Schmallenberg virus (SBV) is a novel Orthobunyavirus causing mild clinical signs in cows and malformations in aborted and neonatal ruminants in Europe. SBV belongs to the family Bunyaviridae and is transmitted by biting midges. This new virus was identified for the first time in the blood samples of cows in the city of Schmallenberg in NorthRhine-Westphalia in November 2011. Since then the virus spread to several European countries. Here we describe the origin and emergence, as well as the transmission and the differential diagnosis of this virus, now known to be a serious threat to Veterinary Public Health.
- Schmallenberg virus
- emerging infections
1.1. The origin of Schmallenberg virus
In 2011, an unidentified disease in cattle was reported in Germany and the Netherlands . Hyperthermia and drop in milk production were reported in adult dairy cows in north-west Germany and the Netherlands, and in some cases, transient diarrhoea was also recorded in the Netherlands . Farmers and veterinarians in North Rhine-Westphalia, Germany, and in the Netherlands reported an unidentified disease in dairy cattle with a short period of clear clinical signs to the animal health services, local diagnostic laboratories and national research institutes . All classical endemic and emerging viruses, such as pestiviruses, bovine herpesvirus type-1 (BHV-1), foot-and-mouth disease (FMD) virus, bluetongue virus (BTV), epizootic haemorrhagic disease (EHD) virus, Rift Valley fever (RVF) virus and bovine ephemeral fever (BEF) virus, could be excluded as the causative agent .
The first identification of this new virus succeeded in samples of cattle housed next to a small town in Germany with 25,000 inhabitants, called Schmallenberg, in North Rhine-Westphalia (Figure 1).
At that time and following elimination of the usual causes of such clinical signs in cattle, blood samples from three bovine were subjected to the new technology of deep sequencing known as metagenomic analysis, which allows the sequencing of all nucleic acids present in a sample . Metagenomics is the application of modern genomics techniques to the study of communities of microbial organisms directly in their natural environments, bypassing the need for isolation and lab cultivation of individual species . As is typical with this approach, a large amount of host genomic and known bacterial sequences were identified, the latter most likely as a consequence of prolonged sample storage. However, present within the samples were genetic sequences from a novel
1.2. Structure and taxonomy
SBV is now known to belong to the genus
SBV is typical of the Bunyaviridae, characterized by a tripartite negative-sense RNA genome that encodes four structural and two non-structural proteins . The SBV is an enveloped virus with a surface of glycoproteins . The diameter of these viruses is approximately 100 nm. Their genetic structure comprises of three segments of single-stranded negative-sense RNA: large (L) with 6865 nucleotides, medium (M) with 4415 nucleotides and small (S) with 830 nucleotides (Figure 2) [1, 3].
The large (L) segment encodes the viral RNA-dependent RNA-polymerase or L protein, the medium (M) segment encodes the virion glycoproteins Gn and Gc, and the small (S) segment encodes the nucleoprotein (N). Non-structural proteins are encoded by some viruses on the M (NSm protein) and by some on the S (NSs protein) segment .
The full genome sequence of the first described SBV is provided under the Genbank accession number HE649912 and has a length of 6864 base pairs .
1.3. The emergence of Schmallenberg virus
From November 2011 to date, the disease spread rapidly and widely throughout Europe. Since 2011 cases have been reported: Belgium (December 2011), the UK and France (January 2012), Luxembourg and Italy (February 2012), Spain (March 2012), Denmark (June 2012), Switzerland and Sweden (July 2012), Austria and Finland (September 2012), Ireland and Poland (October 2012), Norway (November 2012), Czech Republic (December 2012), Estonia, Slovenia, Hungary and Croatia (January 2013), Latvia (April 2013), Greece (March 2013), Russia (May 2013), Serbia (June 2013) and Romania (July 2013) . There are also reports of cases outside Europe . Recently a new study shows the circulation of the virus in Portugal  (Figure 3).
In the future, new outbreaks are expected depending on many conditions like the vector transmission .
1.4. Disease transmission
As viruses belonging to the genus
Rasmussen et al.  demonstrated the presence of SBV RNA in
The transmission by a wide range of
Viruses more closely related to SBV are not considered zoonoses; hence, most authorities have concluded that the probability of SBV infecting humans is minimal . Because SBV emerged recently, transmission from animals to human cannot yet be completely excluded. A seroprevalence study by Ducomble et al.  conducted among exposed shepherds in the area of Germany most affected by SBV showed no evidence of transmission to humans. However, further studies on whether SBV poses a risk to humans are vital .
