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Sinus tumors of Rocky Mountain bighorn sheep: investigation of an infectious etiology

Date

2013

Authors

Fox, Karen A., author
Quackenbush, Sandra L., advisor
Miller, Michael W., committee member
Wootton, Sarah K., committee member
Huyvaert, Kathryn P., committee member

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Abstract

Rocky Mountain bighorn sheep are an icon in Colorado. As our state animal, bighorn sheep are a well-recognized symbol of the wildlife, wildlands, and wilderness-centric people that Colorado is famous for. Efforts to manage and conserve this species are a priority in Colorado and throughout western North America. As part of those efforts a great deal of research has been conducted to understand bighorn sheep respiratory disease, the leading infectious cause of death in these animals. In the process of investigating respiratory disease in bighorn sheep in Colorado, we discovered a surprisingly high occurrence of sinus tumors within the upper respiratory tracts of many animals. This disease had not been described previously and became the focus of work for this dissertation. Here, I have compiled our findings regarding the characterization of bighorn sheep sinus tumors and the results of our efforts to identify an infectious etiology for this disease. Through the examination of naturally-occurring cases, we identified characteristic histologic and gross features of bighorn sheep sinus tumors to define this disease. We also analyzed factors associated with sinus tumors at a population level. The results of this study suggest that bighorn sheep sinus tumors are an infectious disease, maintained within specific geographic areas corresponding to distinct populations of animals. Our results also suggest a role for bighorn sheep sinus tumors in predisposing animals to secondary infections by bacterial agents that can cause pneumonia. To specifically test the hypothesis that bighorn sheep sinus tumors are a transmissible disease, we experimentally inoculated bighorn sheep and domestic sheep lambs with a cell-free filtrate derived from a naturally-occurring bighorn sheep sinus tumor and its associated exudates. Within 18 months post-inoculation we demonstrated transmission of the disease to both bighorn sheep and domestic sheep species, supporting our hypothesis that bighorn sheep sinus tumors represent an infectious process. This experiment also provided an opportunity to examine tumors early in development, further characterize the cells comprising the tumors, and suggest mechanisms for pathogenesis. With evidence that bighorn sheep sinus tumors are caused by an infectious agent, we also attempted to identify a specific etiology for this disease. We primarily used PCR methods with degenerate PCR primers to evaluate samples from bighorn sheep sinus lining tissues for the presence of herpesviruses and retroviruses, which are well-known causes of infectious tumors. We successfully identified the presence of herpesviral and (likely endogenous) retroviral sequences in our samples, but we were unable to find an association between these viruses and the occurrence of sinus tumors. Based on similarities between bighorn sheep sinus tumors and oncogenic retroviral diseases of domestic sheep and goats, we specifically screened our samples for the presence of Jaagsiekte sheep retrovirus (JSRV), and enzootic nasal tumor viruses (ENTV-1 and ENTV-2). We successfully identified ENTV-2-specific sequences from some of our samples, but an association between this virus and bighorn sheep sinus tumors was not clear. We found an association between ENTV-2 and early tumor cases, but not well-defined tumors. While our PCR data alone did not definitively identify ENTV-2 as the cause of bighorn sheep sinus tumors, our histologic, histochemical, and immunohistochemical results have helped us to develop a hypothesis for the pathogenesis of bighorn sheep sinus tumors, and provided additional support for the hypothesis that this disease is caused by ENTV-2. Our working hypothesis for the pathogenesis of bighorn sheep sinus tumors is that epithelial cells of the sinus lining are infected by ENTV-2, but that uninfected periosteal pluripotent cells are stimulated to replicate, resulting in predominantly stromal tumors. This hypothesis is based on histologic observations, histochemical stains used to differentiate cell types, and IHC results specifically identifying the presence of ENTV antigen within surface epithelial cells of experimentally-induced tumors, but not within the predominating stromal cells of the tumors. These results help to explain why detection of the virus is uncommon in well-developed stromal tumors, but more easily detected in early tumor cases with less stromal proliferation. Additional research will help to further elucidate the pathogenesis of bighorn sheep sinus tumors, and the potential role that tumors may play in predisposing bighorn sheep to fatal respiratory disease. The definitive identification of an etiologic agent for bighorn sheep sinus tumors, and the development of an antemortem diagnostic assay will greatly enhance efforts to understand and manage this disease.

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Subject

bighorn sheep
Ovis canadensis
enzootic nasal tumor virus
Pasteurella
Jaagsiekte sheep retrovirus
sinus tumors

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