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Hydranencephalic brain of newborn calf infected with bluetongue virus at 125 days of gestation. Thin rim of cerebral tissue has been reflected to expose unaffected brain stem and cerebellum. Fig. 2: Subcortical cerebral cyst in brain shown in fig. 1. M = meninges; V = lateral ventricle; C = subcortical cyst. HE.
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Direct inoculation of bluetongue virus into 125-day bovine fetuses resulted in development of hydranencephaly. The earliest lesions after virus inoculation were a severe necrotizing encephalitis, which was most prominent in the cerebrum, and an associated nonsuppurative meningitis. At birth, the brains of infected fetuses had thin-walled cerebral h...
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... friable. Gross lesions were detected only in the brains of the two term calves in which the cerebral hemispheres consisted of fluctuant fluid-filled sacs bounded by a thin rim of parenchyma ( fig. 1). This narrow rim of cortical tissue was reduced focally to a transparent membrane, and in other areas there were fluid-filled cerebral cysts ( fig. 2). These two lesions were most obvious in the rostral aspects of the cerebral hemispheres. In both brains, the septum pellucidum was intact but extremely thin. Structures such as olfactory lobes, basal ganglia, hippocampus, thalamus, colliculi, hypophysis, and cerebellum all appeared ...
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DEVELOPMENTAL lesions of the central nervous system (CNS) have been described associated with transplacental infection with bluetongue virus (BTV) in cattle ([MacLachlan and others 1985][1]) and sheep ([Osburn 1972][2]). In the past, the development of these deformations was mostly associated with
An outbreak of hydranencephaly in aborted foetuses and newborn calves occurred following the 2007 epidemic of bluetongue serotype 8 (BTV8\net2006) in the Netherlands. In total 35 aborted foetuses and 20 live-born calves, submitted from September 2007 to May 2008, were examined pathologically. Foetuses with gestational ages between 4 and 9 months (m...
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... Early studies established BTV tropism for brain tissue in infected fetuses that resulted in congenital brain malformation [77][78][79]. The structural protein VP5 has been associated with viral neural tropism in newborn mice [80]. ...
... The pros and cons of BTV vaccine strategies are summarized in Table 1. As previously discussed, the main problem of BTV live attenuated vaccines is the possibility that, in spite of their attenuation, they acquire a phenotype capable of crossing the placental barrier that leads to abortions and teratogenesis in the fetus [61,[77][78][79]. Moreover, live attenuated vaccines can be contaminated with exogenous viruses that can be pathogenic in some cases [72,107,108]. ...
Bluetongue virus (BTV) produces an economically important disease in ruminants of compulsory notification to the OIE. BTV is typically transmitted by the bite of Culicoides spp., however, some BTV strains can be transmitted vertically, and this is associated with fetus malformations and abortions. The viral factors associated with the virus potency to cross the placental barrier are not well defined. The potency of vertical transmission is retained and sometimes even increased in live attenuated BTV vaccine strains. Because BTV possesses a segmented genome, the possibility of reassortment of vaccination strains with wild-type virus could even favor the transmission of this phenotype. In the present review, we will describe the non-vector-based BTV infection routes and discuss the experimental vaccination strategies that offer advantages over this drawback of some live attenuated BTV vaccines.
... BT in sheep causes severe haemorrhagic syndrome characterized by fever, oedema, haemorrhages, dyspnoea, mucosal erosions and ulcerations, and coronitis 3 . BTV infection in pregnant animals has led to abortions, congenital deformities and cerebral malformations such as hydranencephaly, and also the birth of viraemic calves [4][5][6][7] . ...
... This might the reason for lesions noticed during early stage in the present study. The results of the present study have been in concordance with the earlier findings 5,6,10,30 . In Israel and Australia, modified live vaccine strain of BTV-23 in pregnant Merino sheep during 35 to 43 days of gestation caused 40-56% of early foetal mortality with much lesser extent or no CNS malformations like hydranencephaly in their offsprings 31,36 . ...