1.5. Schmallenberg virus impact on ruminant health
SBV has the ability to infect exclusively ruminant species . Within the domestic ruminants, the most affected are cattle, followed by sheep and goats . Horizontal transmission occurs through various
2. Differential diagnosis of SBV
The clinical symptoms of acute SBV infection are unspecific and vary among animal populations. Thus, possible causes of high fever, diarrhoea, decrease in milk production, increased incidence of abortion and congenital malformations should be taken into account in the establishment of the differential diagnosis and consequently in obtaining definitive diagnosis. In contrary to cattle, clinical signs reported in adult small ruminants may be present only during the viraemic phase, but in most cases the infection is mostly asymptomatic .
Malformation in newborn or stillborn lambs and clinical signs correlate with the stage of development at which the foetus was infected but these are also not specific of SBV infection. Foetal Schmallenberg virus infection in naïve ewes and goats can result in stillborn offspring, showing a congenital arthrogryposis-hydranencephaly syndrome ; however, other congenital malformations may be present such as hydrocephaly, brachygnathia inferior, ankylosis, torticollis and scoliosis.
The lack of specificity of the observed clinical signs in infected adults, stillborn foetuses and malformed neonates means that a definitive diagnosis of SBV infection can only be made accurately based on clinical evaluation and specific laboratory examinations .
Although several differential diagnosis for abortion and congenital abnormalities have been suggested to include several factors such as genetic (spider lamb syndrome), teratogenic chemicals or toxins (
The main infectious diseases to consider include:
• Bluetongue disease
Bluetongue is an arthropod-borne disease affecting wild and domestic ruminants although clinical disease is present mostly in sheep; cattle and goats hosts [20, 21]. The disease occurs worldwide and is caused by bluetongue virus (BTV), which belongs to the genus
BTV infection of livestock is distinctly seasonal (late summer and fall) in the temperate region once is transmitted biologically by certain species of Culicoides midges that consequently show maximum activity in high temperature and high humidity [21–23], and these conditions can influence the activity of the vector as well as the viability of the virus. Some authors propose that the global climate changes as well as geography and altitude affect the activity of the vector and are responsible for sudden outbreaks worldwide [21, 23, 24].
The types of characteristic lesions of BTV in affected sheep include: haemorrhage and erosion/ulcers on mucous membrane of the oral cavity and upper gastrointestinal tract, necrotic lesions on the lips, dental footpad and tongue as well as oedema , necrosis of skeletal and cardiac muscle, coronitis, subintimal haemorrhage in the pulmonary artery; oedema of the lungs, ventral subcutis and fascia of the muscles of the neck and abdominal wall; and pericardial, pleural and abdominal effusions .
Other unspecific signs include drop in milk production, loss of body weight, fever, depression, excessive salivation, serous to bloody nasal discharge, facial oedema, hyperaemia, lameness and death [20, 26]. In goats, the infection demonstrated an acute drop in milk production, oedema of the lips and head, nasal discharge and erythema of the skin and udder ; however, in goats and cattle infection may be unapparent . Newborn lambs may reveal porencephaly and cerebral necrosis; however, this type of lesions is more frequent after vaccination using an attenuated virus. The severities of clinical signs seem to vary with the species, breed, age, immune status and the serotype/strain of the infecting virus and with certain rather ill-defined interactions with the environment. Bluetongue typically occurs when susceptible animal species are introduced into areas with circulating virulent BTV strains, or when virulent BTV strains extend their range to previously unexposed populations of ruminants [24, 27].
The outcome of BTV infection of foetal ruminants is age-dependent and transplacental infection , which may result in either stillbirths, abortions or the birth of non-viable lambs with severe lesions of the central nervous system [20, 25]. In cattle, most infections are unapparent [20, 21]; however, a few animals may develop clinical signs that include fever, salivation, facial oedema, lesions on lips and nostrils, ulcerations in the oral and nasal mucosa, including tongue and gingiva, and coronitis [29, 30]. In utero transmission occurs in cattle and can result in birth of viraemic calves, abortion, congenital defects such as cerebellar hypoplasia, hydranencephaly or porencephaly accompanied with behavioural abnormalities (head pressing, ataxia, inability to stand and suck well, dullness, disorientation and impaired vision)and congenital musculoskeletal deformities (agnathia, brachygnathia and arthrogryposis) [29–31].
• Epizootic haemorrhagic disease (EHD)
Epizootic haemorrhagic disease virus is a member of the genus
• Foot and mouth disease (FMD)
FMD is a highly contagious disease caused by an aphtovirus that belongs to the Picornaviridae family [40, 41], which affects cloven-hoofed animals, mostly cattle, swine, sheep, goats and many species of wild ungulates; however, sheep and goats can be carriers, some studies reveal that the last two species are infrequent carriers. In adult cattle, the main symptoms are characterized by a sudden decrease in milk production, fever (40–41°C), lameness, as well as severe diarrhoea and anorexia, followed by the appearance of vesicles and erosions in the mouth, teats and feet , and abortion in pregnant animals. Secondary infections can appear in these areas in which the more notable one is the acute painful stomatitis. Although FMDV rarely causes death in adult animals, young animals are more susceptible and may suffer from severe lesions in the myocardium . Reproductive failure and abortion may also be reported [43–45].
