Seelig, Davis Martin, authorHoover, Edward Arthur, 1942-, advisorMason, Gary L., committee memberZabel, Mark Douglas, committee memberRoss, Eric D., committee member2007-01-032007-01-032010http://hdl.handle.net/10217/39328Department Head: Edward Arthur Hoover.Chronic wasting disease (CWD) is a naturally occurring, horizontally transmitted prion disease of cervids, including deer, elk and moose. Typical of all prion diseases, CWD is characterized by the forced conversion of the normal prion protein (PrPC) into a misfolded isoform (PrPCWD), which accumulates in tissues of the lymphoid, endocrine, and nervous systems. The accumulation of PrPCWD in the nervous system results in a constellation of 4 microscopic brain lesions: (1) neuronal degeneration and/or loss, (2) neuronal and neuropil degenerative spongiosis, (3) reactive gliosis with absent-to-minimal inflammation, and (4), in some form, protease-resistant (amyloid) plaques of PrPCWD. CWD is unique in that it is the only transmissible spongiform encephalopathy (TSE) known to infect free-ranging wildlife species and in its facile lateral transmission. This disease has been shown to be transmissible to deer fawns by oral exposure and infectious prions have been demonstrated in the saliva, blood, and muscle tissue of CWD-infected deer, although mechanisms of horizontal transmission in nature and in vivo prion trafficking remain uncertain. Given the limits inherent in experimental inoculation studies in the native cervid host, characterization of an efficient murine transgenic model is crucial to advance understanding of CWD and in the elucidation of novel features inherent to CWD which may help to explain the high degree of horizontal transmission, the infectivity of blood, and the shedding of prions via the urine and saliva. In this dissertation, the two lineages of cervid prion protein (Tg[CerPrP]) expressing mice are shown to be effective surrogates for the study of CWD through their faithful recapitulation of the clinical and pathologic features of the disease as described in native species. Using tissue-based in situ immunohistochemistry (IHC) protocols, systemic expression of PrPC was detected in the lymphoid, nervous, hemopoietic, endocrine, and certain epithelial tissues of Tg[CerPrP] mice. In multi-route inoculation longitudinal studies of CWD-infected mice, PrPCWD was identified in tissues of the nervous, lymphoid, endocrine, hemopoietic, and gastrointestinal (GI) systems. The pathway by which CWD prions efficiently transit from the periphery to the central nervous system remains incompletely understood. In the longitudinal evaluation of CWD-inoculated Tg[CerPrP] mice, increasing amounts of PrPCWD were identified in the cells and fiber tracts of the constituents of the autonomic nervous system, including the parasympathetic, sympathetic, and enteric nervous systems. Such a temporal-spatial pattern of PrPCWD accumulation implicates these elements as major pathways for CWD prion neuroinvasion and GI prion invasion and shedding. These findings may explain the ease by which CWD prions are taken up from and shed into the environment, and thereby its high degree of horizontal transmission. While the infectious nature of urine, saliva, and blood from CWD-infected cervids has been confirmed, the manner in which such infectivity is acquired is unknown. To address this uncertainty, I evaluated tissues of the urinary, salivary, and hemopoietic systems from CWD-infected deer using enhanced IHC. In these studies, PrPCWD was identified in the renal tubular epithelium and in selected populations of bone marrow cells, suggesting that these populations are, in part, responsible for the previously described phenomena of "prionuria" and "prionemia."born digitaldoctoral dissertationsengCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.prionimmunohistochemistryChronic wasting disease -- TransmissionWhite-tailed deer -- Diseases -- TransmissionImmunohistochemistryCervidae -- Diseases -- TransmissionPrion diseases in animals -- TransmissionText