Akabane virus infection
P.D. Kirkland
Virology Laboratory, Elizabeth Macarthur Agriculture Institute, Woodridge Road, Menangle, NSW, Australia
E-mail: peter.kirkland@dpi.nsw.gov.au
Summary
Akabane virus is a Culicoides-borne orthobunyavirus that is teratogenic to
the fetus of cattle and small ruminant species. Depending upon the stage of
gestation at which infection occurs, and the length of gestation of the mammalian
host, a range of congenital defects may be observed. The developing central
nervous system is usually the most severely affected, with hydranencephaly
and arthrogryposis most frequently observed. Less commonly, some strains
of Akabane virus can cause encephalitis in the neonate or, rarely, adult cattle.
Akabane viruses are known to be widespread in temperate and tropical regions
of Australia, Southeast Asia, the Middle East and some African countries. Disease
is infrequently observed in regions where this virus is endemic and the presence
of the virus remains unrecognised in the absence of serological surveillance. In
some Asian countries, vaccines are used to minimise the occurrence of disease.
Keywords
Akabane virus – Arthrogryposis – Congenital defect – Culicoides – Hydranencephaly –
Orthobunyavirus.
Rev. Sci. Tech. Off. Int. Epiz., 2015, 34 (2), 403-410
The virus
Akabane virus is an arbovirus that was first isolated in
Japan in 1959 (1, 2). Taxonomically this virus is classified
in the genus Orthobunyavirus in the family Bunyaviridae.
Historically, Akabane virus was grouped in the Simbu
serogroup based on serological relationships with other
orthobunyaviruses
(3). This serological classification
remains useful as it reliably describes closely related
orthobunyaviruses and often provides an insight into their
in vivo biological characteristics. For example, the most
recently discovered virus in this group, Schmallenberg
(4),
has a number of biological properties that are similar to those
of Akabane virus. The term ‘Akabane disease’ has been used
to describe the clinical syndrome resulting from in utero
infection with Akabane virus but this can be misleading
because some or all of the elements of the syndrome, e.g.
congenital arthrogryposis and hydranencephaly, can be
caused by other viruses, especially other orthobunyaviruses.
The tripartite segmented genome of the bunyaviruses
facilitates the development of reassortants, with segments of
Akabane virus being found in closely related Simbu viruses
such as Tinaroo (5), though this virus is not recognised as
being pathogenic in nature.
Arthropod vectors
The principal vectors of Akabane virus are small biting
midges (or gnats) belonging to the genus Culicoides (6, 7).
Other species within this genus are vectors of bluetongue
virus, and some species are competent vectors of both
viruses. Multiple Culicoides species are often present in
the same place at the same time, but while the occurrence
of vectors of Akabane virus in a region increases the
likelihood that there might be a competent vector(s) of
bluetongue virus, this cannot be assumed. There is also
a high probability that vectors of bluetongue virus will
be competent vectors of a Simbu virus. For example, in
Europe, following the emergence of Schmallenberg virus,
the proven vectors of bluetongue viruses have also been
shown to be efficient vectors of Schmallenberg virus. From
an epidemiological perspective, an important consideration
is the vector competence and infection rates of Culicoides
with Akabane virus. Compared to bluetongue viruses, the
Simbu viruses are transmitted to mammalian hosts with a
high level of efficiency, in part due to the high virus infection
rates detected in Culicoides and the very large number
of insects that may attack an animal. The distribution of
Akabane virus antibodies in cattle can be considered a
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Rev. Sci. Tech. Off. Int. Epiz., 34 (2)
very sensitive indicator of the presence of a competent
population of Culicoides, even if the numbers in a region
are small. Although Akabane virus has been isolated from
mosquitoes (1, 8), these are not considered to be true
vectors of the virus.
Geographical and seasonal
distribution
Akabane virus has been reported in a number of countries
on the African continent, the Middle East, Southeast Asia
and Australia
(9). It is considered likely that Akabane virus
or other Simbu viruses are also present in neighbouring
countries in these regions. Its presence is suspected in
many other countries in the tropical and temperate zones,
especially those where bluetongue is reported. Within
a country, the distribution of the virus is absolutely
restricted to that of the insect vector (10). In countries
with a temperate climate, there is also a distinct seasonal
pattern of virus transmission, coinciding with warm, moist
summer and autumn months. This seasonal pattern is
also a consequence of the abundance of the insect vector.