In sheep and goats, the disease is generally mild and is important mainly because of the risk of transmission to cattle and can be difficult to distinguish from other common conditions [41, 46].The more common syndrome in this species is the appearance of a few small lesions, but with a more severe involvement of all four feet. The principal mechanism of transmission is the respiratory route [41, 47] or by ingestion through direct or indirect contact with secretions or excretions from infected animals; however, the possibility of aerogenous infection exists between cloven-hoofed species . Cattle are the most susceptible, followed by sheep, whereas pigs are very resistant . The period of maximum infectivity occurs during the early clinical phase of the disease when there is contact with the vesicular fluid when vesicles are discharged.
• Bovine viral diarrhoea (BVD) and Border disease virus of sheep
These viruses are members of the Flaviviridae family and belong to
Although clinical presentations depend on several factors, such as on strain of virus, species of host, immune status of host, reproductive status of host, age of host, concomitant infections and time of gestation , BVD virus is known to produce from subclinical infections (persistently infected animals) to a large number of diverse diseases, including reproductive disorders (decrease in conception rate and pregnancy rate, increased embryonic mortality), early embryonic death, foetal reabsorption abortion, stillbirths, central nervous system defects (microencephaly, cerebellar hypoplasia, hydranencephaly, hydrocephalus, hypomyelinogenesis, hypomyelination, cerebellar-ocular agenesis, ocular abnormalities), ocular abnormalities (microphthalmia, cataracts, retinal degeneration, optic neuritis), musculoskeletal deformities (brachygnatism), thymic aplasia, hypotrichosis, alopecia, pulmonary and renal hypoplasia [29, 50], growth retardation , enteritis and mucosal disease [51–53]. The most dramatic clinical symptoms are associated with the peracute form of the disease that is characterized by a sudden decrease in milk production, fever, watery and bloody diarrhoea, dehydration, tenesmus, tachypnea, tachycardia, drooping ears, anorexia, excessive lacrimation, nasal discharge, hypersalivation, petechial and ecchymotic haemorrhages of the visible mucosa, and development of ulcers of the nares, muzzle, lips and oral cavity  mucous membranes as well as skin lesions around the inguinal and perineal regions, the inner thighs and inside the ears . Thrombocytopenia and haemorrhagic syndrome  may also be present in animals affected with the disease. Mucosal disease may also appear as a chronic form which persists for weeks to months and is manifested by inappetence, intermittent to chronic diarrhoea and weight loss. Cattle that have chronic mucosal disease appear unthrifty, may show lameness due to laminitis or interdigital necrosis, and may develop alopecia and hyperkeratinization. Acute or chronic mucosal disease usually occurs in cattle younger than 3 years of age .
The virus is transmitted by direct contact between animals and by transplacental transmission to the foetuses. The primary source of infection is the introduction of persistently infected animals into the farm . Nose-to-nose contact is the most effective method of transmitting the virus. Another way of transmission is through contact with fomites such as contaminated needles, obstetric gloves or other equipment [53, 57]. Another indirect way of contact is the transmission through blood-feeding flies and artificial insemination .
Border disease (BD) is a congenital virus disease of sheep and goats and is caused by a pestivirus closely related to classical swine fever virus and bovine viral diarrhoea virus . Ewes in acute infection are clinically normal, and viraemia is transient and difficult to detect, and the infection in goats is rare and mainly characterized by abortion. Clinical signs in sheep include barren ewes, abortions, stillbirths, birth of unviable lambs, foetal death with resorption and mummification [58–60]. Affected newborn lambs can show clonic rythmic tremors, abnormal body conformation, inability to stand, gait anomalies and abnormally hairy birthcoat so-called ‘hairy-shaker’ or ‘fuzzy’ lambs which is due to hypertrophy of primary follicles and medullation of wool fibres . Nervous signs are due to a defective myelinogenesis and tend to disappear at a later age [61–63]. Some authors showed that major skeletal abnormalities are brachygnathia, prognathia and arthrogryposis . Although some lambs die shortly after birth, surviving lambs, as well as apparently normal lambs, can be persistently infected with the virus and excrete it constantly for the rest of their lives. The virus is excreted with saliva, nasal discharge, urine and faeces . Persistently infected animals are the major source of infection and are responsible for the vertical transmission to other susceptible flock or even cattle when mixed grazing is present . The surviving lambs are persistently infected with the virus. Acute infection is usually subclinical, and sheep may also be infected following a close contact with cattle excreting the closely related BVDV .
