21 days. In horses, a virus titer of up to 105.0 TCID50 ml 1 may be recorded but viremia usually lasts for only 4–8 days and has not been detected beyond 21 days. In zebra, viremia occasionally extends for as long as 40 days but peaks at a titer of only 102.5 TCID50 ml 1. Viremia in donkeys is intermediate between that in horses and zebra in titer and duration, while in dogs it is considered to be very low level and transitory.
In experimentally infected horses, high concentrations of AHSV accumulate in the spleen, lungs, caecum, pharynx, choroid plexus, and most lymph nodes. Subsequently,virus is found in most organs, probably due to their blood content. In the blood, virus is associated with the cellular fraction (both red blood cells and the buffy coat) and very little is present in the plasma. This may be similar to the situation that occurs with bluetongue virus, in infected ruminants where virus is sequestered in the cell membrane of infected red blood cells and is thereby protected from the effects of humoral antibody. This leads to both virus and antibody circulating in the system together. In ruminants, this leads to extended viremia. This seems not to occur with AHSV in horses although viremia in the presence of circulating antibody has been reported in zebra. For AHSV, the onset of viremia usually corresponds with the appearance of fever and persists until it disappears. In experimentally infected horses, exhibiting the peracute form of disease, antigen is found primarily in the cardiovascular and lymphatic systems and to a lesser extent throughout the body. In animals with horse sickness fever, antigen is concentrated in the spleen, with lesser amounts elsewhere. The main locations of antigen 6 African Horse Sickness Virusesare endothelial cells (suggesting that they are a primary target for the virus) and large cells of the red pulp of the spleen. The presence of antigen in large mononuclear cells and surrounding lymphoid follicles suggests that these cells might also be involved in virus replication and in the transport of viral protein to the lymphoid follicles.
Equids are by far the most important vertebrate hosts of AHSV and the horse is the species most susceptible to disease, with mules and European donkeys somewhat less so. African donkeys are fairly resistant to clinical AHS, while zebra are usually only affected subclinically. Occasionally, dogs or wild carnivores may become infected with AHSV by ingesting virus-contaminated equid meat and can die from the disease. Some reports also suggest that they can be infected by insect bite but most authorities believe that they play little or no part in the epidemiology of AHS and are merely dead-end hosts. AHS is not a zoonosis. Although at least four human cases of severe disease have been documented, these were all infections acquired in an AHSV vaccine plant under conditions unlikely to be duplicated elsewhere.
CLINICAL SIGNS
AHSV can cause four forms of disease in equids and these are discussed in ascending order of severity. Horse sickness fever is the mildest form of disease involving only a rise in temperature and possibly, edema of the supraorbital fossae; there is no mortality. It occurs following the infection of horses with less virulent strains of virus, or when some degree of immunity exists. It is usually the only form of disease exhibited by the African donkey and zebra. The cardiac or subacute form of disease has an incubation period of about 7–14 days and then the first clinical sign is fever. This is followed by edema, first of the supraorbital fossae and surrounding ocular tissues (which may also exhibit hemorrhage), then extending to other areas of the head, neck, and chest. Petechial hemorrhages may appear in the conjunctivae and ecchymotic hemorrhages on the ventral surface of the tongue. Colic is also a feature of the disease. The mortality rate in horses from this form of disease may be as high as 50%and death usually occurs within 4–8 days of the onset of fever. The next most severe is the mixed form of AHS which is a combination of the cardiac and pulmonary forms with mortality rates in horses as high as 80%. The pulmonary form is peracute and may develop so rapidly that an animal can die without prior indication of disease. Usually, there will be marked depression and fever (39–41 C) followed by onset of respiratory distress. Coughing spasms may also occur, the head and neck tend to be extended, and severe sweating develops. There may be periods of recumbence and terminally, frothy fluid or foam may be discharged from the nostrils. Death is from congestive heart failure or asphyxia and the mortality rate in horses is frequently over 90%. During epizootics in naive populations of horses all forms of disease can occur but the mixed and pulmonary forms usually predominate, so mortality rates well in excess of 80% are likely, making AHS one of the most lethal of all horse diseases.
PATHOGENESIS
On entry into the vertebrate host, initial multiplication of AHSV occurs in the regional lymph nodes. This is followed by dissemination throughout the body via the blood (primary viremia) and subsequent infection of the lungs, spleen, and other lymphoid tissues, and certain endothelial cells. Virus multiplication in these tissues and organs gives rise to secondary viremia, which is of variable duration and titer dependent upon a number of factors including host species. Under natural conditions, the incubation period to the commencement of secondary viremia is less than 9 days, although experimentally it has been shown to vary between 2 and 21 days. In horses, a virus titer of up to 105.0 TCID50 ml 1 may be recorded but viremia usually lasts for only 4–8 days and has not been detected beyond 21 days. In zebra, viremia occasionally extends for as long as 40 days but peaks at a titer of only 102.5 TCID50 ml 1. Viremia in donkeys is intermediate between that in horses and zebra in titer and duration, while in dogs it is considered to be very low level and transitory.
