bovine coronavirus infection

Pictures

Picture	Title	Caption	Copyright
Title Bovine coronavirus infection. Symptoms. Caption Calf suffering from bovine coronavirus infection. Calf appears weak, dehydrated with sunken eyes, bloody diarrhoea and its hind quarters are soiled with liquid faeces. Copyright S. Kapil	Bovine coronavirus infection. Symptoms.	Calf suffering from bovine coronavirus infection. Calf appears weak, dehydrated with sunken eyes, bloody diarrhoea and its hind quarters are soiled with liquid faeces.	S. Kapil
Title Pathology Caption Lesions are confined to the ventral part of the lungs. Haemorragic lesions are evident. On histopathology there are pools of blood in alveoli and pneumonia is observed. Copyright S. Kapil	Pathology	Lesions are confined to the ventral part of the lungs. Haemorragic lesions are evident. On histopathology there are pools of blood in alveoli and pneumonia is observed.	S. Kapil
Title Histology Caption Interstitial pneumonia in a calf injected with pneumoenteric BCV isolate. Copyright S. Kapil	Histology	Interstitial pneumonia in a calf injected with pneumoenteric BCV isolate.	S. Kapil
Title Histology Caption Haemorrhages and congestion in lung section of calf experimentally infected with pneumoenteric isolate of BCV. Copyright S. Kapil	Histology	Haemorrhages and congestion in lung section of calf experimentally infected with pneumoenteric isolate of BCV.	S. Kapil
Title Histopathology Caption Section of intestine in which the cells are stained with Z3A5 monoclonal antibody. Z3A5 reacts with spike protein of BCV. These cells are lining the lumen of the villi and there are some dead necrotic cells that have bovine coronavirus antigen inside the villi. Cells are present between villi, which could be macrophages that are loaded with viral antigen.|Section of intestine in which the cells are stained with Z3A5 monoclonal antibody. Z3A5 reacts with spike protein of BCV. These cells are lining the lumen of the villi and there are some dead necrotic cells that have bovine coronavirus antigen inside the villi. Cells are present between villi, which could be macrophages that are loaded with viral antigen. Copyright S. Kapil	Histopathology	Section of intestine in which the cells are stained with Z3A5 monoclonal antibody. Z3A5 reacts with spike protein of BCV. These cells are lining the lumen of the villi and there are some dead necrotic cells that have bovine coronavirus antigen inside the villi. Cells are present between villi, which could be macrophages that are loaded with viral antigen.|Section of intestine in which the cells are stained with Z3A5 monoclonal antibody. Z3A5 reacts with spike protein of BCV. These cells are lining the lumen of the villi and there are some dead necrotic cells that have bovine coronavirus antigen inside the villi. Cells are present between villi, which could be macrophages that are loaded with viral antigen.	S. Kapil
Title Histopathology Caption Nasal smear with BCV antigen appearing as apple green fluorescence. Uninfected cells appear brick red. Copyright S. Kapil	Histopathology	Nasal smear with BCV antigen appearing as apple green fluorescence. Uninfected cells appear brick red.	S. Kapil

Identity

Preferred Scientific Name

• bovine coronavirus infection

International Common Names

• English: BCV infection; bovine coronavirus-associated enteritis; bovine coronavirus-associated respiratory disease; bovine coronavirus-associated shipping fever; bovine viral scours; bovine winter dysentry; calf diarrhoea; calf viral diarrhoea; coronaviral enteritis of calves; coronaviral scours; coronavirus infection in calves and cattle; epizootic diarrhoea; infectious diarrhoea; neonatal calf diarrhoea; neonatal diarrhoea; reo-coronavirus calf diarrhoea; scours; winter dysentery; winter dysentery in cattle; winter haemorrhagic enteritis; winter scours