Transplacental transmission (TPT) of wild-type Indian BTV-1 had never been experimentally proved. This study was first time investigated TPT of Indian BTV-1 (isolated from aborted and stillborn goat fetal spleens). The sequential pathology, virological and immune cell kinetics (CD4+, CD8+ T-lymphocytes and NK cells in spleen and PBMCs), and apoptosis in IFNAR1-blocked pregnant mice during early (infected on 1 GD) and mid (infected on 8 GD) gestation have been studied. There was higher rate of TPT during mid stage (71.43%) than early (57.14%) stage. In early stage reduced implantation sites, early embryonic deaths, abortions, and necro-haemorrhagic lesions had observed. Mid stage, congenital defects and neurological lesions in foetuses like haemorrhages, diffuse cerebral edema, necrotizing encephalitis and decreased bone size (Alizarin red staining) were noticed. BTV-1 antigen was first time demonstrable in cells of mesometrium, decidua of embryos, placenta, uterus, ovary, and brain of foetuses by immunohistochemistry and quantified by real-time qRT-PCR. BTV-inoculated mice were seroconverted by 7 and 5 dpi, and reached peak levels by 15 and 9 dpi in early and mid gestation, respectively. CD4+ and CD8+ cells were significantly decreased (increased ratio) on 7 dpi but subsequently increased on 15 dpi in early gestation. In mid gestation, increased CD8+ cells (decreased ratio) were observed. Apoptotic cells in PBMCs and tissues increased during peak viral load. This first time TPT of wild-type Indian BTV-1 deserves to be reported for implementation of control strategies. This model will be very suitable for further research into mechanisms of TPT, overwintering, and vaccination strategies.
... [233][234][235] Likewise, buffalo fetus with arthrogryposis was relieved by partial fetotomy. 236 Fetal anencephaly has been reported to develop in 125-day bovine fetuses by inoculation of Blue tongue virus. 237 Similarly BVD virus is known to result in congenital malformations in calves. ...
We review the causes of fetal dystocia in cows and buffalo. Two fetal causes are distinct fetal oversize and fetal abnormalities. Fetal oversize is common in heifers, cows of beef cattle breeds, prolonged gestations, increased calf birth weight, male calves and perinatal fetal death with resultant emphysema. Fetal abnormalities include monsters, fetal diseases and fetal maldispositions, and it is difficult to deliver such fetuses because of their altered shape. Although monsters are rare in cattle, a large number of monstrosities have been reported in river buffalo; yet also here, overall incidence is low. Diseases of the fetus resulting in dystocia include hydrocephalus, ascites, anasarca and hydrothorax. The most common cause of dystocia in cattle seems to be fetal maldispositions, of which limb flexion and head deviation appear to be the most frequent. We provide a brief description of the management of dystocia from different causes in cattle and buffalo. A case analysis of 192 and 112 dystocia in cattle and buffalo, respectively, at our referral center revealed that dystocia is significantly higher (P<0.05) in first and second parity cows and buffalo, and that dystocia of fetal origin is common in cows (65.62%) but less frequent (40.17%) in buffalo. In buffalo, the single biggest cause of dystocia was uterine torsion (53.57%). Fetal survival was significantly (P<0.05) higher both in cows and buffalo when delivery was completed within 12 h of second stage of labor.
... The BTV serotypes or strains are neuropathogenic in nature, occasionally causing fetal death and congenital cerebral malformations in newborn calves and lambs (Enright and Osburn, 1980;MacLachlan and Osburn, 1983;MacLachlan et al., 1985;van der Sluijs et al., 2013). Experimental in-utero infection of BTV in sheep and cattle induced fetal death and/ or teratogenic effects, including severe encephalomalacia, hydranencephaly, porencephaly and retinal dysplasia varying with the gestational age of the fetus (Osburn et al., 1971;Barnard and Pienaar, 1976;Luedke, 1985;Richardson et al., 1985). ...