In experimentally infected horses, high concentrations of AHSV accumulate in the spleen, lungs, caecum, pharynx, choroid plexus, and most lymph nodes. Subsequently,virus is found in most organs, probably due to their blood content. In the blood, virus is associated with the cellular fraction (both red blood cells and the buffy coat) and very little is present in the plasma. This may be similar to the situation that occurs with bluetongue virus, in infected ruminants where virus is sequestered in the cell membrane of infected red blood cells and is thereby protected from the effects of humoral antibody. This leads to both virus and antibody circulating in the system together. In ruminants, this leads to extended viremia. This seems not to occur with AHSV in horses although viremia in the presence of circulating antibody has been reported in zebra. For AHSV, the onset of viremia usually corresponds with the appearance of fever and persists until it disappears. In experimentally infected horses, exhibiting the peracute form of disease, antigen is found primarily in the cardiovascular and lymphatic systems and to a lesser extent throughout the body. In animals with horse sickness fever, antigen is concentrated in the spleen, with lesser amounts elsewhere. The main locations of antigen 6 African Horse Sickness Virusesare endothelial cells (suggesting that they are a primary target for the virus) and large cells of the red pulp of the spleen. The presence of antigen in large mononuclear cells and surrounding lymphoid follicles suggests that these cells might also be involved in virus replication and in the transport of viral protein to the lymphoid follicles.
PATHOLOGY
A. Macrolesions
These vary in accordance with the type of disease. In the pulmonary form, the most conspicuous lesions are interlobular edema of the lungs and hydrothorax. The sub pleural and interlobular tissues are infiltrated with a yellowish gelatinous exudate and the entire bronchial tree may be filled with a surfactant, stabilized froth. Ascites can occur in the abdominal and thoracic cavities and the stomach mucosa may be hyperemic and edematous. In the cardiac form, the most prominent lesions are gelatinous exudate in the subcutaneous, subfascial and intramuscular tissues, and lymph nodes. Hydropericardium is seen and hemorrhages are found on the epicardial and/or endocardial surfaces. Petechial hemorrhages and/ or cyanosis may also occur on the serosal surfaces of the cecum and colon. In these instances, a distinct demarcation can often be seen between affected and unaffectedparts. This may be due to a selective involvement of endothelial cells. As in the pulmonary form, ascites may occur but edema of the lungs is usually absent. In the mixed form of AHS, lesions common to both the pulmonary and cardiac forms of the disease occur.
B. Microlesions
The histopathological changes are a result of increased permeability of the capillary walls and consequent impairment in circulation. The lungs exhibit serous infiltration of the interlobular tissues with distension of the alveoli and capillary congestion. The central veins of the liver may be distended, with interstitial tissue containing erythrocytes and blood pigments while the parenchymous cells show fatty degeneration. Cellular infiltration can be seen in the cortex of the kidneys while the spleen is heavily congested. Congestion may also be seen in the intestinal and gastric mucosae, and cloudy swelling in the myocardial and skeletal muscles.
EPIDEMILOGY AND TRANSMISSION
AHSV is widely distributed across sub-Saharan Africa. It is enzootic in a band stretching from Senegal and Gambia in the west to Ethiopia and Somalia in the east, and reaching as far south as northern parts of South Africa. The virus is probably also enzootic in northern Yemen, the only such area outside the African continent. From these zones, the virus makes seasonal extensions both northward and southward in Africa. The degree of extension is dependent mainly upon the climatic conditions and how these affect the abundance, prevalence, and seasonal incidence of the vector insects. More rarely, the virus has spread much more widely and has extended as far as Pakistan and India in the east and Spain and Portugal in the west. However, prior to the 1987–91 Spanish, Portuguese, and Moroccan outbreaks, AHSV had been unable to persist for more than 2–3 consecutive years in any area outside sub-Saharan Africa or Yemen.
AHSV is transmitted between its vertebrate hosts almost exclusively via the bites of hematophagous arthropods. Various groups have been implicated over the years, ranging from mosquitoes to ticks, but certain species of Culicoides biting midge are considered to be by far the most significant vectors. Biting midges act as true biological vectors and support virus replication by up to 10 000-fold. Subsequent to feeding upon a viremic equid, susceptible species of become capable of Culicoides transmission after an incubation period of 8–10 days at 25 C. This period lengthens as the temperature falls, and becomes infinite below 15–18 C. The incubation or prepatent period in the vector is the time interval necessary for ingested virus to escape from the gut lumen by entering and replicating in the mid-gut cells, and then for progeny virus particles released into the hemocoel to reach and replicate in the salivary glands. Transovarial or vertical transmission of AHSV by biting midge vectors does not occur.
Culicoides imicola, a widely distributed species found across Africa, southern Europe, and much of Asia, is the major vector of AHSVand has long been considered to be the only important field vector. However, a closely related species C. bolitinos has recently been identified as a second vector in Africa, and the North American C. sonorensis (= varripennis) (¼ ) is a highly efficient vector in the laboratory. The identification of additional vectors is likely. In general, Culicoides species have a flight range of less than a few kilometers. However, in common with many other groups of flying insects, they have the capacity to be transported as ‘aerial plankton’ over much greater distances. In this context, a considerable body of evidence suggests that the emergence of AHSV from its enzootic
zones may sometimes be due to long-range dispersal flights by infected vectors carried on the prevailing winds.