There is a critical population density required before virus
spread can occur. Vector numbers begin to increase in the
late spring and early summer, usually peaking in early
autumn. Even in tropical and subtropical regions, there is
a tendency towards seasonal transmission, with the highest
infection rates in the summer months. In temperate regions,
transmission ceases with the onset of very low temperatures
and the first frosts, while in tropical regions transmission
rates decline with the onset of the periods of lower rainfall.
Mammalian host range
Akabane virus infects a wide range of domesticated
ruminants and wildlife species, especially bovids
(10, 11, 12, 13). In endemic areas there is a high prevalence
of antibodies in cattle, buffalo, sheep, goats and also horses.
In Chinese Taipei, a high prevalence of Akabane virus
infection has been reported in pigs held outdoors (14).
However, it is not clear whether pigs play a role in the
maintenance of Akabane virus in nature and no disease has
been described. Human infection has not been reported.
In Australia, even in areas where there is frequent virus
transmission, infection of marsupials has not been detected.
Pathogenesis
The onset of viraemia with Akabane virus generally occurs
one to six days after infection and may last four to six days
before antibodies to the virus are detected and the virus is
cleared. Antibodies are detectable by serological tests from
about 14 days after infection. The virus may persist for a
considerably longer period in the developing fetus and
clinical signs are usually not observed for months until an
affected fetus is aborted or reaches term.
The outcome of infection of a susceptible mammalian host
is determined almost exclusively by its age and reproductive
status. In endemic areas, there is often annual transmission,
and young animals become infected in their first year
of life soon after maternally derived antibodies decline.
Postnatal infection with most strains of Akabane virus is
asymptomatic.
Akabane virus is a potent teratogen and almost exclusively
affects the developing fetus. Infection of the female during
pregnancy can result in a range of severe fetal defects affecting
the limbs (particularly arthrogryposis) and the central
nervous system (CNS). These have been described in several
reviews (9, 15, 16). Defects in the brain range from small
cystic defects (porencephaly) to almost complete absence of
the cerebral hemispheres, with replacement by fluid-filled
sacs (hydranencephaly). Infection of calves around the time
of, or soon after, birth may cause encephalitis.
The type of abnormality, and also the incidence, is influenced
by the stage of gestation at which the dam is infected.
Soon after being bitten by the insect, the adult develops a
viraemia (7) and the virus crosses the placenta to infect the
developing fetus. In most species, the impact of the virus is
greatest in mid-gestation. There is no documented evidence
of damage to the conceptus following infection in the very
early stages of pregnancy (the first three weeks in sheep and
goats; the first two months in cattle). The most susceptible
stages of gestation in small ruminants range from 28 to
56 days (especially 28 to 36 days) (17, 18, 19, 20, 21) and
in cattle from three to six months (22, 23). In the latter
stages of gestation (after 60 days in small ruminants and the
last two months in cattle), the incidence of abnormalities
declines to a very low level.
In cattle, the major defects involve the brain and spinal cord;
the effects on skeletal muscle are mainly secondary, although
a primary viral myositis sometimes occurs. The damage is
evident mainly as hydranencephaly, porencephaly and
arthrogryposis. In cattle, there is a successive progression
of different defects as a result of the long gestation period
(23). Infection of the fetus between approximately 80 and
105 days of gestation results almost exclusively in the
development of hydranencephaly and porencephaly. The
lesions are markedly more severe in fetuses infected early
on in this period and gradually decline in severity until
abnormalities are no longer grossly apparent. Arthrogryposis
occurs following infection between approximately 105 and
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170 days of gestation. There may be a small number of calves
born with both mild hydranencephaly and arthrogryposis
due to infection around 100 to 120 days of gestation. Calves
with arthrogryposis as a result of infection between 100 and
150 days of gestation are more severely affected, with
abnormalities involving multiple joints on several, or even
all four, limbs. Defects are less severe following infection
later in gestation and may involve a single joint on one limb.
In sheep and goats, due to the shorter gestation and shorter
period of susceptibility, there is usually a combination of
severe defects of the limbs with gross CNS lesions (15, 17,
19, 20, 21). In addition to lesions in the CNS, in sheep and
goats there may be an impact on the development of other
organs, such as pulmonary hypoplasia (21). When calves
are infected close to term, encephalitis can occur and may
be clinically apparent at birth (23).
Clinical signs
Although Akabane virus infects most ruminant species,
disease outbreaks of significance are mainly seen in cattle.
