Diseases caused by Akabane and related Simbu-group viruses

Previous authors: T D ST GEORGE AND P D KIRKLAND

Current authors:
P D KIRKLAND - Senior Principal Researcher Scientist, Manager Virology Laboratory, BVSc, PhD, FAMS, Elizabeth Macarthur Agriculture Institute, Woodbrigde Road, Menangle, New South Wales, 2568, Australia
T D ST GEORGE - Retired from Commonwealth Scientific & Industrial Research Organisation, DVM, MVSc, BVSc, Virus Consultants International, 44/260 Cliveden Avenue, Corinda, Queensland, 4075, Australia

GENERAL INTRODUCTION: BUNYAVIRIDAE

Introduction

Many viruses in the Simbu-group of the genus Orthobunyavirus family Peribunyaviridae, order Bunyavirales¹ have not been identified as pathogens but those that are pathogenic usually cause congenital defects after infection of a susceptible pregnant small stock and  cattle. The defects  are principally arthrogryposis (AG) and hydranencephaly (HE) and can be associated with abortion in cattle, sheep and goats.  These viruses usually produce clinically inapparent infections in non-pregnant animals. However, in pregnant cattle, sheep and goats, if the viruses reach the foetus at a critical stage of development, marked teratology, particularly of the central nervous system, may result. The defects are usually only apparent some months later with the birth of affected calves and lambs. Some Simbu-group viruses also occasionally cause post-natal encephalitis in a range of mammalian species. Antibodies to Akabane and related arboviruses are found in cattle, sheep, goats and wild and other domestic animals in Africa, Middle East and the Asian-Pacific region.  In 2011 Schmallenberg virus, a previously unrecognised Simbu virus, has emerged and spread throughout most of Europe.³⁰

The name ‘Akabane disease’ has been used,³⁵ but it is not apt as Akabane virus is only one member of the Simbu-group, several of which may produce similar defects, including the recently recognised Schmallenberg virus. Akabane virus is nevertheless by far the best studied and probably most pathogenic member of the group.

The relationship between Akabane virus and congenital AG/HE was first recognized in Japan between 1972 and 1975.³⁵ The studies in Japan and Australia, which in 1974 confirmed the link between infection with Akabane virus and AG/HE, have been reviewed.^{35, 63} Disease caused by Simbu-group viruses in Africa is poorly defined, though AG/HE has been observed in cattle in KwaZulu-Natal, South Africa, and in sheep in Zimbabwe.⁶⁹

Although the association of Akabane and related viruses with epidemics of AG/HE is comparatively recent (1974), the syndrome was recognized much earlier. There are reliable records of its occurrence in Australia in the early 1930s²⁹ when it was attributed to plant poisoning, in Japan in 1949³⁵ and in Israel in 1969/70.⁵⁰

Other viruses of the Simbu-group which have been associated with similar disease are Aino,¹² Peaton, Schmallenberg,⁶ Shamonda³¹ Shuni⁸¹ and Tinaroo, although clinical cases in the field due to Aino are not common and are rare with Peaton⁵² and Tinaroo.⁴³ Schmallenberg virus has been responsible for an extensive outbreak of congenital defects in cattle, sheep and goats following its emergence in fully susceptible livestock populations in western Europe in 2011.^{6, 17} Shuni virus has been associated with encephalitis in horses and a range of wildlife species in South Africa⁸¹ and congenital defects in ruminants in Israel.²² Cache Valley virus, which belongs to a separate serogroup within the family Peribunyaviridae, is widely distributed in North America and has been reported to produce AG/HE in sheep in Texas.¹⁹

Aetiology

Viruses within the Simbu-group, one of the 36 antigenic clusters within the family Peribunyaviridae, have spherical, enveloped virions, 90 to 100 nm in diameter. They have tripartite segmented single-stranded RNA and are readily inactivated by chloroform, ether and trypsin. Akabane virus degrades moderately quickly at 37 °C,³⁵ remains viable in blood samples kept at 4 °C for several months, and can be stored indefinitely at −70 °C or lower. For more information on the properties of the viruses which belong to the Peribunyaviridae, see General Introduction: Bunyaviridae and Rift Valley fever.