Bluetongue virus (BTV) is neurotropic in nature, especially in ruminant fetuses and in-utero infection results in abortion and congenital brain malformations. The aim of the present study was to compare the neuropathogenicity of major Indian BTV serotypes 1, 2, 10, 16 and 23 by gross and histopathological lesions and virus distribution in experimentally infected neonatal BALB/c mice. Each BTV serotype (20 μl of inoculum containing 1 × 105 tissue culture infectious dose [TCID]50/ml of virus) was inoculated intracerebrally into 3-day-old mice, while a control group was inoculated with mock-infected cell culture medium. Infection with BTV serotypes 1, 2 and 23 led to 65–70% mortality at 7–9 days post infection (dpi) and caused severe necrotizing encephalitis with neurodegenerative changes in neurons, swelling and proliferation of vascular endothelial cells in the cerebral cortex, cerebellum, midbrain and brainstem. In contrast, infection with BTV serotypes 10 and 16 led to 25–30% mortality at 9–11 dpi and caused mild neuropathological lesions. BTV antigen was detected by immunohistochemistry, direct fluorescence antibody technique and confocal microscopy in the cytoplasm of neuronal cells of the hippocampus, grey matter of the cerebral cortex and vascular endothelial cells in the midbrain and brainstem of BTV-1, -2, -10, -16 and -23 infected groups from 3 to 20 dpi. BTV nucleic acid was detected in the infected brain tissues from as early as 24 h up to 20 dpi by VP7 gene segment-based one-step reverse transcriptase polymerase chain reaction. This study of the relative neurovirulence of BTV serotypes is likely to help design suitable vaccination and control strategies for the disease.
... Teratogenic BTV affects neuronal and glial precursor cells in the brain. Furthermore, vascular injury and infarction in the cerebrum may contribute to cerebral defects [69,70]. Foetuses infected at later stages of gestation show encephalitis but no brain malformations [70][71][72]. ...
... Furthermore, vascular injury and infarction in the cerebrum may contribute to cerebral defects [69,70]. Foetuses infected at later stages of gestation show encephalitis but no brain malformations [70][71][72]. ...
Diagnosing the cause of bovine congenital malformations (BCMs) is challenging for bovine veterinary practitioners and laboratory diagnosticians as many known as well as a large number of not-yet reported syndromes exist. Foetal infection with certain viruses, including bovine virus diarrhea virus (BVDV), Schmallenberg virus (SBV), blue tongue virus (BTV), Akabane virus (AKAV), or Aino virus (AV), is associated with a range of congenital malformations. It is tempting for veterinary practitioners to diagnose such infections based only on the morphology of the defective offspring. However, diagnosing a virus as a cause of BCMs usually requires laboratory examination and even in such cases, interpretation of findings may be challenging due to lack of experience regarding genetic defects causing similar lesions, even in cases where virus or congenital antibodies are present. Intrauterine infection of the foetus during the susceptible periods of development, i.e. around gestation days 60–180, by BVDV, SBV, BTV, AKAV and AV may cause malformations in the central nervous system, especially in the brain. Brain lesions typically consist of hydranencephaly, porencephaly, hydrocephalus and cerebellar hypoplasia, which in case of SBV, AKAV and AV infections may be associated by malformation of the axial and appendicular skeleton, e.g. arthrogryposis multiplex congenita. Doming of the calvarium is present in some, but not all, cases. None of these lesions are pathognomonic so diagnosing a viral cause based on gross lesions is uncertain. Several genetic defects share morphology with virus induced congenital malformations, so expert advice should be sought when BCMs are encountered.
Electronic supplementary material
The online version of this article (doi:10.1186/s13028-015-0145-8) contains supplementary material, which is available to authorized users.
... Licensed inactivated vaccines have not been commercially available in the United States, presumably because the estimated market has been small as it is limited to sheep. The combination of perceived efficacy issues (cross-serotype protection and incomplete immunity with polyvalent preparations) and safety issues (reversion to virulence, incomplete attenuation, and vector spread with gene reassortment) also contribute to the preferred use of inactivated vaccines as compared to MLV (MacLachlan, et al. 1985, MacLachlan and Osburn 1983, MacLachlan and Osburn 1988, Flanagan and Johnson 1995, Murphy et al. 2005. Autogenous vaccines have been produced in the United States using inactivated BTV and EHDV antigens. ...