Pathogen/s

Overview

Bovine coronavirus (BCV) was characterized as a viral cause of calf enteritis by Mebus et al. (1973) and is now recognized as a leading cause of calf enteritis around the world. The virus infects the enteric and/or upper respiratory tract of calves that are 1-week to 3-months-old. In adult animals, the disease is usually sub-clinical, and the virus may be excreted intermittently at low titre (Schoenthaler and Kapil, 1999). Bovine coronavirus has also been identified as the etiological agent of winter dysentery in adult cows (Saif, 1990). The incidence of BCV varies in different parts of the world but published and annual reports indicate that BCV causes 15-30% of calf enteritis cases (Langpap et al., 1979). The incidence of diarrhoea from bovine coronavirus may be underestimated because many laboratories around the world are not equipped with BCV antigen detection methods such as electron microscopy and BCV ELISA; also the isolation of BCV in tissue culture is difficult (Kapil et al., 1996). Bovine coronavirus infection occurs in combination with other enteric viral, bacterial, parasitic, and protozoal pathogens. Other than enteric infection and sporadic respiratory infections, BCV is not associated with any other system/disease in cattle. Based on published reports, bovine coronavirus does not produce disease in humans.

Host Animals

Hosts/Species Affected

All breeds of cattle are hosts for BCV. There is no known cattle breed that is resistant to the disease. However, animals may differ in their susceptibility, which might be controlled by the number of receptors in the intestinal epithelium. Interaction between the viral spike glycoprotein (anti-receptor) and a specific carbohydrate receptor is essential for viral infectivity. The carbohydrate receptor used by bovine coronaviruses for viral attachment is N-acetyl-9-O-acetylneuraminic acid (Schultze and Herrler, 1992).

Wild ruminants are also infected with the virus. Even though wild ruminant coronavirus may be antigenically, genetically, and biologically very close to coronaviruses, it is an accepted rule that a coronavirus isolated from any species is named after that host. Elk coronavirus has been found to be related closely to BCV both genetically (Majhdi et al., 1997) and antigenically (Daginakatte et al., 1999). Distinguishing between different BCV isolates with monoclonal antibodies is difficult. Most BCV isolates and wild ruminant strains can be distinguished on the basis of a haemagglutination inhibition test using mouse erythrocytes. The differences between strains also lie in the haemagglutinin-esterase genes (Crouch et al., 1985). The haemagglutinin gene facilitates haemagglutination and esterase activities, both of which can differ among BCV isolates. The haemagglutinin-esterase gene may have been acquired by coronaviruses during evolution from influenza viruses by random recombination events. A vaccine against BCV might protect against heterologous infection in other ruminants.

Systems Affected

Distribution

Bovine coronavirus has a worldwide distribution and has been reported on six continents. Major antigenic characteristics are shared among isolates around the world; however, minor antigenic variations may be found among BCV isolates from different areas. European BCV isolates are antigenically similar to the American BCV isolates (Woode et al., 1978).

Distribution Table

The distribution in this summary table is based on all the information available. When several references are cited, they may give conflicting information on the status. Further details may be available for individual references in the Distribution Table Details section which can be selected by going to Generate Report.

Pathology

Bovine coronavirus antigen is present in the epithelial lining of the villi, the crypts and in the nasal glands and nasal epithelium. Occasionally, an isolated macrophage is seen in the lamina propria and in the Peyer’s patches (Zhang et al., 1997). This indicates that although the virus may be distributed by macrophages, it probably does not infect other parts of the body. Haemorrhages, enlargement of Peyer’s patches and fluid diarrhoea are evident upon examination of infected animals. Immunohistochemistry with BCV-specific monoclonal antibodies was used to study the pathology of BCV. A monoclonal antibody (Z3A5) was developed and found to be highly specific for detection of BCV spike protein in paraffin-embedded, formalin-fixed intestines (Zhang et al., 1997). A monoclonal antibody (8F2) against the nucleoprotein of coronavirus can also be used (Daginakatte et al., 1999). Anti-nucleoprotein monoclonal antibodies are more sensitive in ruminant coronavirus detection than the anti-spike protein monoclonal antibodies, because the nucleoprotein accounts for the major viral protein in BCV-infected cells.

