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United States Department of Agriculture

Agricultural Research Service

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Research Project: HOST IMMUNOGENETICS PREDICT CLINICAL DISEASES IN OVINE PROGRESSIVE PNEUMONIA VIRUS INFECTED SHEEP

Location: Animal Diseases Research

2010 Annual Report


1a.Objectives (from AD-416)
(1) Determine the genetic organization and expression of Ovine MHC Class I, IIa, and IIb loci, (2) Determine and validate that specific MHC Class I and/or MCH Class II alleles associate with OPPV clinical disease phenotypes and, (3) Determine the functional significance and subsequent immune responses of MHC alleles that associate with OPPV clinical disease phenotypes.


1b.Approach (from AD-416)
OPPV is a sheep lentivirus that infects 24% of U.S. sheep flocks and causes economic losses to the sheep producer due to mastitis, dypsnea, and lameness. Serological diagnostic tests which test for the presence of anti-OPPV antibodies have provided a highly sensitive and specific means of testing but have not shown statistical correlations with pathology or other clinical markers of disease. Therefore, an OPPV test that predicts or determines which infected sheep will proceed to clinical disease progression is highly sought. Our laboratory is currently evaluating two different tests for the prediction or determination of OPPV clinical disease. One test is a quantitative PCR test utilizing real time technology, which targets a conserved region of the transmembrane protein of OPP provirus, and the second test is an immunogenetics test for MHC Class II DRB1. With one or both of these tests, we hope to provide a diagnostic OPPV test that determines or predicts whether the sheep will progress to OPPV clinical signs. In addition, these types of tests will significantly reduce the number of other tests necessary for determining infection and possibly lower the transmission potential in a flock. Therefore, these new tests offer significant long-term economic advantages for the producer over conventional serological diagnostic tests. Replacing 5348-32000-025-00D, April 2007.


3.Progress Report
Ovine progressive pneumonia virus (OPPV) is a lentivirus of sheep, which causes breathing problems, hard-udder, lower milk production, swollen and/or arthritic joints, wasting syndrome, and in rare cases, the loss of full control of bodily movements. Identifying a host genetic factor that associates with the severity of disease in OPPV infected sheep is one possible diagnostic tool to control OPPV. Our last progress report indicated that OPPV levels in the blood were found to quantitatively correlate with the severity of disease as measured by tissue changes in the lungs, udder, joints, and brain of naturally infected sheep. In addition, variants of two different immune response genes, CCR5 and DRB1 significantly associated with the control of OPPV levels in the blood. Confirmation of these variants with control of OPPV in different flocks is currently being investigated. In addition, ewes with the CCR5 gene variant that associates with the control of OPPV were found to not have any production trait deficits. The major histocompatibility complex (MHC) class II had been previously implicated as a receptor for OPPV. Given that certain MHC class II DRB1 gene variants associate with controlling OPPV levels in the blood, in vitro transfections of human cell lines with ovine MHC class II DR and infection of these ovine MHC class II DR transfected cells with OPPV are being pursued. In addition, a whole genome scan has been conducted on blood samples from an OPPV infected flock, and several host gene variants have been found to significantly associate with reduced OPPV infection or the control of OPPV levels in the blood. With the establishment of a sensitive, experimental infection model, sheep with CCR5 gene variants, DRB1 gene variants, and/or other gene variants that associate with reduced OPPV infection and/or control of OPPV levels in the blood can be challenged with OPPV for in vivo validation. Identifying the cell type that harbors OPPV in the affected tissues may also help to identify host factors that control OPPV. In this period, we also showed that CD163 and CD172a positive alveolar macrophages in the lung and mammary gland harbor OPPV. The long-term outcome of this research is to provide viral or host genetic tools that predict the disease course of OPPV infection in sheep thereby greatly decreasing the economic impact of this infection. This work also serves as an example for other chronic persistent infections for which the economic losses are derived later in the life of the infected animal.


4.Accomplishments
1. Model for testing vaccine or genetic resistance to respiratory disease virus of sheep. The respiratory disease virus ovine progressive pneumonia virus (OPPV) is a source of significant economic loss to U. S. sheep producers. These losses are both from disease and export restrictions. ARS scientists at Pullman, WA and Ames, IA determined the minimal dose necessary to cause infection in sheep. This finding provides the basis for testing of a vaccine or genetic resistance to infection and disease caused by this virus.

2. Genetic resistance to respiratory disease virus of sheep. The respiratory disease virus ovine progressive pneumonia virus (OPPV) is a source of significant economic loss to U. S. sheep producers. These losses are both from disease and export restrictions. ARS scientists at Pullman, WA and Dubois, ID discovered the presence of a gene (CCR5) which is strongly associated with lower levels of OPPV in infected sheep. Further validation of this genetic marker for virus control will provide a selection tool to aid in reduced OPPV caused disease.

