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Title:   Author  item
                                            Vrentas, Catherineitem
                                            Greenlee, Justinitem
                                            Tatum, Trudyitem
                                            Nicholson, Eric
  Submitted to: PLOS ONE
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 7/18/2012
                                    Publication  Date: 8/14/2012
                                    Citation: Vrentas, C.E., Greenlee, J.J., Tatum, T.L., Nicholson, E.M. 2012. Relationships between PrPSc stability and incubation time for United States scrapie isolates in a natural host system. PLoS ONE. 7(8):e43060.Interpretive Summary: Scrapie is a prion disease of sheep. Prion diseases are also referred to as transmissible spongiform encephalopathy (TSE) diseases. TSEs are caused by the misfolding of the normal prion protein encoded by the host (sheep, cattle, deer or humans). Despite the fact that TSEs lack the genetic material typically associated with infectious agents, TSEs exist as different strains. Here we investigated a novel adaptation of an approach to measure the property of the misfolded protein referred to as "stability" in TSE affected brain tissue in order to distinguish between strains. A unique part of what we did is that we applied this novel adaptation to naturally occurring scrapie rather than laboratory animal models of TSEs. We showed, that in the natural sheep host, the stability correlates with incubation time and that the process known as strain stabilization whereby a TSE is passed serially through a host species does not alter the physical properties of the infectious agent. In addition, changes in disease incubation time that are known to occur are likely due to changes such as increased infectious dose in the inoculating material created upon repeated experimental passage. Understanding how the biochemical properties of U.S. scrapie strains relate to host sheep genetics and the incubation time of disease has implications for TSE inactivation and scrapie eradication management in the field. The methodologies used here can also be applied to research on other species (such as cattle and elk) to improve our understanding of the properties of TSE strains in other natural hosts.
                                Technical Abstract: Transmissible spongiform encephalopathies (TSEs), including scrapie in sheep (Ovis aries), are fatal neurodegenerative diseases caused by the misfolding of the cellular prion protein (PrP**C) into a beta-rich conformer (PrP**Sc) that accumulates into higher-order structures in the brain and other tissues. Distinct strains of TSEs exist, characterized by different pathologic profiles upon passage into rodents and representing distinct conformations of PrP**Sc. One biochemical method of distinguishing strains is the stability of PrP**Sc upon treatment with guanidine hydrochloride (GdnHCl), which is tightly and positively correlated with the incubation time of disease upon passage into mice. Here, we utilize a rapid, protease-free version of the stability assay to characterize strains present in United States scrapie isolates, including a fast-acting isolate for which incubation time is highly dependent on the genotype at codon 136 of the prion gene (PRNP). We utilize the stability methodology to identify the presence of two distinct strains in the isolate, and compare strain properties to those of a host-stabilized reference strain of U.S. scrapie (NADC 13-7) in order to provide evidence for the stability/incubation time correlation in a natural host system. We demonstrate the utility of the stability methodology in characterizing TSE isolates throughout serial passage in livestock, which is applicable to a range of natural host systems, including strains of cattle and cervid TSEs.


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