Diagnosis

Enteric BCV infections generally are diagnosed by examination of faecal samples or intestinal contents. When faecal samples are submitted to laboratories, BCV is diagnosed by direct electron microscopy (EM) or antigen capture ELISA. If intestinal contents are submitted, then the test of choice is direct EM. The virus has a mean diameter of 126 nm as determined by transmission EM. A double-ring of surface proteins is evident. Other enteric viral agents (such as Rotavirus, Parvovirus, Bredavirus, and Adenovirus) could be present along with the bovine coronavirus infection and also be detected. However, routine use of electron microscopy for testing is tedious, needs trained assistance, requires an expensive microscope and lacks sensitivity. The technique can be improved using immuno-electron microscopy (Saif et al., 1991). In addition, ELISA may be used to detect viral antigen and is highly sensitive and specific. Kansas State University, USA, has developed a BCV-specific ELISA. The sensitivity of this ELISA is 10⁴ BCV particles per ml of 10% faecal suspension. Compared to EM, this BCV ELISA had 96% specificity (Schoenthaler and Kapil, 1999). In addition, a bovine coronavirus antigen test kit is available commercially from Syracuse Bioanalytical, Ithaca, New York, USA.

No diagnostic tools are available for cow-side testing or in-office testing for veterinarians. When sending samples to diagnostic services it is important to include at least five sections from different parts of the gut, including the spiral colon because this is the common site of virus persistence (Kapil et al., 1994a; Kapil et al., 1994b). Sometimes BCV infections are focal and are easy to miss if only a few sections are examined. In remote areas of the world where diagnostic services are not easily accessible, the gut can be cut into 5 cm pieces, the ends tied and sent (on dry ice or ice packs) to the nearest diagnostic laboratory for fluorescent antibody or EM analysis. Enteric viral agents are common in most ruminant animals. Every animal is exposed to BCV within a lifetime and the serological incidence of BCV is close to 100%. They may or may not develop the disease depending on the level of age susceptibility (Torres-Medina et al., 1985).

In respiratory coronavirus disease the viral antigen can easily be demonstrated in washed nasal epithelial cells by direct fluorescent antibody test using conjugate obtained from National Veterinary Services Laboratory (Kapil et al., 1991). Demonstrating the antigen in the lower respiratory tract is difficult. In the future, diagnosis could be made more specific, if antibodies against spike protein (protective antigen) are monitored through a sub-unit ELISA.

Serological tests, such as indirect fluorescent antibody, are used to monitor the presence of antibody in colostrum, serum, and intestinal contents. However, these are not yet commercially available; the Kansas State University Diagnostic Laboratory, USA conducts such tests. Of equal significance is the performance of direct fluorescent antibody technique for diagnosis of the virus in tissue sections (Mebus et al., 1973). A tendency for autofluorescence because of the presence of mucus could give misleading results; however, these problems are rare in incidence.

Primary isolation of BCV in tissue culture is difficult. It can grow by serial passage in continuous cell lines e.g. Vero, MDBK, and porcine kidney cell lines. A cytopathic effect is clearly evident at the second and third passages. Treatment of cells with trypsin (20 µl/ml) increases the production of BCV in cell culture (Dea et al., 1980).

The protective immune responses against BCV occur on mucosal surfaces; serum antibodies do not provide any protection. The levels of immunoglobulins (IgM, IgA, IgG1, and IgG2) differ depending on the level of bovine coronaviral antigen in different regions of the gut (Kapil et al., 1994a; Kapil et al., 1994b). The role of cell-mediated immunity in BCV has not been well characterized. The absorption of colostral antibodies occurs in an open gut for up to 24 hours after birth. Thus, colostrum having a high titre for BCV and other enteric viral agents should be fed within this period. If the calf does not receive a sufficient amount of colostrum during this time it becomes extremely susceptible not only to enteric diseases but to other perinatal diseases such as pneumonia. Diarrhoea and pneumonia are the major causes of death in calves.

