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United States Department of Agriculture

Agricultural Research Service

Research Project: Intervention Strategies to Control Viral Diseases of Cattle
2013 Annual Report


1a.Objectives (from AD-416):
Objective 1: Determine the impact of variant and emerging viruses on the development and control of respiratory disease in ruminants. Develop means to detect and survey for variant viruses and develop models for evaluating infections with emerging variant viruses. Subobjectives: (1a) Determine impact of variant and emerging viruses; (1b) Improve current surveillance methods and diagnostic tools used to detect and control emerging viruses.

Objective 2: Elucidate the host-pathogen interactions associated with the Bovine Respiratory Disease Complex (BRDC) by defining host pathways modulated as a result of viral infections and characterizing the role of stress and immunological related host effector molecules in BRDC. Subobjectives: (2a) Define interactions of viral pathogens that may contribute to the development of respiratory disease; (2b) Define modulation of host immune response to viral infection associated with stress caused by vitamin D insufficiency.

Objective 3: Evaluate formulations and delivery systems for vaccination of neonates by identifying means to modulate stress and immunological factors associated with BRDC. Generate identification criteria and means to generate “vaccine ready” calves to develop intervention strategies for controlling viral respiratory infections of ruminants. Subobjectives: (3a) Identify factors, associated with common management practices, that modulate immune function in neonatal calves; (3b) Evaluate candidate vaccine for use in calves.


1b.Approach (from AD-416):
The goal of this project is to reduce the incidence and impact of viral infections in ruminants with particular emphasis on viral infections that contribute to respiratory disease in cattle. The project encompasses three distinct but interrelated research efforts. The first is to determine the incidence and impact of variant viruses, such as subgenotypes of bovine viral diarrhea virus (BVDV), and emerging viruses, such as HoBi-like viruses, to bovine respiratory disease. The purpose of this research is to determine if new antigens, representing variant and emerging viruses, need to be included in vaccines. The second is to examine the interaction of host and virus in respiratory disease. Included in this effort will be the study of host immune dysfunction, resulting from viral infection, nutrition, or stress. The purpose of this research is to define factors that contribute to respiratory disease in order to develop means of intervention that negate or ameliorate those factors. The third is to determine means by which host resistance to viral infection can be enhanced with emphasis on improving protective innate and acquired immune responses in calves. The information generated from these three research areas will be used in the development of intervention strategies to control and eliminate viral pathogens. Improved control of viral pathogens will benefit consumers by ensuring a healthful food supply, enhance animal health and well-being, and reduce production costs for farmers and ranchers.


3.Progress Report:
Viruses associated with bovine respiratory disease complex (BRDC) include bovine viral diarrhea viruses (BVDV), infectious bovine rhinotracheitis virus (IBR), Parainfluenza 3 virus (PI3), Bovine respiratory syncytial virus (BRSV) and bovine corona virus (BoCV). In support of objective 1, ARS researchers at Ames, IA are in the process of comparing currently circulating BVDV, IBR, PI3, BRSV and BoCV to viral strains currently in vaccines. Based on comparison of viral genetic material, the currently circulating viruses differ from vaccine viruses suggesting that protection against BRDC may be improved by using new vaccine strains. HoBi-like viruses are an emerging species of pestivirus, related to BVDV. NADC researchers demonstrated that HoBi-like viruses cause persistent infections in cattle. These persistently infected cattle can transmit the virus to other cattle, sheep, pigs and goats. Exposure to HoBi-like viruses could be differentiated from infection or vaccination with BVDV using a test designed by ARS NADC researchers. This test was used to screen serum samples originating in the U.S. No exposure to HoBi-like viruses was detected.

In support of objective 2, ARS researchers in Ames, IA compared immune tissue collected from non infected calves and calves infected with BVDV strains of varying virulence. They found that regardless of virulence, BVDV infections leave calves with damaged lymphoid tissues which might make them less able to fight off subsequent infections. We have also examined host genetic markers that are associated with BVDV immunosuppression and persistent infection. Studies are being designed to determine the function of these genetic markers. We have evaluated the effects of vitamin D status on immune response to infection with BRSV and BVDV. Results suggested that vitamin D status has a positive effect the immune response to BRSV and BVDV infections. We also found that proteins produced by BVDV bind host proteins associated with immune response. This may slow the host’s ability to fight off pathogens.

In support of Objective 3, two collaborations focused on vaccine development. In one, ARS researchers in Ames, IA made a vaccine against BRSV based on the attachment of proteins to small spheres (nanoparticles). This vaccine has been tested in cultured cells and plans are to test it in cattle. In another, ARS researchers at Ames, IA and a commercial biologics company developed a killed BVDV vaccine, based on expression of BVDV proteins in a defective Alphavirus particle called a replicon. Replicons infect cells and make viral proteins but do not to give rise to offspring viruses that are able to infect cells. It was shown that the new vaccine protected calves from disease. A third collaboration between ARS researchers in Ames, IA and a land grant university examined response to vaccination in cattle herds. It was found that not all cattle are protected from infection following vaccination. Future research will focus on why some cattle are protected and others are not.


4.Accomplishments
1. Evaluation of protection afforded, by current vaccines, against a newly emerging virus related to bovine viral diarrhea viruses (BVDV). Recently a new group of viruses, known as HoBi like viruses, have been isolated from cattle in Brazil, Italy and Thailand. HoBi like viruses are related to bovine viral diarrhea viruses (BVDV) and cause very similar diseases in cattle. Introduction of HoBi like viruses into North America could result in significant economic loss by cattle producers. There are no vaccines available for the prevention of infection of cattle by HoBi like viruses. ARS researchers at Ames, Iowa performed studies to determine if cattle vaccinated using BVDV vaccines would be protected against infection with HoBi like viruses. It was found that cattle vaccinated against BVDV would have little or no protection against infection with HoBi like viruses. This suggests that new vaccines, specific for HoBi like viruses, need to be developed to control this emerging pathogen.

