Prion diseases are inevitably fatal, transmissible disorders inducing a progressive neurologic dysfunction after a prolonged incubation period. Oral transmission is the primary route of infection for BSE, scrapie and TME and is the suspected route of transmission for vCJD and CWD. TSEs share several hallmark characteristics including the accumulation of a disease-specific structurally abnormal form of the prion protein (PrPSc). We have recently demonstrated that prions bind to soil, clay minerals and silicon dioxide (Johnson et al., 2007). We have analyzed the binding of PrPSc to montmorillonite clay (Mte) and found it to be extremely avid. When laboratory animals are orally challenged with PrPSc bound to Mte, more animals succumbed to disease with shorter incubation periods than were observed with just PrPSc. Survival analysis of oral transmission experiments demonstrate that prions bound to clay are approximately 700 times more orally transmissible than unbound agent (Johnson et al., 2007). Whole soils have a similar effect;two of three tested soils enhance transmission and the third is no less infectious than unbound PrPSc (Johnson et al., 2007). Our studies support the hypothesis that soil and soil microparticles bind to prion protein (PrPSc) enhancing disease transmission for scrapie and CWD. In this application, we propose to examine the effect of soil microparticles on CWD transmission in deer (SA1). These studies will emphasize whole soils, their ability to bind CWD agent and the impact of this interaction on CWD disease transmission. In SA2, we will determine the mechanism(s) by which clay-bound prions have increased orally transmissible by examining the resistance to degradation, uptake of clay-bound agent and the aggregation state and other biophysical parameters of PrPSc bound to clay. Microparticles are found in many other substances than soil. Meat and bone meal (MBM), a commonly used cattle food supplement thought responsible for BSE in Europe. We present data demonstrating MBM is rich in microparticles and will test if MBM-associated agent enhances oral transmissibility similar to Mte. Finally we will determine if endogenous calcium (Ca) phosphate microparticles, formed in the intestine, promote TSE infection. These studies will assess the infectivity of TSE agent sorbed to Ca phosphate and examining oral infectivity in animals with reduced Ca content. We hypothesize that animals with reduced Ca phosphate microparticles will be less susceptible to TSE infection and that agent sorption to intestinal calcium phosphate represents a step in the pathway by which oral TSE infections in initiated.

Public Health Relevance

Prion diseases are transmissible neurologic disorders that can affect animals (sheep scrapie, cervid chronic wasting disease, bovine spongiform encephalopathy) and humans (Creutzfeldt-Jakob disease and Kuru). The potential for the environment to maintain and become a source of infectivity for sheep scrapie and cervid CWD is well documented and, undoubtedly, involves oral transmission of low levels of infectious agent. Since oral transmission is, in general, not an efficient means of infecting susceptible animals, we hypothesize a role for soil in the enhancement of oral transmission. Our studies support the hypothesis that soil and soil microparticles bind to prion protein (PrPSc) enhancing disease transmission for scrapie and CWD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060034-05
Application #
8248804
Study Section
Special Emphasis Panel (ZRG1-IDM-Q (92))
Program Officer
Wong, May
Project Start
2008-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$338,418
Indirect Cost
$61,433
Name
University of Wisconsin Madison
Department
Biology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Johnson, Chad J; Aiken, Judd M; McKenzie, Debbie et al. (2012) Highly efficient amplification of chronic wasting disease agent by protein misfolding cyclic amplification with beads (PMCAb). PLoS One 7:e35383
Johnson, Christopher J; McKenzie, Debbie; Pedersen, Joel A et al. (2011) Meat and bone meal and mineral feed additives may increase the risk of oral prion disease transmission. J Toxicol Environ Health A 74:161-6
Smith, Christen B; Booth, Clarissa J; Pedersen, Joel A (2011) Fate of prions in soil: a review. J Environ Qual 40:449-61
Moody, Laura R; Herbst, Allen J; Yoo, Han Sang et al. (2009) Comparative prion disease gene expression profiling using the prion disease mimetic, cuprizone. Prion 3:99-109