Sheep and goats are usually raised in areas where the vector
is either absent or uncommon. Further, small ruminants are
usually bred at the end of or after the vector season, so there
is little risk of fetal infection.
Akabane infection of adult animals is usually asymptomatic
(7). Some strains of Akabane virus have been associated with
encephalitis in newborn calves (24), but this is generally
uncommon. The Iriki strain of Akabane virus in Japan and
Korea has been associated with cases of encephalitis in adult
cattle (25, 26, 27).
The greatest impact of the virus is on the developing
fetus. The range of defects observed will vary depending
on herd management and the time of virus transmission.
In year-round calving herds (such as some temperate and
subtropical dairy herds), the full range of congenital defects
may be seen, while in a seasonal calving herd with a very
restricted mating period, only one type of abnormality
may be noticed. There have been a number of detailed
descriptions of the range of calf defects that may occur
following infection with Akabane virus (22, 23, 28, 29, 30).
The descriptions that follow relate to a herd with a prolonged
(or year-round) calving period.
The first indication of an outbreak of Akabane infection
is abortion of abnormal fetuses at between four and
six months of gestation. Infected fetuses may appear to
be grossly normal but careful examination may detect
fixation of joints. Removal of the calvarium at post-mortem
examination will often reveal severe hydranencephaly.
The first calves that are born during the outbreak will
have been infected late in gestation and may show signs
of acute encephalitis, such as flaccid paralysis of the legs,
hyperextension of joints and difficulty in standing.
Calves which are infected in the fifth or sixth month of
gestation may be born with arthrogryposis and have grossly
apparent deformities. Those infected in about the sixth
month of gestation may have only one or two joints affected
on a single limb, whereas calves that have been infected a
little earlier, in the fifth month of gestation, are likely to have
more severe lesions, involving multiple joints on all limbs
and perhaps abnormalities of the spinal column such as
kyphosis or lordosis. Dystokia is common in cows delivering
these calves, most of which are stillborn. Many require
embryotomy or Caesarian delivery. A small proportion of
cows die as a result of obstetric complications, while others
suffer permanent infertility. Calves with relatively mild
lesions, involving one or two joints on a single limb, are
usually born alive and are able to stand.
About six weeks into the outbreak there will be few
cases of arthrogryposis but the incidence of calves with
hydranencephaly will increase. Those calves that do have
arthrogryposis may also have lesions of porencephaly.
The severity of hydranencephaly then increases during
an outbreak, leading to severe hydranencephaly, with
virtual absence of the cerebral hemispheres (23). Most
calves delivered in the last four to six weeks of an outbreak
will have severe hydranencephaly. Some are stillborn but
many will be born alive. The lesions in the brain result in
a range of behavioural abnormalities. These animals are
usually blind, unaware of their surroundings and wander
aimlessly. These defects are usually life-threatening and
most affected animals die soon after birth if close supervision
and care are not provided. However, due to the nature and
severity of the abnormalities, most surviving animals are
euthanased.
The brain stem appears to be grossly normal, even when
there is complete absence of the cerebral hemispheres.
In Akabane cases in cattle, the cerebellum is consistently
intact and apparently normal. Torticollis, scoliosis, and
brachygnathism are sometimes observed but are more
frequent in small ruminants.
In lambs and kids born to sheep and goats that are pregnant
during the vector season, congenital defects can be observed
following infection 28 to 56 days into pregnancy. However,
at term, the chronological progression of defects observed
in cattle is not usually apparent. Lambs and kids are likely
to show a range of defects of both the skeletal and central
nervous systems. Severe hydranencephaly and severe
arthrogryposis may be seen affecting the same animal.
Other developmental abnormalities such as pulmonary and
thymic hypoplasia may also occur (21).
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The incidence of congenital abnormalities is determined
by the stage of gestation at which the fetus is infected and
also by the strain of virus. In cattle, the incidence of defects
may be as high as 50% (31) if they are infected at the most
critical stages of gestation (three to four months). If they
are infected in the fourth month, incidence is typically
around 25% and this declines to 5% in those infected in
the seventh month (23). In sheep, at the most susceptible
stages of gestation, the incidence of fetal infection can range
from 15% to 80% depending upon the strain of virus (19).
Epidemiology
The occurrence of Akabane disease is determined entirely
by the distribution of the insect vector. This is strongly
influenced by climatic conditions, especially temperature
and, to a lesser extent, rainfall. Culicoides species typically
have a well-defined geographical distribution (7, 10).
