Role of bovine viral diarrhea virus in the bovine respiratory disease complex (Proceedings)

Bovine viral diarrhea virus (BVDV) is one of the most important infectious agents of cattle. The annual economic loss caused by BVDV is difficult to quantify but certainly is significant. The insidious nature of BVDV combined with the biology of the virus and complex disease pathogenesis has made control and prevention of this virus challenging. BVDV has been associated with many clinical diseases. There is little doubt that BVDV plays a role in bovine respiratory disease (BRD). This review will present past and current information on the role that BVDV plays in BRD.

Role in Bovine Respiratory Disease

Bovine respiratory disease is the most frequent cause of morbidity and mortality in North American feedlots and is the major cause of economic loss. It is generally agreed that Mannhemia haemolytica is the major contributor to pneumonic lesions. Considerable research has focused on the mechanisms by which M. haemolytica colonizes the lungs. Many predisposing factors have been implicated in reducing the local clearance mechanisms of the lungs including stress from weaning, transportation, mixing of cattle, handling, and processing. Viruses, including parainfluenza-3, bovine respiratory syncytial virus, bovine herpes virus-1, coronavirus, and BVDV, have been implicated as predisposing causes of BRD.

BVDV has been implicated in bovine respiratory disease since it was first described by Olafson, MacCallum and Fox in 1946. Although not conclusive, both circumstantial and experimental evidence suggest that BVDV is involved in BRD.

Clinical: Circumstantial evidence that BVDV is involved in BRD comes from clinical pathological observation. As mentioned earlier, clinical descriptions of cattle undergoing acute BVDV infection often involve respiratory signs. In Sweden, severe respiratory disease outbreaks were described involving both BVDV and PI-3. In the United States, BVDV has been reported as the most commonly isolated virus from pneumonic lungs and in outbreaks of BRD.

Experimental studies attempting to reproduce respiratory disease with BVDV alone have resulted in mild lesions. In studies by Potgeiter et al., calves infected with BVDV alone had less severe clinical signs and pulmonary pathology when compared to calves infected with both BVDV and P. haemolytica. Synergistic effects between BVDV and P. haemolytica, BHV-1 and BRSV have been documented. Differences in pneumopathogenicity have been demonstrated for isolates of BVDV. These findings suggest an immunocompromising role for BVDV in bovine respiratory disease.

Epidemiological: Epidemiological studies have both implicated and shown no evidence that BVDV is associated with outbreaks of respiratory disease. Interpretation of results is often difficult because of the multiple etiologies of the BRD complex and the variability of exposure to various pathogens prior to being studied. It is obvious from a review of seroepidemiological studies that the risk of developing BRD in association with BVDV seroconversion varies. In two studies by Martin et al. involving feedlot calves, seroconversion to BVDV was significantly associated with the development of BRD. Similarly, young calves seronegative to BVDV were at higher risk for developing respiratory disease while seroconversion to BVDV was associated with respiratory disease. Protection from respiratory disease has been shown in calves entering a feedlot seropositive to BVDV. Highlighting the importance of colostral antibodies, a protective effect against respiratory disease has been shown in calves being born to BVDV seropositive dams. In contrast, other studies have provided no evidence between seroconversion to BVDV and risk of developing BRD. Allen et al. reported a 51% rate of seroconversion to BVDV in both BRD cases and controls. In young dairy calves entering a commercial calf rearing unit, BVDV was not identified as a risk factor for developing clinical respiratory disease. It should be noted that in all of the above studies, other agents in addition to BVDV were identified as being associated with respiratory disease. This highlights the complex nature of BRD and the fact that it is a multifactorial disease.Immunosuppressive Role: Several field studies have reported that clinical disease caused by a particular organism appears to be more severe when concurrent BVDV infection is present. The compromising effect of BVDV is thought to be due to immunosuppressive effects of the virus. The most important role that BVDV may play in BRD is in suppressing local immune system function in the lungs, thus allowing pathogenic bacteria to become established.