List of Symptoms/Signs

Disease Course

Bovine coronavirus causes both acute and chronic disease. Most calves suffer from acute infection, but in later stages calves may periodically shed the virus. Adult cattle have only chronic BCV infection. Incubation time is about 20 hours, and symptoms appear at around 24 hours after experimental infection (Kapil et al., 1990). After 3-4 days of viral excretion at high titre, the titre level falls dramatically. Therefore, samples should be collected during early stages of the disease. Tests, such as electron microscopy, that lack sensitivity will miss a positive diagnosis if samples are taken in later stages of infection. Approximately 50,000 virus particles per gram of faeces should be present to detect the virus by EM (Flewett, 1978). Clinically normal cattle in contact with calves showing BCV signs should also be sampled, because they may be in the early stage of disease and will be secreting high amounts of virus. It is preferable to submit two pools of faecal samples from acutely affected (clinically infected) and contact animals (clinically normal) for testing by EM.

BCV antigen can be detected in approximately 25% of calves affected by BCV-associated disease in the respiratory tract but not in the intestinal tract (respirotropic isolates). In another 25% of affected calves, BCV can be detected only in the intestinal tract but not in the respiratory tract (enterotropic isolates). In the remaining 50% of animals, BCV antigen can be demonstrated in both enteric and respiratory tracts (pneumoenteric isolates) (Kapil and Goyal, 1995). Isolates of BCV produce enteric disease and isolates of bovine respiratory coronavirus produce both enteric and respiratory coronavirus disease. Most isolates of BCV are either enterotropic or pneumoenteric. There is very limited evidence that indicates that purely respiratory tropic strains exist. Respiratory and enteric diseases in calves and cattle may be different manifestations of the same virus at different stages of infection. On the basis of experimental infection, the pneumoenteric affected calves suffer first from enteric infection and then later with respiratory infection (Kapil et al., 1991).

Virus infection of the enteric tract starts in the small intestine and spreads to the large intestines. Rarely, mild fibrinonecrotic typhlocolitis is recognized. Exfoliation of epithelium and microerosions may be seen. The extent of lesions depends on the severity and duration of infection. The lamina propria may be moderately infiltrated with mononuclear inflammatory cells. Necrosis of cells in mesenteric lymph nodes is associated with viral replication. Peyer’s patches in animals examined after 4 or 5 days of clinical infection often appear involuted. After infected epithelial cells die they are replaced by immature cells, severely diminishing the absorption in the gut. Immature cells are also unable to secrete normal amounts of digestive enzymes. This decrease in absorbant and digestive ability leads to metabolic imbalance. Diarrhoea causes dehydration, acidosis, and hypoglycaemia. If uncontrolled, calves may die of acute shock and heart failure. However, calves may recover from infection because the virus rarely attacks crypt epithelial cells. These epithelial cells produce cells that are virus-resistant and replace damaged cells (Clark, 1993).

Bovine coronavirus resulting in respiratory disease is more than likely transmitted by aerosols. After initial infection of the nasal epithelium, the virus is swallowed along with saliva, subsequently affecting the intestinal tract. Calves develop nasal discharge, cough, laboured breathing, and fever of up to 41°C due to dehydration and metabolic imbalance. Respiratory distress may result from metabolic effects of the disease due to extreme dehydration. In calves there is extreme respiratory distress followed by death. Based on experimental studies, ventral parts of the lungs are involved (Kapil et al., 1991). Respiratory coronavirus lesions are atelectasis, interstitial pneumonia, emphysema, haemorrhage, and presence of antigen in the nasal cavity, nasal glands, and upper one-third of the trachea.

Bovine coronavirus has been consistently identified as the primary pathogen in faeces of cows with winter dysentery. Many characteristics of winter dysentery closely coincide with the traits of BCV infection. Disease outbreaks usually occur during the winter months; cows that are pregnant or recently calved are most frequently affected. Faecal and respiratory transmission of coronavirus could account for outbreaks of winter dysentery in confined cattle (Saif, 1990). A severe drop in milk production and haemorrhagic diarrhoea characterizes winter dysentery.