Within that range, Akabane virus transmission occurs
frequently and usually each year. Consequently, there is a
high level of population immunity and most animals are
immune before reaching breeding age. There is also a distinct
seasonal pattern of spread. Within an endemic area, midge
numbers increase during the late spring/early summer and
peak in autumn. There is typically a lag phase between the
first occurrence of the midge and virus transmission, which
commences once insects become abundant. Conversely,
there is a rapid decline in transmission with the onset of
cold weather and a cessation with the first frost.
Outbreaks of Akabane disease occur after environmental
conditions that are markedly different from usual patterns.
For example, prolonged mild moist conditions in autumn
can result in spread of the midge well beyond its usual range
into areas where there are large populations of susceptible
livestock (30). Even a limited period of transmission can
result in a significant disease outbreak. Adverse climatic
conditions can also result in reduced midge activity and
virus transmission within an endemic area. This results in a
reduced level of population immunity and the opportunity
for an increase in the number of susceptible animals that
will reach breeding age before the next or even a subsequent
vector season (32). Inevitably, normal transmission patterns
return, with the concomitant birth of deformed calves
delivered by heifers or young cows (23).
As a result of the interaction between vector and climatic
factors, outbreaks of Akabane disease usually follow a well-
defined distribution, occurring in areas adjoining regions
where vectors are endemic. Exceptions to this pattern
occur when pregnant cows are either permanently moved
into a vector area or are held temporarily in a vector area
and then returned to their home property (31). Because of
the distinct seasonal pattern of virus transmission, there is
also a clear pattern of seasonal occurrence of disease. In
most areas where outbreaks occur, clinical cases in cattle are
first observed in early winter and reach a peak in the early
spring months (30).
Pathology
Akabane infection may be suspected from the seasonal
clustering of the birth of large numbers of calves with
congenital defects and with highly suggestive gross
pathology and histopathology. There may also be an
increase in cases of neurological disease in newborn calves.
Calves with flaccid paralysis as a result of infection late in
gestation have histological lesions of a non-suppurative
polio-encephalomyelitis (22, 23).
In calves with arthrogryposis, apart from the fixation or
severely restricted range of movement of joints, there are
few other grossly detectable changes. There are, however,
microscopically detectable severe degenerative changes in
the motor horns of the spinal cord (22, 23). In some cases,
degenerative changes are also apparent in the skeletal muscle.
When calves are stillborn or show behavioural changes,
grossly apparent defects are likely to be apparent in the
brain. These can vary from small cystic lesions to the virtual
absence of the cerebral hemispheres and replacement with
fluid-filled meningeal sacs (22, 23, 30, 33). Histopathology
on Akabane cases with severe hydranencephaly is
unrewarding and of minimal diagnostic value. There
will be an absence of large areas of brain surrounded by
tissues with relatively normal architecture. In cattle, the
cerebellum is rarely, if ever, affected, a useful differential
feature to distinguish Akabane virus from other congenital
infections such as bovine viral diarrhoea virus. However,
gross cerebellar lesions may be detected in calves that have
been infected with other orthobunyaviruses such as Aino
and Schmallenberg.
If a fresh aborted fetus is found, depending on the age of the
fetus and the time since it was infected, gross lesions may
not be apparent. A range of acute, necrotic, degenerative
changes may be detected and perhaps also a mild to
moderate non-suppurative encephalomyelitis suggestive of
a viral infection. The lesions can be detected in all parts of
the CNS, with perivascular cuffing, neuronal degeneration
and cavitation of the brain, and neuronal degeneration in
the motor neurones of the spinal cord. Muscular dystrophy
may also be observed.
Diagnosis
Akabane disease should be considered when there is an
outbreak of congenital defects in cattle, sheep or goats
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Rev. Sci. Tech. Off. Int. Epiz., 34 (2)
commencing in the winter months and extending to
spring. The gross pathology should provide a strong index
of suspicion. An aetiological diagnosis and confirmation
of Akabane infection depends on the detection of specific
antibody in blood or fluids of fetuses and affected neonates
that have been deprived of colostrum. Most stillborn or
aborted fetuses and calves that are born at term mount a
specific antibody response to the virus (28, 34). Testing can
be carried out systematically by initially examining fetal
fluids or pre-colostral serum to determine the IgG levels.