Several reports have suggested synergistic effects between BVDV and other pathogenic organisms. In calves infected simultaneously with BVDV and BHV-1, the latter virus became systemically disseminated as compared to remaining localized in the respiratory tract in calves not infected with BVDV. BVDV infection has also been associated with concurrent Salmonella, E. coli, bovine papular stomatitis and rotavirus and coronavirus infections.

In experimental studies involving BVDV and Mannheimia haemolytica, sequential infection with the two organisms produced more severe fibrinopurulent bronchpneumonia when compared to each organism by itself. Interestingly, when calves were inoculated with BVDV only, bacteria could often be cultured from the lower respiratory tract and was assumed to be endogenous bacteria originating from the upper respiratory tract. In contrast, Lopez et al. showed no effect of BVDV on inhibiting pulmonary clearance of M. haemolytica. In a small study, Pollreisz et al. provided evidence that BVDV and bovine respiratory syncytial virus (BRSV) can potentiate each other in dual virus infections of calves.38 In this study, the severity of clinical signs and extent of lung injury was greater in calves infected simultaneously with BVDV and BRSV was greater than that caused by either virus alone.

The mechanisms of immunosuppression may involve several aspects of the immune system. Lymphocytes and macrophages are specific targets of BVDV. Systemically, acute infection with BVDV results in a transient leukopenia with lymphoid depletion often noted. A decrease in CD4+ and CD8+ T-lymphocytes, B-lymphocytes and neutrophils has been reported. In vitro studies have suggested different causes of immunosuppression. These include a decreased responsiveness of infected lymphocytes to mitogen stimulation, decrease in interferon production, reduction in monocyte interleukin-1, interleukin-2 and tumor necrosis factor-alpha production and a decrease in the chemotactic responses by monocytes. Neutrophils from BVDV infected cattle have decreased activity in their myeloperoxidase, halide, and hydrogen peroxide systems which are bacteriocidal. In addition , neutrophil-mediated, antibody-dependent, cell-mediated cytotoxicity can be impaired significantly. BVDV mediated immunosuppression may be the indirect result of prostaglandin production from infected cells. This was suggested when indomethacin, a prostaglandin synthesis inhibitor, reversed the immunosuppressive effects of infected cell culture supernatant.

Evidence also exists that infection with BVDV may have a direct effect on local pulmonary immune functions. Virus has been shown to replicate in bovine alveolar macrophages. In bovine alveolar macrophages recovered from calves acutely infected with BVDV, the ability to phagocytize bacteria and the expression of compliment receptors (C3R) and antibody Fc receptors (FcR) was significantly reduced when compared to control calves (Table 4). Similar findings were found in alveolar macrophages infected in vitro. In addition, Olchowy et al. demonstrated that BVDV infected macrophages independently have an increased propensity to produce procoagulant which is part of the fibrin deposition cascade. Increased fibrin deposition in the alveoli may provide an enhanced environment for secondary bacterial replication.

Regardless of the mechanism; host, agent, and environmental factors undoubtedly influence the degree of immunosuppression that occurs following acute infection with BVDV.

Summary

The involvement of BVDV in respiratory disease is obviously complicated. However, enough evidence exists to include it as an integral part of the bovine respiratory disease complex. This warrants further study on its importance so that sound judgments can be made on developing and instituting control and prevention programs. Current available technology for preventing BVDV infection should be implemented when possible, including vaccination, biosecurity and the elimination of persistently infected cattle. Vaccination programs should be targeted to provide high levels of antibodies at times of maximum exposure.

References

Baker JC. Bovine viral diarrhea virus: A review. J Am Vet Med Assoc 1987;1499-1458.

Martin SW, Meek AH, Davis DG, et al. Factors associated with mortality and treatment costs in feedlot calves: The Bruce County beef project, years 1978,1979,1980. Can J Comp Med 1982;46:341-349.

Yates WDG. A review of infectious bovine rhinotracheitis, shipping fever pneumonia and viral bacterial synergism in respiratory disease in cattle. Can J Comp Med 1982;46:225-263.