Epidemiology

Most of Africa, Asia (excluding Russia), and Australia may be regarded as endemic for Akabane virus and, in all probability, many of its antigenic relatives. Schmallenberg virus is the only Simbu virus that has been identified in Europe and England. The American continent (except for the presence of Cache Valley virus of the Bunyamwera serogroup), Papua-New Guinea and the island countries of the Pacific are believed to be free of infection with Simbu-group bunyaviruses.⁷⁴ However, the distribution of Akabane and related viruses within each country is affected by the distribution, seasonal activity and abundance of  insect vectors.

The isolation of Akabane virus from mosquitoes⁶² and the biting midge, Culicoides brevitarsis,¹⁸ preceded its incrimination as a cause of disease in sheep or cattle and was a necessary step in unravelling the aetiology. Despite the association between Akabane virus and biting arthropods, the virus has not yet been transmitted experimentally to any vertebrate by any species of insect. The virus has, however, been shown to multiply in experimentally infected C. brevitarsis and to reach the salivary glands in 10 days.⁵⁹ Transovarial transmission was not demonstrated in a study involving 11 600 C. brevitarsis, indicating that transovarial transmission is not a frequent event if it occurs at all.³ The effects of local climate on the relative densities of  Culicoides spp. and on the transmission of Akabane virus have been described.⁶⁰ Since its recognition in Europe in 2011, extensive research of the biology and epidemiology of Schmallenberg virus infection has also been undertaken.^{6, 17, 78}

The majority of Simbu-group virus isolations in Africa were made in the course of arbovirus surveys and little is known of their veterinary significance. Akabane virus has been isolated from mosquitoes in Kenya⁵⁶ and Culicoides midges in Zimbabwe.⁴⁸ It is not known whether the virus occurs in South Africa.⁵ Simbu virus, originally isolated from mosquitoes in South Africa,^{54, 83, 85} has since been isolated from mosquitoes in Cameroon, Senegal and the Central African Republic.³⁶ Ingwavuma virus, originally isolated from the viscera of a weaver bird and from mosquitoes in South Africa,^{53, 55} has been isolated from birds and mosquitoes in the Central African Republic and Nigeria.³⁶ Sabo, Sango, Shamonda and Shuni viruses were all originally isolated from cattle or goat sera, and subsequently from midges,⁷⁹ in the course of surveys in Nigeria.^{9, 36} Sango virus has also been isolated from mosquitoes in Kenya³⁶ and Shuni virus from mosquitoes in South Africa.⁵⁴ A serological survey of horses in various regions in South Africa failed to detected antibodies to Simbu, Ingwavuma or Sathuperi viruses, a few animals had titres to Akabane and Shuni viruses, and antibody titres to Shamonda and Sabo viruses were prodominant.³² A serological study of cattle in Tanzania⁵¹ showed a similar distribution of a number of Simbu viruses, including Sabo, Sathuperi and Shamonda viruses. Interestingly, results suggest that Aino, Douglas, Peaton and Tinaroo viruses may also be present. None of these viruses had been detected previously in Africa.

Other than in Japan, Indonesia, Malaysia and Australia, where serological surveys have demonstrated their presence, information on infection with closely related viruses (Aino, Peaton, Tinaroo and Douglas viruses) is patchy. In Japan, Sathuperi and Shamonda viruses have  been identified³¹ while Akabane virus infection has been found in pigs.⁸⁶

Virus identification and characterization may  be complicated by the occurrence of reassortant viruses or dual infections.¹³

Akabane virus has been isolated from two species of mosquitoes and Culicoides oxystoma in Japan⁴⁶ and from C. brevitarsis and C. wadai in Australia.⁷⁴ In Australia, the principal Culicoides vector species are dependent on cattle dung for breeding sites and their highest density is in areas of moderate to high rainfall. In Africa, the probable vectors are not so restricted and can breed in pastures rich in organic matter (see Vectors: Culicoides spp.). In Europe, Schmallenberg virus has been detected in several Culicoides species.⁸²

The presence of infection in wildlife species complicates the epidemiology in Africa — in contrast to Australia where marsupials are not infected and Asian countries where there are few susceptible wildlife species. Neutralizing antibodies have been found in a wide range of African species including several antelope species, elephants, giraffe, impala, kudu, warthog and wildebeest.^{2, 15} In Europe, antibodies to Schmallenberg virus have been detected in a wide range of wildlife species including bison, roe deer, llama and wild boar.⁵⁸ No disease has been linked to the infection of wildlife with Akabane virus and related Simbu-group viruses, but most new-born animals with congenital defects would be taken by predators.

