Transportation of prion protein across the intestinal mucosa of scrapie-susceptible and scrapie-resistant sheep

Abstract

To determine the mechanisms of intestinal transport of infection, and early pathogenesis, of sheep scrapie, isolated gut-loops were inoculated to ensure that significant concentrations of scrapie agent would come into direct contact with the relevant ileal structures (epithelial, lymphoreticular, and nervous). Gut loops were inoculated with a scrapie brain pool homogenate or normal brain or sucrose solution. After surgery, animals were necropsied at time points ranging from 15 min to 1 month and at clinical end point. Inoculum-associated prion protein (PrP) was detected by immunohistochemistry in villous lacteals and in sub-mucosal lymphatics from 15 min to 3.5 h post-challenge. It was also detected in association with dendritic-like cells in the draining lymph nodes at up to 24 h post-challenge. Replication of infection, as demonstrated by the accumulation of disease-associated forms of PrP in Peyer's patches, was detected at 30 days and sheep developed clinical signs of scrapie at 18-22 months post-challenge. These results indicate discrepancies between the routes of transportation of PrP from the inoculum and sites of de novo-generated disease-associated PrP subsequent to scrapie agent replication. When samples of homogenized inoculum were incubated with alimentary tract fluids in vitro, only trace amounts of protease-resistant PrP could be detected by western blotting, suggesting that the majority of both normal and abnormal PrP within the inoculum is readily digested by alimentary fluids.

Spreading of prions from the immune to the peripheral nervous system: a potential implication of dendritic cells

“…This intramural nervous system is composed of two networks, the submucosal and the myenteric plexi, which contain the neuronal cell bodies and their processes. It is likely that prion infection of the ENS occurs within Wne nerve Wbers directly underneath the villous or crypts epithelium (JeVrey et al 2006). It is also possible that transmissible spongiform encephalopathy (TSE) agents are transported through the epithelium of the Peyer's patches (Defaweux et al 2005).…”

Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes

“…The prion diseases are unique in that a single pathologic process may present as a sporadic, genetic, or infectious illness (2). Despite a wealth of data arguing that prions are composed solely of isoforms of the disease-causing prion protein, designated PrP Sc , the composition of the infectious prion particle continues to be debated (3)(4)(5), largely because prions exist in many different strains.…”

The influence of the commensal and pathogenic gut microbiota on prion disease pathogenesis

“…When prions are shed into the environment, they can bind to soil particles and can remain infectious for long periods (Bartelt-Hunt & Bartz, 2013). Despite this resilience, ovine alimentary fluids appear to have sufficient proteolytic capacity to digest disease-specific PrP derived from sheep scrapie or BSE (Dagleish et al, 2010;Jeffrey et al, 2006). However, BSE agent-derived PrP Sc can survive incubation with bovine ruminal and colonic microbiota preparations (Bohnlein et al, 2012) or raw sewage (Maluquer de Motes et al, 2012).…”