DIAGNOSIS
In enzootic areas, the typical clinical features of AHS (described earlier) can be used to form a presumptive African Horse Sickness Viruses 7diagnosis. Laboratory confirmation should then be sought. The specimens likely to be required are:
1. Boold for virus isolation
2. Tissue for virus isolation (or for antigen detection by ELISA or RT-PCR-based assays) : Spleen is best, followed by lung, liver, heart, and lymph nodes.
3. Serum for serologycal test : Preferably, paired samples should be taken 14–28 days apart.
Confirmation of AHS is by one or more of the following:
1. Identification of the virus in submitted samples by the group specific, antigen detection ELISA or RT-PCR–based assays. AHSV RNA can be identified by RT-PCR assays using virus-species-specific oligonucleotide primers. This identification can be confirmed by sequence analyses of the resulting cDNA products and comparison to sequences previously determined for reference strains of AHSV and other orbiviruses.
2. Isolation of infectious virus in suckling mice or embryonating hens’ eggs identification first by the group specific antigen-detection ELISA, and then by the serotype-specific, virus neutralization or RT-PCR tests.
3. Identification of AHSV-specific antibodies by the group-specific antibody detection ELISA, CF, or the serotype-specific virus neutralization tests.
TREATMENT
Apart from supportive treatment, there is no specific therapy for AHS. Affected animals should be nursed carefully, fed well, and given rest as even the slightest exertion may result in death. During convalescence, animals should be rested for at least 4 weeks before being returned to light work.
CONTROL
Importation of equids from known infected areas to virus-free zones should be restricted. If importation is permitted, animals should be quarantined for 60 days in insect-proof accommodation prior to movement Following an outbreak of AHS in a country or zone that has previously been free of the disease, attempts should be made to limit further transmission of the virus and to achieve eradication as quickly as possible. It is important that control measures are implemented as soon as a suspected diagnosis of AHS has been made and without waiting for confirmatory diagnosis. The control measures appropriate for outbreaks of AHS in enzootic and epizootic situations are described in Mellor and Hamblin.
DIFFERENTIAL DIAGNOSIS
The clinical signs and lesions reported for AHS can be confused with those caused by the closely related EEV. Many aspects of the epidemiology of the diseases caused by these two viruses are also similar. They have a similar geographical distribution and vertebrate host range and the same vector species Culicoides of As a result, both can occur simultaneously in the same locations and even in the same animal. Fortunately, rapid, sensitive, and specific ELISAs are available to enable the detection of the antigen and antibody of both the AHSV and EEV, and if used in conjunction can provide a rapid and efficient differential diagnosis. Several other diseases may also be confused with one or other of the forms of AHS. The hemorrhages and edema reported in cases of purpura hemorrhagica and equine viral arteritis may be similar to those seen in the pulmonary form of AHS, although with AHS the edema tends to be less extensive and the hemorrhages are less numerous and widespread. The early stages of babesiosis Babesia equi ( and ) B. caballi can be confused with AHS, particularly when the parasites are difficult to demonstrate in blood smears.
FURTHER READING
Coetzer JAW and Guthrie AJ (2004) African horsesickness. In: Coetzer JAW and Tustin RC (eds.) Infectious Diseases of Livestock, 2nd edn, pp. 1231–1246. Cape Town: Oxford University Press.
Hess WR (1988) African horse sickness. In: Monath TP (ed.) The Arboviruses: Epidemiology and Ecology, vol. 2, pp. 1–18. Boca Raton, FL: CRC Press.
Howell PG (1963) African horsesickness. In: Emerging Diseases of Animals, pp. 71–108. Rome: FAO Agricultural Studies.
Lagreid WW (1996) African horsesickness. In: Studdert MJ (ed.) Virus Infections of Equines, pp. 101–123. Amsterdam: Elsevier.
Meiswinkel Venter GJ and Nevill EM (2004) Vectors:Culicoides spp. In: Coetzer JAW and Tustin RC (eds.) Infectious Diseases of Livestock, 2nd edn, pp. 93–136. Cape Town: Oxford University
Press.
Mellor PS (1993) African horse sickness: Transmission and epidemiology. Veterinary Research 24: 199–212. Mellor PS (1994) Epizootiology and vectors of African horse sickness virus. Comparative Immunology, Microbiology and Infectious Diseases 17: 287–296.
Mellor PS, Baylis M, Hamblin C, Calisher CH, and Mertens PPC (eds.) (1998) African Horse Sickness. Vienna: Springer.
Mellor PS and Hamblin C (2004) African horse sickness. Veterinary Research 35: 445–466.
Mertens PPC and Attoui H (eds.) (2006) Phylogenetic sequence analysis and improved diagnostic assay systems for viruses of the family
RELEVANT WEBSITE
http://www.oie.int – OIE data on AHSV outbreaks.
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