In Australia the relative simplicity of the vector system and effective surveillance using sentinel cattle has resulted in the ability to forecast epidemics of AG/HE in the most severely affected area.⁴² Major epidemics of AG/HE disease in Japan, involving 30 000 calves, and in Australia, involving approximately 3 000 to 5 000 calves, have been described.^{26, 27, 34} Waves of abortion were detected in both Australia and Japan about two months before the birth of affected calves at full term.^{35, 70} It has been estimated that in Australia there is an ongoing economic loss within the tropical endemic areas with at least a quarter of a million cows at risk each year.⁷⁷ In Europe, when Schmallenberg virus entered an extremely large, naive livestock population, a large number of cases were reported in cattle, goats and sheep but the within herd prevalence was mostly low compared to what is seen with Akabane virus. As a result of having a large number of foetuses at critical stages of gestation, higher losses were sometimes seen when synchronised breeding flocks of ewes were infected.

Pathogenesis

The pathogenesis of disease caused by Akabane virus has been reviewed.^{35, 38, 67, 74} Akabane virus is present in the blood of naturally infected cattle for three to four days.⁷⁵ Using sentinel cattle herds to estimate the time of transmission, it has been possible to accurately relate the time of infection to stage of pregnancy and to anticipate the spectrum of tissue damage in foetuses.^{16, 41, 48} The lesions characteristic of natural disease have been reproduced by infecting pregnant cattle, sheep and goats experimentally with Akabane virus and by allowing them to progress to term.^{45, 49, 65}

The relationship between infection and developmental stage of the foetus determines whether foetal death and abortion, or a range of teratogenic defects will result. During pregnancy, the virus crosses from the maternal to the foetal circulation, infecting the placenta in the process.⁶⁸ The virus then multiplies in the rapidly dividing cells of the foetus, especially in the brain and spinal cord.⁶³ Whether the resultant damage following infection is entirely due to damage to the foetal cells, limiting capacity to divide and develop into mature tissues, or whether it is partially due to necrosis of formed tissues, is uncertain. In cattle, maximal damage occurs at approximately 12 to 16 weeks of gestation, when neural tissues, especially in the brain, are differentiating. Infection of sheep and goats at the most critical stage of gestation (28-36 days) results in extensive damage to the central nervous system and severe  defects.

The duration of infection in the foetus is related to the immunocompetence of individual foetuses to develop antibodies which can neutralize the virus. Immunocompetence develops in calves from about 70 days and in lambs between 65 and 70 days of gestation^{64, 67} (see Bovine viral diarrhoea and mucosal disease, and Border disease).

Comparable observations have been made in ruminants infected with Schmallenberg virus, although the impact has been greater in sheep than in cattle.^{21, 80}

There is little information available on the effects of the other Simbu-group viruses on mammalian hosts, but their mode of action and effects are probably similar to those of Akabane virus.

Clinical signs

Typically, infection of ruminants with Akabane virus after birth results in no clinical signs. However, there are strains of Akabane virus in Japan that have been shown to be a cause of acute encephalitis in both young calves and mature cattle. Aino, Peaton, Douglas and Tinaroo viruses have all been isolated on several occasions from sentinel cattle under close daily observation without the detection of any overt clinical signs.^{71-73, 76} When Schmallenberg virus first emerged in Europe, some cattle were observed with a fever and acute diarrhoea³⁰ while Shuni virus in Africa has been associated with meningoencephalitis in horses and wildlife species including African buffalo, warthogs, sable antelope and white rhinoceros.^{10, 14, 20, 81}

