Prions are comprised of PrPSc, a misfolded isoform of the non-infectious host encoded protein, PrPC. Prion diseases are emerging zoonotic infectious diseases of mammals including humans. Following interspecies transmission, prions can adapt to the new host species resulting in a prion with increased fitness and pathogenicity for the new host species. This process can involve interference between prion strains that are originally present in the inoculum or are generated during interspecies transmission. Recent studies indicate that prions exist as a quasispecies, that is, a mixture of strains. These new studies suggest that prion strain interference may play a larger role in overall dynamics of prion strains. Despite the significance of strain interference in the biology of prion disease, the mechanism(s) underling prion strain interference is not known. We have developed a unique model of strain interference in animals and have recently discovered that in vitro, protein misfolding cyclic amplification recapitulates prion interference. Using these combined approaches, we have determined for interference to occur, the blocking strain PrPSc must be in excess compared to the superinfecting PrPSc in a common cell type and the blocking strain does not convert all of the available PrPC to PrPSc when it prevents superinfecting strain replication. We hypothesize that the blocking strain PrPSc prevents the superinfecting strain PrPSc from gaining access to PrPC or other factors required for prion conversion, therefore inhibiting replication.
The aims of this application will investigate if strain interference is due to the blocking strain PrPSc sequestering PrPC from the superinfecting strain or if the blocking strain PrPSc could bind to and prevent the superinfecting strain PrPSc from replicating. The cumulative results of these studies will provide a detailed mechanism of strain interference and have implications for the biology of prion strains and the factors that contribute to maintenance of the prion quasispecies. Finally, the basic mechanisms of how different conformations of PrPSc interact with each other and the cellular environment may be applicable to other protein misfolding diseases of humans.

Public Health Relevance

Prion diseases are emerging transmissible disorders of humans that are inevitably fatal. These diseases pose a threat to human health via transmission from animal species (e.g. mad cow disease) to humans and between humans (e.g. blood transfusions). This grant application will investigate the mechanisms of interference between prion strains that have been shown to be an important parameter of prion transmission. These are the first steps to understand this complex process that could lead to novel therapeutic avenues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052609-07
Application #
8271368
Study Section
Special Emphasis Panel (ZRG1-BDCN-Y (04))
Program Officer
Wong, May
Project Start
2005-07-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
7
Fiscal Year
2012
Total Cost
$316,094
Indirect Cost
$97,344
Name
Creighton University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178
Saunders, Samuel E; Bartelt-Hunt, Shannon L; Bartz, Jason C (2012) Occurrence, transmission, and zoonotic potential of chronic wasting disease. Emerg Infect Dis 18:369-76
Saunders, Samuel E; Bartz, Jason C; Bartelt-Hunt, Shannon L (2012) Soil-mediated prion transmission: is local soil-type a key determinant of prion disease incidence? Chemosphere 87:661-7
Sigurdson, Christina J; Bartz, Jason C; Nilsson, K Peter R (2011) Tracking protein aggregate interactions. Prion 5:52-5
Ayers, Jacob I; Schutt, Charles R; Shikiya, Ronald A et al. (2011) The strain-encoded relationship between PrP replication, stability and processing in neurons is predictive of the incubation period of disease. PLoS Pathog 7:e1001317
Shikiya, Ronald A; Bartz, Jason C (2011) In vitro generation of high-titer prions. J Virol 85:13439-42
Shikiya, Ronald A; Ayers, Jacob I; Schutt, Charles R et al. (2010) Coinfecting prion strains compete for a limiting cellular resource. J Virol 84:5706-14
Ayers, Jacob I; Kincaid, Anthony E; Bartz, Jason C (2009) Prion strain targeting independent of strain-specific neuronal tropism. J Virol 83:81-7
Kramer, Michelle L; Bartz, Jason C (2009) Rapid, high-throughput detection of PrPSc by 96-well immunoassay. Prion 3:44-8
Schutt, Charles R; Bartz, Jason C (2008) Prion interference with multiple prion isolates. Prion 2:61-3
Bartz, Jason C; Kramer, Michelle L; Sheehan, Meghan H et al. (2007) Prion interference is due to a reduction in strain-specific PrPSc levels. J Virol 81:689-97