Chronic wasting disease (CWD) of deer and elk is an emerging highly transmissible prion disease now recognized in 18 States, 2 Canadian provinces, and Korea. We have shown that Infected deer harbor and shed high levels of infectious prions in saliva, blood, urine, and feces, and in the tissues generating those body fluids and excreta, thereby leading to facile transmission by direct contact and environmental contamination. We have also shown that CWD can infect some non-cervid species, thus the potential risk CWD represents to domestic animal species and to humans remains unknown. Whether prions borne in blood, saliva, nasal fluids, milk, or excreta are generated or modified in the proximate peripheral tissue sites, may differ in subtle ways from those generated in brain, or may be adapted for mucosal infection remain open questions. The increasing parallels in the pathogenesis between prion diseases and human neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases, add relevance to CWD as a transmissible protein misfolding disease. The overall goal of this work is to elucidate the process of CWD prion transmission from mucosal secretory and excretory tissue sites by addressing these questions: (a) What are the kinetics and magnitude of CWD prion shedding post-exposure? (b) Are excreted prions biochemically distinct, or not, from those in the CNS? (c) Are peripheral epithelial or CNS tissues, or both, the source of excreted prions? and (d) Are excreted prions adapted for horizontal transmission via natural/trans-mucosal routes? The specific aims of this proposal are: (1) To determine the onset and consistency of CWD prion shedding in deer and cervidized mice; (2); To compare the biochemical and biophysical properties of excretory vs. CNS prions; (3) To determine the capacity of peripheral tissues to support replication of CWD prions; (4) To determine the protease- sensitive infectious fraction of excreted vs. CNS prions; and (5) To compare the mucosal infectivity of excretory vs. CNS prions. Understanding the mechanisms that enable efficient prion dissemination and shedding will help elucidate how horizontally transmissible prions evolve and succeed, and is the basis of this proposal. Understanding how infectious misfolded proteins (prions) are generated, trafficked, shed, and transmitted will aid in preventing, treating, and managing the risks associated with these agents and the diseases they cause.

Public Health Relevance

Chronic wasting disease (CWD) of deer and elk is an emergent highly transmissible prion disease now recognized throughout the USA as well as in Canada and Korea. We have shown that infected deer harbor and shed high levels of infectious prions in saliva, blood, urine, and feces thereby leading to transmission by direct contact and environmental contamination. In that our studies have also shown that CWD can infect some non-cervid species, the potential risk CWD may represents to domestic animal species and humans remains unknown. The increasing parallels in the development of major human neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases, and prion diseases add relevance to CWD as a model of a transmissible protein misfolding disease. Understanding how infectious misfolded proteins (prions) are generated and transmitted will aid in interrupting, treating, and managing the risks associated with these agents and the diseases they cause.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061902-08
Application #
9237318
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Wong, May
Project Start
2009-09-30
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
8
Fiscal Year
2017
Total Cost
$368,880
Indirect Cost
$120,810
Name
Colorado State University-Fort Collins
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Davenport, Kristen A; Henderson, Davin M; Mathiason, Candace K et al. (2016) Assessment of the PrPc Amino-Terminal Domain in Prion Species Barriers. J Virol 90:10752-10761
Hoover, Clare E; Davenport, Kristen A; Henderson, Davin M et al. (2016) Detection and Quantification of CWD Prions in Fixed Paraffin Embedded Tissues by Real-Time Quaking-Induced Conversion. Sci Rep 6:25098
Pritzkow, Sandra; Morales, Rodrigo; Moda, Fabio et al. (2015) Grass plants bind, retain, uptake, and transport infectious prions. Cell Rep 11:1168-75
Seelig, D M; Nalls, A V; Flasik, M et al. (2015) Lesion profiling and subcellular prion localization of cervid chronic wasting disease in domestic cats. Vet Pathol 52:107-19
Henderson, Davin M; Davenport, Kristen A; Haley, Nicholas J et al. (2015) Quantitative assessment of prion infectivity in tissues and body fluids by real-time quaking-induced conversion. J Gen Virol 96:210-9
Haley, Nicholas J; Hoover, Edward A (2015) Chronic wasting disease of cervids: current knowledge and future perspectives. Annu Rev Anim Biosci 3:305-25
Davenport, Kristen A; Henderson, Davin M; Bian, Jifeng et al. (2015) Insights into Chronic Wasting Disease and Bovine Spongiform Encephalopathy Species Barriers by Use of Real-Time Conversion. J Virol 89:9524-31
Henderson, Davin M; Denkers, Nathaniel D; Hoover, Clare E et al. (2015) Longitudinal Detection of Prion Shedding in Saliva and Urine by Chronic Wasting Disease-Infected Deer by Real-Time Quaking-Induced Conversion. J Virol 89:9338-47
Haley, Nicholas J; Carver, Scott; Hoon-Hanks, Laura L et al. (2014) Detection of chronic wasting disease in the lymph nodes of free-ranging cervids by real-time quaking-induced conversion. J Clin Microbiol 52:3237-43
Perrott, Matthew R; Sigurdson, Christina J; Mason, Gary L et al. (2013) Mucosal transmission and pathogenesis of chronic wasting disease in ferrets. J Gen Virol 94:432-42

Showing the most recent 10 out of 16 publications