When pregnant ruminants are infected with Akabane virus, except for some abortions in the third trimester of pregnancy, there are no other clinical signs until progeny are born.⁷⁵

Calves and lambs that develop HE or AG, or both, as a result of intrauterine infection with Akabane virus may be aborted, stillborn or delivered alive at term. Gestation periods, particularly when sheep are affected, may be prolonged and birth-weights reduced.²⁸

In cattle, the species in which the greatest losses usually occur, the range and severity of congenital abnormalities varies depending on the stage of gestation at which the foetus is infected. In herds with either ‘year round’ or extended calving periods, the full spectrum of abnormalities may be seen. Intensive study of cattle exposed to Akabane virus at different stages throughout gestation has demonstrated the sequential occurrence of defects in calves ranging from AG through to severe HE.⁴¹ Naturally, these conditions are observed in a ‘reverse’ sequence. Those that are the result of infection late in gestation are seen in the first calves born (eg. polioencephalomyelitis followed by AG) while those that result following infection early in gestation HE are seen towards the end of calving. With very restricted seasonal breeding periods or limited periods of exposure to infected vectors, abnormalities may be limited to one type, for example only arthrogryposis. Calves that are infected very late in gestation may develop polioencephalomyelitis. At birth they are alert but unable to stand and have flaccid paralysis or incoordination of the limbs. Infections that occur in cattle from late in the first and throughout the second trimester of  gestation (3-6 months of pregnancy) give rise to the conditions shown in Figures 1 to Figures 4. Animals with AG have fixed joints and muscular atrophy and may not be able to rise. Such defects often give rise to dystocia, and intervention to save the dam may be required. One or more joints on up to all four limbs may be involved to a greater or lesser extent. As calves are infected earlier in gestation (4-5 months), there is a tendency for more severe AG with  more joints and more limbs to be involved and abnormalities of the spinal column (eg. torticollis and scoliosis) may also be observed.⁴⁰ Some new-born animals with only one limb affected can rise and may improve their mobility with time. Hydranencephaly is the outcome of infection during the third and fourth months of gestation, with more severe defects following infection at the earliest stages of pregnancy. In severe cases of HE, the cerebral hemispheres are reduced to membranous fluid-filled sacs with only the brainstem and cerebellum remaining. In lambs and goat kids infected at 28-36 days of gestation, lesions of the brain and spinal cord are even more severe.

Figure 1 Marked arthrogryposis in a stillborn lamb following transplacental infection with Akabane virus (By courtesy of Dr W.J. Hartley)

Figure 2 Marked hydranencephaly in a calf. Note the almost complete absence of the cerebral hemispheres while the midbrain and cerebellum are still relatively well developed (By courtesy of Dr W.J. Hartley)

Figure 3 Hydranencephaly with almost complete absence of cerebrum. The brain stem structures are intact. Before removal of the meninges the cavity was filled with fluid.

Figure 4 Hereford calf with arthrogryposis. The flexure can be best seen in the hind limbs. The shape of the skull is an indication that hydranencephaly may also be present.

Depending on the extent of the defects, calves with brain lesions may have higher functions impaired. Those with some cerebral function may suck without assistance and learn to follow their dam or the group of cattle to which they belong. At the other extreme, calves may be blind, ‘dopey’ or unable to respond to their dam and find her udder and so are eventually abandoned. Usually the sucking reflex is intact and they can be hand-fed. Even when the cerebrum is more or less entirely absent, all vital functions are usually intact and the calf can stand and may be able to walk but may die from misadventure. Some have been reared to maturity and have even calved normally.

An essentially similar pattern occurs in sheep although the successive progession of lesions noted in cattle is less distinct. For example, lambs are often born with both severe AG and HE. The congenital abnormalities described for Schmallenberg virus are indistinguishable from those induced by Akabane virus. However, Schmallenberg is less teratogenic¹¹ and on a flock or herd basis the incidence of abnormal offspring is generally lower.