An elevated IgG level will incriminate an infectious agent
(35, 36) and Akabane virus-specific serology can then be
undertaken. A range of serological tests have been used to
detect antibodies to Akabane virus but virus neutralisation
tests and enzyme-linked immunosorbent assays are most
frequently used.
Virus detection by virus isolation (37) or polymerase chain
reaction (PCR) (38)
may be considered if a fetus has been
aborted in the early stages of pregnancy. Using real-time
PCR, it may be possible to detect residual RNA in affected
tissues of neonates (38). Testing of swabs taken from the
surface of cotyledons of the placenta may also give positive
results. Maternal serology is of value only in regions where
the virus is not endemic. In these situations, positive
maternal serology will raise the index of suspicion, while a
negative result will convincingly exclude Akabane virus as
the aetiological agent.
Germplasm: semen and embryos
Virus has not been detected in the semen of bulls
experimentally infected with Akabane virus (39). There is
no evidence that Akabane virus can infect the developing
embryo and washing techniques are considered to be a safe
approach to ensuring that Akabane virus is not inadvertently
transmitted by embryo transfer (40).
Control
The impact of Akabane virus is best controlled by strategic
vaccination of susceptible animals prior to the time of
potential exposure to vector activity. A live attenuated
vaccine has been used in Japan (41) and inactivated vaccines
have been used in Australia, Japan and Korea (42, 43, 44).
Inactivated vaccines have the advantage of being suitable for
the emergency vaccination of pregnant animals. Alterations
to herd or flock management, such as delaying mating or
changing the calving period from spring to autumn, can be
used to prevent outbreaks if there is warning of impending
vector activity. Vector control measures, such as covering
breeding sites and using insect repellents and insecticide
treatments may be effective for short periods, but are
usually ineffective in preventing fetal infection over a period
of more than a few days.
Infection par le virus Akabane
P.D. Kirkland
Résumé
Le virus Akabane est un orthobunyavirus transmis par les moucherons piqueurs
du genre Culicoides ; il est tératogène pour les fœtus de bovins, de caprins
et d’ovins. Il peut causer un certain nombre de malformations congénitales
dont l’apparition dépend du stade de gestation au moment de l’infection et de
la durée de la gestation de l’espèce mammifère hôte. C’est généralement le
système central nerveux en développement qui est le plus gravement atteint, une
hydranencéphalie et une arthrogrypose étant les affections les plus fréquentes. De
manière moins fréquente, certaines souches du virus Akabane sont responsables
d’encéphalite chez le veau nouveau-né ou plus rarement chez le bovin adulte.
Les virus Akabane sont très présents dans les régions tempérées et tropicales de
l’Australie, de l’Asie du Sud-Est, du Moyen-Orient et de certains pays d’Afrique.
Les maladies dues à ce virus étant rarement observées dans les régions où
celui-ci est endémique, sa présence peut passer longtemps inaperçue si aucune
surveillance sérologique n’est exercée. Certains pays asiatiques pratiquent la
vaccination pour minimiser l’incidence de l’infection.
Mots-clés
Akabane – Arthrogrypose – Culicoides – Hydranencéphalie – Malformation congénitale
– Orthobunyavirus.
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Rev. Sci. Tech. Off. Int. Epiz., 34 (2)
La infección por el virus de Akabane
P.D. Kirkland
Resumen
El virus de Akabane es un orthobunyavirus transmitido por Culicoides que tiene
efectos teratógenos en los fetos del ganado bovino y de pequeños rumiantes.
Dependiendo del estadio de gestación en el que se produzca la infección y de la
duración del embarazo en el mamífero hospedador se podrán observar diversas
anomalías congénitas. Lo que en general resulta más gravemente afectado es
el desarrollo del sistema nervioso central, y las anomalías más comunes son la
hidranencefalia y la artrogriposis. A veces, con menos frecuencia, algunas cepas
del virus causan encefalitis en el vacuno neonato o, más rara vez, en el adulto.
Se sabe que los virus de Akabane están muy extendidos en regiones templadas
y tropicales de Australia, Asia Sudoriental, Oriente Medio y algunos países
africanos. Resulta infrecuente observar la enfermedad en regiones donde el virus
es endémico, por lo que en ausencia de vigilancia serológica su presencia pasa
desapercibida. En algunos países asiáticos se utilizan vacunas para reducir al
mínimo los casos de enfermedad.
Palabras clave
Akabane – Anomalía congénita – Artrogriposis – Culicoides – Hidranencefalia –
Orthobunyavirus.
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