Bluetongue (BT) and epizootic hemorrhagic disease (EHD) are noncontagious, insect-transmitted diseases of domestic and wild ruminants caused by related but distinct viruses. There are significant gaps in our scientific knowledge and available countermeasures to control an outbreak of orbivirus-induced disease, whether BT or EHD. Both BT virus (BTV) and EHD virus (EHDV) cause hemorrhagic fevers in susceptible ruminants; however, BT is principally a disease of domestic livestock whereas EHD is principally a disease of certain species of wild, non-African ungulates, notably white-tailed deer. The live-attenuated (modified live virus [MLV]) vaccines available in the United States for use in small ruminant livestock do provide good protection against clinical disease following infection with the homologous virus serotype. Although there is increasing justification that the use of MLV vaccines should be avoided if possible, these are the only vaccines currently available in the United States. Specifically, MLVs are used in California to protect sheep against infection with BTV serotypes 10, 11, and 17, and a MLV to BTV serotype 10 is licensed for use in sheep throughout the United States. These MLV vaccines may need to continue to be used in the immediate future for protective immunization of sheep and goats against BT. There are currently no licensed vaccines available for EHD in the United States other than autogenous vaccines. If there is a need to rapidly develop a vaccine to meet an emerging crisis associated with either BTV or EHDV infections, development of an inactivated virus vaccine in a conventional adjuvanted formulation will likely be required. With two doses of vaccine (and in some instances just one dose), inactivated vaccines can provide substantial immunity to the epizootic serotype of either BTV or EHDV. This strategy is similar to that used in the 2006-2008 BTV serotype 8 outbreaks in northern Europe that provided vaccine to the field within 2 years of the initial incursion (by 2008). Further research and development are warranted to provide more efficacious and effective vaccines for control of BTV and EHDV infections.
... The effects of BTV infection on reproduction are poorly understood. Abortion, stillbirth and fetal deformities have been attributed to BTV infection of sheep and cattle (9,10,11). Transplacental transmission of live attenuated strains has been described for BTV-2, BTV-9 and BTV-23 (12,13) and studies clearly show that modification of field strains, for example BTV-10 and BTV-11, by growth in embryonated eggs or in cell culture can markedly increase their ability to cross the placenta and cause fetal infection (14,15); nevertheless, it cannot be ruled out that other field strains could share the same properties. Before the 2006 incursion of BTV into Europe, the ability to cross the placenta and cause congenital fetal infection had been largely limited to attenuated BTV strains. ...
Abortions and stillbirths were noticed in pregnant goats on a farm in the state of Gujarat, India. About 50% of the pregnant goats aborted or gave birth to dead kids. Bluetongue virus (BTV) antibody in the sera of affected goats was detected using a competitive enzyme-linked immunosorbent assay (ELISA). Viral antigen in the blood of these goats and in the aborted fetal spleens was detected using a sandwich ELISA. Two viruses (SKN-9, SKN-10) were isolated in cell culture from aborted fetal spleens and were confirmed as Orbivirus by demonstration of ten bands in RNA polyacrylamide gel electrophoresis and identified as BTV-1 by sequencing of the VP2 gene. Sequence analyses revealed thatthese isolates were very closely related to a BTV-1 (strain SKN-8) isolated from Culicoides vectors captured on the same farm one month after the occurrence of abortion. Isolation of BTV-1 from fetuses is probably evidence of transplacental transmission of the wild-type strain, because attenuated or laboratory-adapted BTV-1 strains have never been used in this region. This may have important implications in the epidemiology of bluetongue, considering the presence of many BTV serotypes in India.
... Experimental infection of cattle foetuses demonstrated that the most severe defects (hydranencephaly) occur when foetuses were inoculated between 75 and 130 days gestation, whereas in contrast foetuses infected after this time demonstrated only cerebral cysts and dilated lateral ventricles (MacLachlan and Osburn, 1983;MacLachlan and Thompson, 1985). Barnard and Pienaar (1976) inoculated two cattle foetuses in utero at days 126 and 138 of gestation with a BTV-10 MLV. ...
Experimental infection studies with bluetongue virus (BTV) in the mammalian host have a history that stretches back to the late 18(th) century. Studies in a wide range of ruminant and camelid species as well as mice have been instrumental in understanding BTV transmission, bluetongue (BT) pathogenicity/pathogenesis, viral virulence, the induced immune response, as well as reproductive failures associated with BTV infection. These studies have in many cases been complemented by in vitro studies with BTV in different cell types in tissue culture. Together these studies have formed the basis for the understanding of BTV-host interaction and have contributed to the design of successful control strategies, including the development of effective vaccines. This review describes some of the fundamental and contemporary infection studies that have been conducted with BTV in the mammalian host and provides an overview of the principal animal welfare issues that should be considered when designing experimental infection studies with BTV in in vivo infection models. Examples are provided from the authors' own laboratory where the three Rs (replacement, reduction and refinement) have been implemented in the design of experimental infection studies with BTV in mice and goats. The use of the ARRIVE guidelines for the reporting of data from animal infection studies is emphasised.