Pathology

The gross and histological changes observed in both field and experimental cases resulting from Akabane virus infection of cattle and sheep have been described in detail.^{24, 25, 44, 45, 65, 66, 84} An outline of the sequential occurrence of gross pathological changes has also been described under clinical signs (see Clinical signs). When cows are infected at different stages of pregnancy, the longer gestational length results in less severe lesions in the CNS. The neurological signs that are observed when calves are infected around the time of birth, and occasionally in older animals⁸⁶ are the result of an acute polioencephalomyelitis. The fixation of limbs associated with AG is primarily due to muscular atrophy arising mainly from destruction of motor horn neurons. Arthrogryposis will often involve a single joint following infection in the sixth month of gestation.  When infection occurs at early stages of pregnancy, in the fifth or fourth months of gestation, the lesions become more severe, and multiple joints may be affected on all limbs and the spinal cord may also be involved. Similarly, defects of the brain is first observed as small focal cyst-like cavities (porencephaly) that progressively become more severe and after infection at the end of the third month of gestation, there can be complete destruction of the cerebral hemispheres leaving only fluid-filled sacs (hydranencephaly): The only structures that can be recognised are parts of the brainstem, and in the case of Akabane virus, a relatively normal cerebellum.

In sheep and goats the gross defects of the brain is much more severe, with little normal CNS tissue recognisable. The  lesions and defects described for Akabane are similar for other recognised pathogenic Simbu viruses such as Aino, Peaton, Shamonda and Schmallenberg but the lesions may vary in distribution and symmetry.^{12, 52}

Diagnosis and differential diagnosis

Sporadic cases of AG/HE due to Akabane or related viruses often remain undiagnosed. When a cluster of cases occurs, the presence of AG or brain deformities in aborted or new-born calves or lambs should suggest a teratogenic virus as a possible cause (see Pathology). Serum should be collected, prior to suckling, from the affected calf or lamb to enable the detection of antibodies to potentially teratogenic viruses. Pericardial or pleural fluids are also suitable for the detection of antibodies and are often of higher quality than serum in stillborn animals. Both IgG and IgM antibodies to Akabane and other Simbu viruses are produced in foetuses after they become immunocompetent. Thus, antibodies to a Simbu virus in precolostral serum is strong evidence that the calf or lamb was infected in utero.²⁴ An examination of the abomasum for milk curd should be made as confirmatory evidence that the calf or lamb has not ingested milk. As a further check, a serum sample should be taken from the dam and the two sera tested in parallel for antibodies to the suspect virus, as well as to one or more ubiquitous viruses. If the serum from the new-born contains antibodies to the same range of viruses as that of its dam, the conclusion can be drawn that it has sucked. If antibodies to only a single virus are in the serum of the new-born in contrast to several in its dam’s serum, then the evidence is strong that it has been infected in utero.

Although culture of tissues from affected calves or lambs for viruses usually gives negative results, residual RNA may sometimes be detected by qRT-PCR in samples of CNS tissue, placenta, spleen and lymph nodes.⁷ Virus is also more likely to be detected in the tissues of aborted foetuses.

Despite some cross- reactivity, virus neutralization tests are the most specific serological tests available.⁵⁷ ELISAs have been evaluated in Japan and Australia for Akabane.³³ In Europe there are several ELISAs available to detect antibodies to Schmallenberg.^{4, 8, 61} Some assays are Simbu-group reactive, while others are virus (eg. Akabane, Schmallenberg) specific.

Although the brain defects are suggestive of a Simbu virus infection, laboratory confirmation is essential because these lesions can be caused by a number of other viral infections, most notably the pestiviruses (see Bovine viral diarrhoea and Border disease) and some orbiviruses (see Palyam serogroup orbivirus infections) such as Chuzan as well as bluetongue (see Bluetongue) and Wesselsbron disease (see Wesselsbron disease).²³

Control

Control of winged vectors (Culicoides and mosquitoes) is difficult and in most instances impractical. The most practical option for disease control is to immunize the potential target host before pregnancy occurs.  Inactivated virus vaccines against Akabane virus has been produced in Japan and Australia,^{39, 47} a combination Akabane and Aino vaccine in Japan³⁷ and there are several vaccines against Schmallenberg virus available in Europe.

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