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From: TSS ()
Subject: New evidence questions the simple link between PrP and vCJD
Date: March 30, 2006 at 7:16 am PST


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TSS
New evidence questions the simple link between PrP and vCJD
Thu Mar 30, 2006 09:38
70.110.93.218

New evidence questions the simple link between prion proteins and vCJD

Medical Research News Published: Thursday, 30-Mar-2006


While newly published research confirms that under laboratory circumstances prion-protein can be absorbed across the gut, it also shows that this is unlikely to occur in real life. In addition, the results show that the places in the gut that do take up these disease-associated proteins are different from the locations where infectivity is known to be amplified. The findings will be published in the Journal of Pathology.
Since the outbreak of BSE in cattle and vCJD in humans, scientists have struggled to make sense of how an abnormal variation of a normal protein can trigger an infectious disease. Some are questioning whether this simple relationship exists at all. This paper adds new evidence that can inform the debate.

Firstly, it is known that individual people and animals have different levels of genetic susceptibility to this group of diseases, but no one knows how this resistance is achieved. One option is that resistant people do not absorb the disease-associated prion protein (PrP) from their guts.

To test this, the researchers worked with 50 sheep, with different degrees of genetic resistance to scrapie - the sheep form of the disease. When they injected material containing abnormal prion protein (PrP) into the sheep's gut, it was equally absorbed by all sheep.

"This clearly shows that resistance is not achieved by blocking uptake of abnormal proteins from the gut - it must be achieved by some other mechanism," says lead author Dr Martin Jeffrey.

Secondly, they looked in more detail at the route of absorption in the gut. Using surgically modified sheep, they loaded a small area of the gut with a fluid mixture containing 0.5 grams of scrapie infected brain containing a large amount of the disease specific variant of the PrP protein and watched how it was taken up. They saw the abnormal PrP was rapidly taken up by finger-like projections called villi and passed in to the lymph. It was not, however, taken up by structures called Peyer's nodules, that are believed to be the places where animals amplify the infective agent.

"The fact the PrP isn't taken up by the Peyer's nodules questions whether PrP is really infectious, or whether PrP is really just a secondary marker of the presence of the scrapie agent," says Jeffrey.

His belief in this need to reappraise the fundamental understanding of prion diseases is enhanced by one more observation published in this same paper. The team pre-digested a mixture containing disease specific PrP with standard stomach contents, and then injected the resulting mixture into the gut. No PrP transferred into the villi. When they used a highly sensitive version of Western Blot analysis to examine the contents of this pre-digested mixture, they found only the faintest suggestion that some of the PrP had survived. This was despite the fact that the original mixture had a contained a high level of PrP.

"Think about it - a sheep grazing in a field is not naturally exposed to highly infected brain and could only pick up a tiny amount of PrP from other tissues. This will then be exposed to 48 hours or more digestion before it arrives in the gut, and our experiments show that after this, the chance of there being more than an unmeasurably small amount of PrP left to absorb is very small," says Jeffrey.

"As sheep can become infected, the theoretical probability of this being due to an invisible sub-fraction of digestion resistant PrP molecules is unlikely. The possibility of there being infectious molecules other than PrP must therefore be seriously considered," says Jeffrey.

"A lot of people are completely wedded to the prion hypothesis of diseases like vCJD, but the more you deal with whole animals as opposed to relying purely on in vitro studies, the more cautious you are about saying that prion proteins alone cause the disease," says Martin Jeffrey.

In a commentary published in the same edition of the journal Dr Nicole Sales of the Department of Infectology, at the Scripps Research Institute Jupiter, Florida, suggests that one possible explanation that keeps with the prion hypothesis is that infection occurs as PrPs are absorbed in the mouth, rather than in the gut.

Dr Jeffrey, however, is not convinced by this argument. "Were infection to be acquired from the mouth then the first tissues to accumulate infectivity would be lymph nodes in the throat or the tonsils. But we don't tend to see this in animals, and have no reason to believe it would be different in humans," comments Jeffrey.

http://www.interscience.wiley.com/thejournalofpathology

http://www.news-medical.net/?id=16977

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 (nsales@scripps.edu)

*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.

--------------------------------------------------------------------------------
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 (m.jeffrey@vla.defra.gsi.gov.uk)

*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.

--------------------------------------------------------------------------------
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

New study raises questions about the number of people in the UK who could be incubating vCJD

Original article:

Prevalence of lymphoreticular prion protein accumulation in UK tissue samples
David A Hilton, Azra C Ghani, Lisa Conyers, Philip Edwards, Linda McCardle, Diane Ritchie, Mark Penney, Doha Hegazy, James W Ironside
Published Online: 21 May 2004
DOI: 10.1002/path.1580


http://www3.interscience.wiley.com/homepages/1130/cjd.pdf

TSS



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