Document Type

Dissertation - University Access Only

Award Date

2012

Degree Name

Doctor of Philosophy (PhD)

Department / School

Veterinary and Biomedical Sciences

First Advisor

Christopher Chase

Abstract

Evasion of the host immune response by bovine viral diarrhea virus (BVDV) ensures viral survival and propagation to maintain the virus in nature. BVDV evades the immune system and establishes a persistent infection (PI) in the fetus during a specific time of development during fetal immune ontogeny. BVDV Pis are the epidemiological epicenter for devastating "BVDV wrecks" that result in abortions, weak calves, and PI calves. The actual mechanism for the development and establishment of BVDV viral persistence in the fetus is unknown. PI calves develop mucosa! disease, which emerges sporadically around two years of age. The development of mucosa! disease and the mechanisms responsible for the characteristic gross lesions are also not well understood. This dissertation evaluated laboratory and clinical BVDV PI studies to further increase our understanding of the epidemiology and pathogenesis of BVDV PI infections and mucosa! disease. An experimental study was designed to study the establishment of BVDV PL Fetal calves were infected at 75 days in gestation with a Type 2 BVDV to generate PI fetuses. The hepatic immune response to fetal infection with BVDV was assessed because it is central to immune development in early gestation. Fresh fetal liver samples were collected at necropsy and analyzed by flow cytometry or fixed for immunohistochemistry and immunofluorescence. BVDV antigen was detected in fetuses at 14 days post-maternal infection in Kupffer cells. Isolated PI hepatic immune cells displayed a higher percentage of cells expressing MHC I and MHC II. Kupffer cells were infected with BVDV. Lymphocytes were not virally infected; however they may be activated by BVDV-infected antigen presenting cells. An immune response to fetal BVDV infection in the liver is indicated in this PI model. Infection of Kupffer cells could be opportunistic for BVDV and may be important for the establishment of persistence of BVDV infection. A second field study was used to examine the onset of mucosa! disease in PI calves. In the fall of 2003, 136 bred heifers were purchased from a cattle operation in Butte County, SD and housed at the Antelope Livestock Range Research Station at Buffalo SD. An outbreak ofBVDV PI births resulted in the loss of 44% of the total herd. Forty-four calves were identified as being infected with BVDV by ear notch immunohistochemistry. Five BVDV positive calves died following the stress of weaning. Three of the initial 44 BVDV ear notch positive animals were negative on subsequent infection and were classified transiently infected and developed strong BVDV antibody titers. Twenty-three calves died, 2 were euthanized and 11 were sold for immediate slaughter. Analysis of the case study revealed that PI calves were not born in a cluster but births occurred throughout the entire 2004 calving season. PI calves weighed less at birth than their BVDV negative cohorts, and this weight difference was still significant at 14 weeks of age. The PI viral sequences identified two 2a strains (with highly conserved 5 'UTR and less conserved E2 sequence, 99% and 95% respectively) that spread through the original bred herd. Significant economic losses resulted in this outbreak of BVDV. Twenty-six percent of the animals that died suddenly in this study, had died suddenly had no lesions indicative of mucosal disease onset. Peripheral blood mononuclear cell (PBMC) analysis in the three weeks prior to sudden death or Mucosal-Disease revealed a general decline in the number of circulating CD8+ T lymphocytes and y8 T cells. CD4+ T cells were elevated one week prior to death and circulating monocytes were slightly elevated prior to death. B cell populations were sharply elevated one week prior to mucosal disease-associated death. Hepatic samples from12 of the PI calves that died suddenly were evaluated and analyzed for Kupffer cell distribution by immunohistochemistry of fixed tissue. While the hepatic tissues showed no gross or histomorphological lesions, the number of Kupffer cells in hepatic tissues was significantly increased in 5 of the 12 animals studied and significantly decreased in the remaining 7 when compared to age matched control (nonPI) animals creating two distinct Kupffer cell profiles and it was concluded that PI calves in this group had one of two possible pathological profiles with respect to Kupffer cells at death, KC-high or KC-low; it is not yet clear what this phenotypic distinction means. These cases of sudden death in PI calves without the development of mucosa} disease, and the impact of an altered profile of Kupffer cells will require further investigation. These studies indicate that BVDV maintains the potential to create devastating losses and results in the development of PI calves despite the presence of immune components. An immune response to fetal infection in the liver is also likely and PI calves displayed altered profiles of antigen presenting Kupffer cells at death. Infection of Kupffer cells could be opportunistic for BVDV and may be important for the development of both persistent infection and mucosa} disease.

Library of Congress Subject Headings

Bovine viral diarrhea virus
Cattle -- Virus diseases

Publisher

South Dakota State University

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Rights Statement

In Copyright