2. Evaluation of changes in respiratory viruses over time that might impact effectiveness of vaccines. Bovine respiratory disease complex (BRDC) appears to be the result of interactions of a number of factors including stress, infection with bacterial pathogens and infection with viral pathogens. Viruses associated with BRDC include BVDV, infectious bovine rhinotracheitis virus (IBR), Parainfluenza 3 virus (PI3), Bovine respiratory syncytial virus (BRSV) and bovine corona virus (BoCV). ARS researchers at Ames, Iowa have entered into a series of studies to examine if evolution of viruses over time is reducing the effectiveness of vaccines. In an initial study, researchers at the National Animal Disease Center (NADC) collaborated with a land grant university to examine changes in bovine corona viruses (BoCV), which have recently been isolated from cattle with BRDC. BoCV were first discovered over 50 years ago in samples from calves suffering from diarrhea. In the initial study the BoCV from recent respiratory cases were compared with the BoCV from diarrhea cases (enteric disease). It was found that the respiratory viruses were different from the enteric viruses. This finding suggests that vaccines designed 20 to 30 years ago to combat enteric disease associated with BoCV infection may not work to control respiratory disease associated with more recent BoCV. Similar studies are now in progress to examine changes in other respiratory viral pathogens including PI3 and BRSV. This identified a need for companies to update vaccine strains.


Review Publications
Bannantine, J.P., Olsen, S.C., Kehrli Jr, M.E., Stanton, T.B., Casas, E., Whipple, D.L., Zuelke, K.A. 2013. High-impact animal health research conducted at the USDA's National Animal Disease Center. Veterinary Microbiology. 165(2013):224-233.

Bauermann, F.V., Ridpath, J.F., Weiblen, R., Flores, F.F. 2013. HoBi-like viruses - an emerging group of pestiviruses. Journal of Veterinary Diagnostic Investigation. 25(1):6-15.

Bauermann, F.V., Harmon, A., Flores, E.F., Falkenberg, S.M., Reecy, J.M., Ridpath, J.F. 2013. In vitro neutralization against HoBi-like viruses by antiobodies in serum of cattle immunized with inactivated or modified live vaccines of bovine viral diarrhea virus 1 and 2. Veterinary Microbiology. 166(1-2):242-245.

Jiang, Z., Zhou, X., Michal, J.J., Wu, X.-L., Zhang, L., Zhang, M., Ding, B., Liu, B., Manoranjan, V.S., Neill, J.D., Harhay, G.P., Kehrli, Jr., M.E., Miller, L.C. 2013. Reactomes of porcine alveolar macrophages infected with porcine reproductive and respiratory syndrome virus. PLoS One. 8(3):e59229.

Newcomer, B.W., Marley, M.S., Ridpath, J.F., Neill, J.D., Boykin, D.W., Kumar, A., Givens, M.D. 2012. Efficacy of a novel antiviral compound to inhibit replication of multiple pestivirus species. Antiviral Research. 96(2):127-129.

Richeson, J.T., Kegley, E.B., Powell, J.G., Schaut, R.G., Sacco, R.E., Ridpath, J.F. 2013. Weaning management of newly received beef calves with or without continuous exposure to a persistently infected bovine viral diarrhea virus pen mate: Effects on rectal temperature and serum proinflammatory cytokine and haptog. Journal of Animal Science. 91(3):1400-1408 DOI:10.2527/jas.2011-4875.

Schuster, G.L., Donaldson, J.R., Buntyn, J.O., Duoss, H.A., Callaway, T.R., Carroll, J.A., Falkenberg, S.M., Schmidt, T.B. 2013. Use of bioluminescent Escherichia coli to determine retention during the life cycle of the housefly, Musca domestica (Diptera: Muscidae, L). Foodborne Pathogens and Disease. 10:442-447.

Yates, B.J., Papafragkou, E., Conrad, S.M., Neill, J.D., Ridpath, J.F., Burkhardt, W., Kulka, M., Degrasse, S.L. 2013. Surface plasmon resonance biosensor for detection of feline calicivirus, a surrogate for norovirus. International Journal of Food Microbiology. 162:152-158.

Yilmaz, H., Altan, E., Ridpath, J.F., Turana, N. 2012. Genetic diversity and frequency of bovine viral diarrhea virus (BVDV) detected in cattle in Turkey. Comparative Immunology Microbiology and Infectious Diseases. 35:411-416.

Fulton, R.W., Ridpath, J.F., Burge, L.J. 2012. Bovine coronaviruses from the respiratory tract: Antigenic and genetic diversity. Vaccine. 31(6):886-892.

McGill, J.L., Nonnecke, B.J., Lippolis, J.D., Reinhardt, T.A., Sacco, R.E. 2013. Differential chemokine and cytokine production by neonatal bovine gamma delta T cell subsets in response to viral toll-like receptor agonists and in vivo respiratory syn cytial virus infection. Immunology. 139(2):227-244.

Sacco, R.E., McGill, J.L., Palmer, M.V., Lippolis, J.D., Reinhardt, T.A., Nonnecke, B.J. 2012. Neonatal calf infection with respiratory syncytial virus: drawing parallels to the disease in human infants. Viruses. 4(12):3731-3753.

Last Modified: 9/29/2014
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