Prion diseases are transmissible between animal-to-animal, animal-to-human and human-to- human, however, we still do not understand completely the mechanisms, factors and biological processes controlling the inter-individual transmission of this unique infectious agent. Among animal diseases, chronic wasting disease (CWD) represents a serious problem, because it continues to propagate uncontrollably among wild and captive cervids in North America. The risk of CWD transmission to humans is unknown which is a major concern because the number of sick animals and their geographical distribution is rapidly increasing. The mechanism by which CWD propagates so efficiently among cervids is also unknown, but recent findings have implicated environmental contamination with prions. The main goal of this project is to study the mechanisms controlling the species barrier, particularly to investigate the possibility that CWD may, under determined conditions, infect humans. We will also study the role of environmental contamination in CWD transmission, focusing on plants and various surfaces as vectors for prion propagation.
In Specific Aim 1 we will investigate the role of prion strain adaptation in the zoonotic potential of CWD. The hypothesis for these studies is that the species barrier is a dynamic process that changes over time when prion strains mature and evolve. We will study the molecular mechanism of prion strain maturation, the biochemical and structural properties that differentiate CWD strains able and unable to convert human PrPC into PrPSc and analyze a large collection of natural CWD specimens to investigate differences on the strength of the human species barrier in vitro.
In Specific Aim 2 we will test the hypothesis that the strength of the species barrier is lower in hosts harboring brain damage associated to other neurological diseases or even to subclinical or pre-clinical conditions. We will investigate whether the cervid/human species barrier can be altered in transgenic mice expressing human PrP by the co-existence of another brain abnormality, using established models of chronic neurodegenerative diseases (Alzheimer's and Parkinson's disease) and acute brain damage (traumatic brain injury and stroke).
In Specific Aim 3 we will study the role of plants as fomites for prion transmission by analyzing prion binding to plants, retention of infectivity and transport of PrPSc from soil to different parts of the plants. Studies will be done using natural CWD prions and infectivity experiments will be performed in cultured cells, gene-targeted cervidtransgenic mice and the natural host (white tail deer). We will also test plants collected from CWD affected areas for the presence of PrPSc by PMCA.
In Specific Aim 4 we will test the hypothesis that prions buildup in the environment by progressively binding to diverse environmental surfaces, where they can infect animals by simple contact. We will study the binding affinity of PrPSc to various surfaces (including stones, wood, plastic, glass, concrete, stainless steel and aluminum), the time permanence of PrPSc and infectivity in the surface and the effect of environmental changes on infectivity. We will also investigate the transmission of the disease through casual contact with contaminated surfaces and the mechanism by which this happen. The findings generated in this project will contribute to understand the zoonotic potential of CWD, the factors modulating the transmission of this disease, and the role the environment plays on prion transmission. These studies are essential to design measures to prevent further propagation of CWD, and to avoid the emergence of new diseases with potentially disastrous consequences.

Public Health Relevance

Prion diseases are a group of fatal, infectious neurodegenerative diseases affecting humans and animals. The unprecedented nature of the infectious agent which is composed solely of a protein and the proven transmission of the disease from animals to humans have raised major concerns for public health. The situation is aggravated by the uncontrollable spreading of chronic wasting disease (CWD) among wild and captive cervids in North America. The mechanisms responsible for the efficient transmission of CWD are unknown, but suggest the involvement of environmental contamination, which may become a problem for human health, since it is not yet known whether CWD is transmissible to humans. In this project we will study the factors in the host and the infectious agent which can alter the zoonotic potential of CWD and the role of environmental contamination in CWD transmission, focusing on plants and various surfaces as vectors for prion propagation. These studies may have a profound impact in elucidating the risk imposed by CWD and may contribute to design measures to prevent further propagation of the disease, and to avoid the emergence of new diseases with potentially disastrous consequences.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI077774-10
Application #
9920664
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
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, J├╝rgen 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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