Our broad, long-term objectives are to understand the fundamental properties and operative mechanisms of infectious prion transmission in animals and humans; how properties change during this process; and whether evolution allows infection of additional species.
Aim 1 explores an underappreciated but important phenomenon. When prions infect a new species, despite replicating they unexpectedly cause no disease, but maintain the ability to kill the original species. We will quantify how much and when such prion replication occurs, and define biochemical and biological properties differentiating these from conventional prions.
Aim 2 will address the related issue of how prion strains are propagated, and how prions manifest dominant and recessive traits. Unlike viral characteristics that are genetically controlled, prions, which lack nucleic acids must employ a different mechanism. We find that dominant and recessive prion traits are controlled at the level of protein-protein interactions. We will monitor molecular events in this process using an innovative approach involving antibodies that discriminate subtle prion differences, in much the same way that geneticists discriminate the actions of alternative genes during disease.
In Aim 3, we will use a powerful new mouse model that recapitulates important aspects of chronic wasting disease (CWD), an emerging epidemic of deer, elk and moose. These mice enable us to study aspects of CWD that account for its uniquely contagious transmission. All three aims employ powerful and innovative approaches including uniquely suited genetically modified mice, cell culture assays, cell-free amplification, and antibodies that distinguish prion variants.
These aims address basic, unresolved issues about how prions function which is important because prion diseases occur as unpredictable epidemics (e.g. mad cow disease), are lethal, and currently incurable. CWD is the only known prion disorder affecting wild animals. Its efficient contagious transmission means that it is rapidly increasing in geographic range. Also CWD continues to affect new cervid (antler-bearing) species. Whether CWD or its evolving forms will spread to other species, or to humans, as was the case for mad cow disease, is currently unknown but of significant importance to public health.

Public Health Relevance

Prions are the proteinaceous infectious agents responsible for various fatal animal and human prion diseases. Although these diseases are rare in humans, the reported animal-to-human transmission of the illness and the increasing prevalence of some animal diseases (e.g. chronic wasting disease (CWD) affecting cervids in North America) present important problems for public health. In this Program Project we will investigate the mechanism of prion replication and the generation, adaptation and evolution of prion strains, the routes of transmission of the disease among animals, the evaluation of the zoonotic potential of CWD, the role of the environment on prion transmission and the development of efficient procedures to detect the infectious agent. The findings generated in this project will contribute to prevent further propagation of existing prion disease and to avoid the emergence of new diseases with potentially disastrous consequences. Moreover, understanding of the many uncertainties surrounding prions will be important to design novel therapeutic strategies, and to clarify the molecular basis of this novel type of infectious agent.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI077774-09
Application #
9691119
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Beisel, Christopher E
Project Start
2008-08-15
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Neurology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
Moreno, Julie A; Telling, Glenn C (2018) Molecular Mechanisms of Chronic Wasting Disease Prion Propagation. Cold Spring Harb Perspect Med 8:
Davenport, Kristen A; Mosher, Brittany A; Brost, Brian M et al. (2018) Assessment of Chronic Wasting Disease Prion Shedding in Deer Saliva with Occupancy Modeling. J Clin Microbiol 56:
Haley, Nicholas J; Henderson, Davin M; Wycoff, Sarah et al. (2018) Chronic wasting disease management in ranched elk using rectal biopsy testing. Prion 12:93-108
Haley, Nicholas J; Richt, Jürgen A; Davenport, Kristen A et al. (2018) Design, implementation, and interpretation of amplification studies for prion detection. Prion 12:73-82
Yuan, Qi; Telling, Glenn; Bartelt-Hunt, Shannon L et al. (2018) Dehydration of Prions on Environmentally Relevant Surfaces Protects Them from Inactivation by Freezing and Thawing. J Virol 92:
Pritzkow, Sandra; Morales, Rodrigo; Lyon, Adam et al. (2018) Efficient prion disease transmission through common environmental materials. J Biol Chem 293:3363-3373
Waqas, Muhammad; Lee, Hye-Mi; Kim, Jeeyoung et al. (2017) Effect of poly-L-arginine in inhibiting scrapie prion protein of cultured cells. Mol Cell Biochem 428:57-66
Davenport, Kristen A; Hoover, Clare E; Bian, Jifeng et al. (2017) PrPC expression and prion seeding activity in the alimentary tract and lymphoid tissue of deer. PLoS One 12:e0183927
Kramm, Carlos; Pritzkow, Sandra; Lyon, Adam et al. (2017) Detection of Prions in Blood of Cervids at the Asymptomatic Stage of Chronic Wasting Disease. Sci Rep 7:17241
Iwamaru, Yoshifumi; Mathiason, Candace K; Telling, Glenn C et al. (2017) Chronic wasting disease prion infection of differentiated neurospheres. Prion 11:277-283

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