Commentary
What can we learn from the oral intake of prions by sheep?
N Sales, PhD *
Department of Infectology, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida, USA
email: N Sales (
[email protected])
*Correspondence to N Sales, Department of Infectology, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida, USA.
Keywords
prion • scrapie • sheep • ingestion • vCJD • BSE • TSE
Abstract
The central nervous system is the ultimate target of prions, the agents responsible for fatal neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs). The neuro-invasive phase and its related clinical signs take place after a long incubation period. During this asymptomatic phase, however, active transport and replication of the infectious agent take place in peripheral sites. The oral infection route has been extensively studied because of its implication in the recent epidemic of bovine spongiform encephalopathy (BSE) in cattle and of the resulting human cases of variant Creutzfeldt-Jakob disease (vCJD). Rodent models have been useful in studying some aspects of this pathogenesis. Now, new data on the initial steps of oral infection have been obtained in sheep. This species is naturally infected with scrapie by horizontal transmission and there is strong evidence implicating the oral route. Furthermore, the existence of resistant and susceptible genotypes offers the possibility of comparative studies. The data were obtained using surgical and biochemical procedures to modulate the efficiency of oral infection and show that, in sheep, the abnormal prion protein (PrP) associated with the infectious agent crosses the intact intestinal barrier at the level of the enterocytes and then passes rapidly into lymph. These steps are identical in susceptible and resistant sheep. Thereafter, replication takes place in lymphoid structures. Other results in the same study indicate that alimentary fluids almost completely degrade the PrP of the inoculum. Though not directly transposable to human diseases, in which it is not possible to study these early stages, these data allow the elaboration of a simplified concept for the pathogenesis of TSEs. They also suggest that human contamination at the level of the oral cavity might be more important than previously suspected. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Received: 27 January 2006; Accepted: 27 January 2006
http://www3.interscience.wiley.com/cgi-bin/abstract/112568524/ABSTRACT
Original Paper
Transportation of prion protein across the intestinal mucosa of scrapie-susceptible and scrapie-resistant sheep
M Jeffrey 1 *, L González 1, A Espenes 2, CMcL Press 2, S Martin 1, M Chaplin 3, L Davis 3, T Landsverk 2, C MacAldowie 4, S Eaton 4, G McGovern 1
1Veterinary Laboratories Agency (VLA)-Lasswade, Pentlands Science Park, Bush Loan, Penicuik, Midlothian EH26 0PZ, UK
2Department of Basic Sciences and Aquatic Medicine, Norwegian School of Veterinary Science, N-0033 Oslo, Norway
3VLA-Weybridge, New Haw, Addlestone, Surrey KT15 3NB, UK
4Moredun Research Institute, Pentlands Science Park, Bush Loan, Penicuik, Midlothian EH26 0PZ, UK
email: M Jeffrey (
[email protected].)
*Correspondence to M Jeffrey, Veterinary Laboratories Agency (VLA)-Lasswade, Pentlands Science Park, Bush Loan, Penicuik, Midlothian EH26 0PZ, UK.
Funded by:
UK DEFRA; Grant Number: SE1951, SE1955
EU; Grant Number: QLK5-CT-2001-02332
Keywords
intestine • alimentary • pathogenesis • scrapie • prion
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. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Received: 12 October 2005; Revised: 13 December 2005; Accepted: 23 December 2005
Digital Object Identifier (DO
http://www3.interscience.wiley.com/cgi-bin/abstract/112568745/ABSTRACT
TSS