... Further experiments are necessary in order to elucidate the levels of viraemia that might be potentially dangerous for the foetus and the capability of BTV to cross the placental barrier in the earliest days of conception. Interestingly, all malformed animals turned out to be BT negative by VI and bio-molecular techniques, phenomenon already described in the past (MacLachlan and Osburn, 1983). After an early infection, it seems that foetuses are able to get free of BTV by the time of delivery which might have been responsible for an underestimation of the BTV MLV foetal infections. ...
The recent outbreak caused by Schmallenberg virus, which affected sheep, goats and cattle in Europe, highlighted the importance of having a robust surveillance plan capable of monitoring abortions and malformations in the livestock offspring. In this context, bluetongue viruses (BTVs) represented and represent one of the major threats to the European livestock industry. Aiming to improve the understanding on BTV cross placental transmission and serotype involvement, in this retrospective study foetal spleens and/or brains of 663 ovines, 429 bovines, 155 goats and 17 buffaloes were tested for the presence of BTV by virus isolation. BTV vaccine strains were isolated from 31 foetuses (2.4%; 95% CI: 1.7-3.4%): 24 (3.6%; 95% CI: 2.4-5.3%) from ovine foetal tissues; 6 (1.4%; 95% CI: 0.6-3.0%) from bovine foetal tissues and 1 (0.6%; 95% CI: 0.2-3.5%) from the spleen of a caprine foetus. All foetuses were from animals vaccinated with either BTV-2 or BTV-2, and BTV-9 modified live vaccines (MLVs) produced by Onderstepoort Biological Products (OBP), South Africa. Among the 31 isolated vaccine strains, serotype 9 (n = 28) was more frequently isolated (P < 0.05) than serotype 2 (n = 3). In two cases infectious vaccine strains were found in the foetal tissues 2 months after the vaccine administration. Other pathogens known to be causative agents of abortion in ruminants were not detected nor isolated. This study demonstrates, for the first time, that BTV-2 and BTV-9 vaccine strains are able to cross the placental barrier of sheep, cattle and goats. BTV-2 and BTV-9 vaccine strains are able to infect foetuses and cause abortions or malformations depending on the period of pregnancy at the time of vaccination.
... [233][234][235] Likewise, buffalo fetus with arthrogryposis was relieved by partial fetotomy. 236 Fetal anencephaly has been reported to develop in 125-day bovine fetuses by inoculation of Blue tongue virus. 237 Similarly BVD virus is known to result in congenital malformations in calves. ...
We review the causes of fetal dystocia in cows and buffalo. Two fetal causes are distinct fetal oversize and fetal abnormalities. Fetal oversize is common in heifers, cows of beef cattle breeds, prolonged gestations, increased calf birth weight, male calves and perinatal fetal death with resultant emphysema. Fetal abnormalities include monsters, fetal diseases and fetal maldispositions, and it is difficult to deliver such fetuses because of their altered shape. Although monsters are rare in cattle, a large number of monstrosities have been reported in river buffalo; yet also here, overall incidence is low. Diseases of the fetus resulting in dystocia include hydrocephalus, ascites, anasarca and hydrothorax. The most common cause of dystocia in cattle seems to be fetal maldispositions, of which limb flexion and head deviation appear to be the most frequent. We provide a brief description of the management of dystocia from different causes in cattle and buffalo. A case analysis of 192 and 112 dystocia in cattle and buffalo, respectively, at our referral center revealed that dystocia is significantly higher (P<0.05) in first and second parity cows and buffalo, and that dystocia of fetal origin is common in cows (65.62%) but less frequent (40.17%) in buffalo. In buffalo, the single biggest cause of dystocia was uterine torsion (53.57%). Fetal survival was significantly (P<0.05) higher both in cows and buffalo when delivery was completed within 12 h of second stage of labor.