Olafson O, MacCallum AD, Fox FH. An apparently new transmissible disease of cattle. Cornell Vet 1946;36:205-21

20. Yates WDG. Interactions between viruses and bacteria in bovine respiratory disease. Can Vet J 1984;25:37- 41.

Dinter Z, Bakos K. Viruses associated with acute respiratory and enteric disease in Swedish cattle. Bull Off Internat Epizoot 1961;56:29-34.

Reggiardo C. Role of BVD virus in shipping fever of feedlot cattle. Case studies and diagnostic considerations. Proceedings 22nd Annual Meeting of the American Association of Laboratory Diagnosticians, San Diego, CA, 1979, pp315-320.

Richer L, Marois P, Lamontagne L. Association of bovine viral diarrhea virus with multiple viral infections in bovine respiratory disease outbreaks. Can Vet J 1988;123:122-125.

Potgeiter LND, McCraken MD, Hopkins FM, et al. Experimental production of bovine respiratory tract disease with bovine viral diarrhea virus. Am J Vet Res 1984;45:1582-1585.

Potgeiter LND, McCraken MD, Hopkins FM, et al. Comparison of the pneumopathogenicity of two strains of bovine viral diarrhea virus. Am J Vet Res 1985;46:151-153.

Potgeiter LND, McCraken MD, Hopkins FM, et al. Effect of bovine viral diarrhea virus infection on thedistribution of infectious bovine rhinotracheitis virus in calves. Am J Vet Res 1984;45:687-689.

Brodersen BW, Kelling CL. Respiratory and enteric disease in calves were exacerbated by experimental concurrent bovine respiratory syncytial virus (BRSV) and bovine viral diarrhea virus (BVDV) infections. Proceedings 77th Meeting of the Conference of Research Workers in Animal Diseases, Chicago, IL, 1996, p. 202.

Martin SW, Bateman KG, Shewen PE, et al. The frequency, distribution and effects of antibodies, to seven putative respiratory pathogens, on respiratory disease and wight gain in feedlot calves in Ontario. Can J Vet Res 1989;53:355-362.

Martin SW, Bohac JG. The association between serological titers in infectious bovine rhinotracheitis virus, bovine viral diarrhea virus, parainfluenza-3 virus respiratory syncytial virus and treatment for respiratory disease in Ontario feedlot calves. Can J Vet Res 1986;50:351-358.

Stott EJ, Thomas LH, Collins AP, et al. A survey of virus infections of the respiratory tract of cattle and their association with disease. J Hyg 1980;85:257-269.

Ganaba R, Belanger D, Dea S, Bigras-Poulin M.A seroepidemiological study of the importance of respiratory and enteric viruses in beef operations from northwest Quebec. Can J Vet Res 1995;59:26-33.

Allen JW, Viel L, Bateman KG, et al. Serological titers to bovine herpesvirus 1, bovine viral diarrhea virus, parainfluenza 3 virus, bovine respiratory syncytial virus and Pasturella haemolytica in feedlot calves with respiratory disease: Association with bacteriological and pulmonary cytological values. Can V Res 1992;56:281-288.

Caldow GL, Edwards S, Peters AR, et al. Association between viral infections and respiratory disease in artificially reared calves. Vet Rec 1993;133:85-89.

Lehmkuhl HD, Gough PM. Investigation of causative agents of bovine respiratory tract disease in a beef cow-calf herd with an early weaning program. Am J vet Res 1977;38:1717-1720.

Lopez A, savan MG, Ruhnke HL, et al. The pulmonary clearance of Pasturella haemolytica in calves infected with bovine virus diarrhea or mycoplasma bovis. Can J Comp Med 1982;46:302-306.

Penny CD, Low JC, Nettleton PF, et al. Concurrent bovine viral diarrhoea virus and Salmonella typhimurium DY 104 infection in a group of pregnant dairy heifers. Vet Rec 1996;138:485-489.