• Bovine herpesvirus type-1 and other herpesviruses
Infectious bovine rhinotracheitis/infectious pustularvulvovaginitis (IBR/IPV) is caused by bovine herpesvirus type-1 (BHV-1) , and is a disease of domestic and wild cattle. BoHV-1 is a member of the genus
In adult goats, infection with caprineherpesvirus-1 (BHV-6) is responsible for abortion during the second half of pregnancy, stillbirth and neonatal deaths,and the infection leads to vulvovaginitis  or balanoposthitis . In newborn kids, ulcerative and necrotic lesions  are distributed throughout the enteric tract, and a complex and purulent respiratory compromise and systemic disease is present .
• Rift Valley fever
Rift Valley fever (RVF) virus belongs to the
Many species of mosquitoes have been identified as vectors [73, 74]. Some
In general, clinical signs of the disease tend to be unspecific; however, the sudden onset of numerous abortions (with rates near 100%) and high mortality among young animals along with the clinical history and the environmental factors can help in the establishment of the clinical diagnoses. In sheep, the most common symptoms are (highly susceptible) fever (40–41°C), inappetence, nasal discharge, incoordination, weakness, depression, bloody or fetid diarrhoea . Newborn lambs are considered extremely susceptible, and the main symptoms are: sudden death, fever prior to death (40–42°C), weakness, depression, listless, abdominal pain, tachypnea, increased respiratory rate abdominal respiration prior to death .
• Bovine ephemeral fever (BEF)
BEF is an arthropod-borne rhabdovirus that causes a debilitant disease of cattle and water buffaloes with considerable economic impact [77–79]. Bovine ephemeral fever virus belongs to
• Akabane virus
Akabane virus is an
In 1979, Hashiguchi et al.  demonstrated that foetal infection in sheep, between 30 and 50 days pregnancy, result in most congenital abnormalities such as ankylosis of the limbs, scoliosis, hydranencephaly, porencephaly, stillbirth with dwarfism and death after birth with dwarfism and weakness. Few, if any, clinical findings are seen after infection in adult animals [84, 91]. In small ruminants, the lesions of arthrogryposis and hydranencephaly are often seen concurrently and are common in the same animals as well as cerebellar hypoplasia, porencephaly, brachygnathia [31, 92]. This type of lesions may or may not be accompanied by inflammation of the central nervous system . Most Akabane-infected lambs or kids are stillborn or die soon after birth.
• Aino virus
Aino virus is a member of the Simbu serogroup of the genus
Aino virus infection in adult animals is subclinical, and newborn calves infected can exhibit a wide variety of skeletal and neurological abnormalities [29, 93, 96]. This virus infection is closely related to the Akabane and SBV infection; therefore, confirmatory diagnosis requires viral detection to differentiate infection between these three viruses [94, 98].
In naturally infected pregnant cattle, Aino virus has been associated with abortion , stillbirths, premature births and birth congenital malformation, including severe hydranencephaly  and/or arthrogryposis , unilateral cavitation in the cerebrum, microcephaly and cerebellar hypoplasia [92, 93]. The type of abnormality seen can be related to the time of infection of the foetus : early infection results in hydranencephaly and later infection results in arthrogryposis . Scoliosis , sunken eyes, cataracts, maxillary retraction and dental irregularities are also clinical findings. Surviving calves may be weak and can have difficulty suckling or standing. They may also be blind or have poor eyesight. In addition, they may display a variety of neurologic signs, including ataxia, torticollis, tetany, paresis, swimming movements, opisthotonus and circular walking.
• Cache Valley virus
Cache Valley virus (CVV) is a mosquito-borne , teratogenic
• Chuzan virus
Chuzan virus is a member of Palymserogroup from genus
• Wesselsbron disease
Wesselsbron disease is an acute, arthropod-borne infection caused by a flavivirus, member of the Flaviridae family. This virus affects sheep, goats and sporadically cattle [50, 111]. Infection in adult animals and calves is usually subclinical or inapparent [112–114], although in sheep with preexisting liver disease clinical findings can be more expressive and severe. Newborn lambs and kids are most susceptible, and it is often accompanied by a high mortality rate [112, 115]. Outbreaks of congenital abnormalities in foetal or newborn ruminants, musculoskeletal deformities, neonatal deaths , abortion in adult animals [31, 50, 112] as well as hydropsamnii  in ewes, stillbirths and mummified foetuses  have been related. The main lesions found in foetuses are arthrogryposis, brachygnathia inferior, hydranencephaly, hydranencephaly, porencephaly, cerebellar hypoplasia , hypoplasia or segmental aplasia of the spinal cord and neurogenic muscular atrophy .
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