Epidemiology

The primary routes of entry for bovine coronavirus are through the mouth or nasal cavity (Clark, 1993). Adult cattle are carriers and excrete the virus at low titre; however, during parturition, cows shed higher titres of the virus. It is possible that increased levels of progesterone and other hormones play a role in amplifying the viral titre and thus increase the chances of transmission (Crouch et al., 1985). Close contact between dam and offspring increases the chance of viral transmission because the calf has an immature immune system. The hindquarters of dams should be hosed in order to minimize faecal transmission of the virus to calves. Cleanliness of the maternity pens is extremely important. Even though cows are considered to be the source of BCV for calves, the prolonged excretion of BCV in calves indicates that these calves may be another possible source of the virus for other calves that become clinically sick (Kapil et al., 1990).

Although BCV is sensitive to environmental conditions such as sunlight, heat, lipid solvents, and disinfectants, coronaviral scours may occur in a herd year-after-year. The virus can survive in organic material, such as soiled hay, for long periods of time, especially during winter months. Delivery of beef calves in pasture under extreme winter conditions might increase the chances of disease because of depression in the immune system, stress, and greater survival of virus due to lower ambient temperatures. Animals will also be more susceptible to infection with the feeding of colostrum that does not contain sufficient amount of BCV-specific antibody or if a calf is not able to suckle and obtain colostrum.

Arthropod or small mammal vectors of the disease are not known. However, BCV and other ruminant coronaviruses are related antigenically; wild ruminants such as deer, water buck, wild antelopes and bison may play a role in the transmission of the disease (Tsunemitsu et al., 1995). In areas of the world where wildlife and domestic cattle share common pastures, infection may cross among these species. Thus, transmission is due to direct or indirect contact. Animals are more susceptible to BCV during periods of long travel when they are in close contact. Therefore, BCV has been recognized as a cause of shipping fever (Storz et al. 1996).

Impact: Economic

The exact economic impact of BCV infection is not known; however, the impact of calf diarrhoea has been estimated. Annual losses of $250 million and $1,700 million are attributed to bovine scours around the world (Ratafia, 1988). Intensive beef and dairy management practices leading to close confinement of large numbers of calves exacerbate losses from calf scours (Saif, 1990).

Progress in veterinary medicine is leading to better control of bacterial scours by use of antibiotics. Though the incidence of viral scours from BCV is as high as 30%, a relative increase in incidence will occur. Improved diagnostic techniques and strategies such as use of ELISA technologies that are rapid and specific will lead to more accurate assessment of the incidence and economic impact of bovine coronavirus.

Zoonoses and Food Safety

Although bovine coronavirus is not zoonotic, human coronaviruses exist that are related antigenically. There is a single report on the possible transmission of BCV from an experimentally infected calf to a human investigator; however, this information was anecdotal (Storz and Rott, 1981).

Bovine coronavirus is not transmitted through meat or any other food sources.

Disease Treatment

Treatment of BCV is generally symptomatic. Fluid therapy is given orally or intravenously. Astringents also are used to control diarrhoea. Additional feeding of fortified colostrum may be useful in preventing the clinical disease in newborn calves (Murakami et al., 1986). It is suggested that milk containing high amounts of coronavirus-specific antibodies be fed to calves for the first 14 days of life to reduce the incidence and duration of viral shedding (Heckert et al., 1991). Addition of the neutralizing monoclonal antibody (Z3A5) against the spike protein to immune colostrum might also provide protection, but it is not yet commercially available. It has also been reported that in vitro Hygromycin B inhibits the replication of virus in cell culture (Zhang et al., 1997); however, the drug has not been tested in calves.

Prevention and Control

On the basis of field trials and experimental trials the vaccines available so far are generally non-effective (Thurber et al., 1977). To be effective, vaccination must be given immediately at birth, before colostrum and possible infection with field virus. Levels of coronavirus antibodies in colostrum may inactivate the vaccine. Also, colostrum from dams is only secreted for 3-5 days after birth and is replaced by milk, which contains little antibody. Colostrum antibody only remains in calf intestine for approximately 2 days. Thus, at 5-7 days after birth there is little coronavirus protection in the intestine even though the calf may present high anti-coronavirus titres in serum. Administration of immune colostrum can be continued for further protection. Antigenic variation among BCV isolates and the inability of the vaccine to replicate sufficiently in the calf intestine may also lead to lower vaccine efficacy.

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Distribution Maps