Prion diseases are a group of fatal neurodegenerative disorders affecting animals and humans. The central pathogenic event is the conversion of the host-encoded prion protein (PrPC) into a misfolded isoform (PrPSc). PrPSc appears to be the main or sole component of the infectious agent (termed prion) that has the surprising ability to propagate the disease in the absence of nucleic acid. Prions can infect an individual by various routes, including oral ingestion, enter into the body and remain silently replicating in various tissues for a long time before causing a devastating disease in the brain. Our working hypothesis is that several biological processes, including absorption across intestinal barrier, tissue distribution, metabolism, clearance and peripheral prion replication control the fate of PrPSc in the body and determine whether or not the initial oral infection will progress into full-blown disease. The main goal of this project is to study in a detailed and quantitative manner the initial fate of prions upon oral exposure, including the estimation of gut metabolism, intestinal absorption, excretion, whole body tissue distribution, and brain uptake. In addition, we will investigate the gastrointestinal site responsible for prion absorption and the mechanism by which PrPSc penetrates the intestinal barrier. We will also study the effect of prion strains on these parameters in various animal species, including a natural prion host in large animals (cervids). Furthermore, we will study the role of PrPC expression and the interaction of PrPSc with soil particles in its fate upon ingestion in vivo. Finally, we will investigate the dynamic distribution of prions across the entire body during the period from initia infection to the manifestation of the clinical disease. The findings generated in this study will substantially increase our understanding of the mechanism controlling the fate of prions and the pathways implicated in the transport of PrPSc from the mouth to the brain. This data will provide important information to assess the risk of prion contamination in diverse tissues. More importantly, the findings generated in this project will open novel avenues to develop therapeutic strategies aiming for example to prevent prions to be absorbed in the intestine, to decrease uptake into the brain or to increase prion metabolism and elimination.

Public Health Relevance

Prions are the protein-only component of the infectious agent responsible for prion diseases. The main goal of this project is to study the mechanism by which prions enter and get distributed in the body after oral ingestion in various experimental (mice, hamsters and transgenic mice) and natural animal species (cervids). Our studies will aim to determine in a detailed and quantitative manner gut metabolism, intestinal absorption, excretion, whole body tissue distribution, and brain uptake of prions after oral administration. The results o our study will be helpful to understand the mechanisms of prion spreading, to assess the risk of prion contamination and to design measures to avoid further spreading of prion diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS078745-01A1
Application #
8439892
Study Section
Special Emphasis Panel (ZRG1-IDM-B (04))
Program Officer
Wong, May
Project Start
2012-09-30
Project End
2017-05-31
Budget Start
2012-09-30
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$402,509
Indirect Cost
$125,000
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
77225
Pritzkow, Sandra; Morales, Rodrigo; Lyon, Adam et al. (2018) Efficient prion disease transmission through common environmental materials. J Biol Chem 293:3363-3373
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
Hoover, Clare E; Davenport, Kristen A; Henderson, Davin M et al. (2017) Pathways of Prion Spread during Early Chronic Wasting Disease in Deer. J Virol 91:
Urayama, Akihiko; Concha-Marambio, Luis; Khan, Uffaf et al. (2016) Prions efficiently cross the intestinal barrier after oral administration: Study of the bioavailability, and cellular and tissue distribution in vivo. Sci Rep 6:32338
Denkers, Nathaniel D; Henderson, Davin M; Mathiason, Candace K et al. (2016) Enhanced prion detection in biological samples by magnetic particle extraction and real-time quaking-induced conversion. J Gen Virol 97:2023-9
Morales, Rodrigo; Hu, Ping Ping; Duran-Aniotz, Claudia et al. (2016) Strain-dependent profile of misfolded prion protein aggregates. Sci Rep 6:20526
Hu, Ping Ping; Morales, Rodrigo; Duran-Aniotz, Claudia et al. (2016) Role of Prion Replication in the Strain-dependent Brain Regional Distribution of Prions. J Biol Chem 291:12880-7
Pritzkow, Sandra; Morales, Rodrigo; Moda, Fabio et al. (2015) Grass plants bind, retain, uptake, and transport infectious prions. Cell Rep 11:1168-75
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
Moda, Fabio; Gambetti, Pierluigi; Notari, Silvio et al. (2014) Prions in the urine of patients with variant Creutzfeldt-Jakob disease. N Engl J Med 371:530-9

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