3. Determined which cells become infected with a respiratory virus of sheep. The respiratory disease virus ovine progressive pneumonia virus (OPPV) is a source of significant economic loss to U. S. sheep producers. These losses are both from disease and export restrictions. ARS and Washington State University scientists Pullman, WA showed which cells (macrophages) become infected with OPPV in the lung and mammary gland of infected sheep. This knowledge provides a basis for testing vaccines or genetic markers to reduce or eliminate OPPV transmission.

4. Improved diagnostic testing for respiratory virus of sheep. The respiratory disease virus ovine progressive pneumonia virus (OPPV) is a source of significant economic loss to U. S. sheep producers. These losses are both from disease and export restrictions. ARS scientists at Pullman, WA and Dubois, ID demonstrated that a commercially available test for detection of OPPV infection had lower than expected sensitivity in certain sheep flocks within the U. S. This finding has led to collaborative work, which is in progress, to improve this diagnostic assay (a competitive ELISA).

5. High production maintained in sheep with genetic marker for viral resistance. The respiratory disease virus ovine progressive pneumonia virus (OPPV) is a source of significant economic loss to U. S. sheep producers. These losses are both from disease and export restrictions. ARS scientists at Pullman, WA and Dubois, ID demonstrated that sheep with a genetic marker (CCR5) associated with lower OPPV in infected sheep maintained high production traits (lambs born, lambs raised to weaning, weight of lambs and lamb survival) as sheep without this marker. Therefore selection of sheep with this viral resistance marker will maintain economically important production traits.


5.Significant Activities that Support Special Target Populations
We continue to monitor the performance of the molecular diagnostic test, OPPV levels in the blood, against a serological diagnostic test, a competitive enzyme-linked immunosorbent assay, within differing production and U.S. state sheep populations. We collaborate with a number of small sheep producer operations in the U.S. states of New York, Montana, North Dakota, Iowa, Colorado, Minnesota, and Oregon. In these collaborations, we provide OPPV diagnostic test results to the producers while the producers allow us to genetically test their sheep.


Review Publications
White, S.N., Mousel, M.R., Reynolds, J.O., Lewis, G.S., Hoesing, L.M. 2009. Common promoter deletion is associated with 3.9-fold differential transcription of ovine CCR5 and reduced proviral level of ovine progressive pneumonia virus. Animal Genetics. 40(5):583-589.

Hoesing, L.M., Noh, S.M., Snekvik, K.R., White, S.N., Schneider, D.A., Truscott, T.C., Knowles Jr, D.P. 2010. Ovine Progressive Pneumonia Virus Capsid Antigen as Found in CD163- and CD172a-Positive Alveolar Macrophages of Persistently Infected Sheep. Veterinary Pathology. 47(3):518-528.

Hoesing, L.M., Broughton-Neiswanger, .L., Gouine, K., White, S.N., Mousel, M.R., Lewis, G.S., Marshall, K.L., Knowles Jr, D.P. 2010. Evaluation of a Caprine Arthritis-Encephalitis Virus/Maedi-Visna Virus Indirect Enzyme-Linked Immunosorbent Assay in the Serological Diagnosis of Ovine Progressive Pneumonia Virus in U.S. Sheep. Clinical and Vaccine Immunology. 17(2):307-310.

Mousel, M.R., White, S.N., Hoesing, L.M. 2010. Association analysis of a CCR5 variant with ewe lifetime production in 3 breeds of sheep. Animal Genetics. 41(2):222-223.

Hoesing, L.M., Lehmkuhl, H.D., Cutlip, R.C. 2009. Minimum intravenous infectious dose of ovine progressive pneumonia virus (OPPV). Research in Veterinary Science. 87(2):329-331.

Besser, T.E., Cassirer, K.A., Potter, K.A., Vanderschalie, J., Fischer, A., Knowles Jr, D.P., Herndon, D.R., Rurangirwa, F.R., Weiser, G.C., Srikumaran, S. 2008. Association of Mycoplasma ovipneumoniae Infection with Population-Limiting Respiratory Disease in Free-Ranging Rocky Mountain Bighorn Sheep (Ovis canadensis canadensis). Journal of Clinical Microbiology. 46(2):423-430.

Lawrence, P.K., Nelson, W.R., Liu, W., Knowles Jr, D.P., Foreyt, W.J., Srikumaran, S. 2008. Beta(2) integrin Mac-1 is a receptor for Mannheimia haemolytica leukotoxin on bovine and ovine leukocytes. Veterinary Immunology and Immunopathology. 122(3-4):285-294.

Dassanayake, R.P., Call, D.R., Sawant, A.A., Casavant, N.C., Weiser, G.C., Knowles Jr, D.P., Srikumaran, S. 2010. Bibersteinia trehalosi Inhibits the Growth of Mannheimia haemolytica by a Proximity-Dependent Mechanism. Applied and Environmental Microbiology. 76(4):1008-1013.

Miller, M.W., Knowles Jr, D.P., Bulgin, M. 2008. Pasteurellosis Transmission Risks between Domestic and Wild Sheep. Council for Agricultural Science and Technology Issue Paper. QTA2008-1.

Last Modified: 8/22/2014
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