Lambert G, Fernelius AL. Bovine viral diarrhea virus and Escherishia coli in neonatal calf enteritis. Can J Comp Med 1968;32:440-446.

38. Bocha JG, Yates WDG. Concurrent bovine virus diarrhea and bovine papular stomatitis infection in a calf. Can Vet J 1980;21:310 313.

Van Opdenbosch E, Wellemans G, Oudewater J. Interaction of BVDV, corona and rotavirus in neonatal calf diarrhea: Experimental infection in newborn calves. Vlaams Diergenseek Tijdshr 1981;50:163-173.

Truitt RL, Shechmeister IL. The replication of bovine viral diarrhea-mucosal disease virus in bovine leukocytes in vitro. Arch Ges Virusf 1973;42:78-87.

Bolin SR, McClurkin AW, Coria MF. Effects of bovine viral diarrhea virus on the percentages and absolute numbers of circulating B and T lymphocytes in cattle. Am J Vet Res 1985;46:884-886.

Muscoplat CC, Johnson DW, Stevens, JB. Abnormalities of in vitro lymphocyte response during bovine viral diarrhea virus infection. Am J Vet Res 1973;34:753-755.

Diderholm H, Dinter Z. Interference between strains of bovine virus diarrhea virus and their capacity to suppress interferon of a heterologous virus. Proc Soc Exp Biol Med 1966;121:976-980.

Adler H, Jungi TW, Pfister H, et al. Cytokine regulation by virus infection: Bovine viral diarrhea virus, a flavivirus, downregulates production of tumor necrosis factor alpha in macrophages in vitro. J Virol 1996;70:2650-2653.

Ketelsen AT, Johnson DW, Muscoplat CC. Depression of bovine monocyte chemotactic responses by bovine viral diarrhea virus. Infect Immunol 1979;25:565-568.

Brown GB, Bolin SR, Frank DE, et al. Defective function of leukocytes from cattle persistently infected with bovine viral diarrhea virus, and the influence of recombinant cytokines. Am J Vet Res 1991;52:381-387.

Markham RJF, Ramnaraine ML. Release of immunosuppressive substances from tissue culture cells infected with bovine viral diarrhea virus. Am J Vet Res 1985;46:879-881.

Ellis JA, Davis WC, Belden ET, et al. Flow cytofluorimetric analysis of lymphocyte subset alterations in cattle infected with bovine viral diarrhea virus. Vet Pathol 1988;25:231-236.

Jensen J, Schultz RD. Effect of infection by bovine viral diarrhea virus (BVDV) in vitro on interleukin-1 activity of bovine monocytes. Vet Immunol Immunopath 1991;29:251-265.

Atluru D, Xue W, Polam S, et al. In vitro interactions of cytokines and bovine viral diarrhea virus in phytohemagglutinin-stimulated bovine mononuclear cells. Vet Immunol Immunopath 1990;25:47-49.

Roth JA, Kaeberle ML, Griffith RW. Effects of bovine viral diarrhea virus infection on bovine polymorphonuclear leukocyte function. Am J Vet Res 1981;42:244-250.

Moerman A, Straver PJ, de Long MCM, et al. Clinical consequences of a bovine virus diarrhea infection in a dairy herd: A longitudinal study. Vet Quart 1994;16:115-119.

Pollreisz JP, Kelling CL, Perino LJ, et al. Potentiation of bovine respiratory syncytial virus infection in calves by bovine viral diarrhea virus. Bov Pract 1997:31:32-38.

Toth T, Hesse RA. Replication of five bovine respiratory virusesin cultured bovine alveolar macrophages. Arch Virol. 1983:75:219-224.

Welsh MD, Adair BM, Foster JC. Effect of BVD virus infection on alveolar macrophage infection. Vet Immunol Immunopath. 1995;46:195-210.

Olchowy TW, Slauson DO, Bochsler PN. Induction of procoagulent activity in virus infected bovine alveolar macrophages and the effect of lipopolysaccharide. Vet Immunol Immunopath. 1997;58:27-37.