Volume 17, Number 9–September 2011
Research
Classical Bovine Spongiform Encephalopathy by Transmission of H-Type Prion in Homologous Prion Protein Context
Juan-María Torres, Olivier Andréoletti, Caroline Lacroux, Irene Prieto, Patricia Lorenzo, Magdalena Larska, Thierry Baron, and Juan-Carlos Espinosa Author affiliations: Centro de Investigación en Sanidad Animal, Madrid, Spain (J.-M. Torres, I. Prieto, P. Lorenzo, M. Larska, J.-C. Espinosa); Ecole Nationale Vétérinaire de Toulouse, Toulouse, France (O. Andréoletti, C. Lacroux); and Agence Francaise de Sécurité Sanitaire des Aliments, Lyon, France (T. Baron)
Abstract
Bovine spongiform encephalopathy (BSE) and BSE-related disorders have been associated with a single major prion strain. Recently, 2 atypical, presumably sporadic forms of BSE have been associated with 2 distinct prion strains that are characterized mainly by distinct Western blot profiles of abnormal protease-resistant prion protein (PrPres), named high-type (BSE-H) and low-type (BSE-L), that also differed from classical BSE. We characterized 5 atypical BSE-H isolates by analyzing their molecular and neuropathologic properties during transmission in transgenic mice expressing homologous bovine prion protein. Unexpectedly, in several inoculated animals, strain features emerged that were highly similar to those of classical BSE agent. These findings demonstrate the capability of an atypical bovine prion to acquire classical BSE–like properties during propagation in a homologous bovine prion protein context and support the view that the epidemic BSE agent could have originated from such a cattle prion.
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Transmissible spongiform encephalopathies, or prion diseases, are a group of neurodegenerative disorders that include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep and goats, and bovine spongiform encephalopaty (BSE) in cattle. Prion diseases are characterized by specific histopathologic lesions and deposits of an abnormal conformational isoform (PrPSc) of the host-encoded physiologic prion protein (PrPC) in the central nervous system. PrPSc but not PrPC is partially resistant to digestion by proteinase K, resulting in an N terminally truncated prion protein termed PrPres that can be detected by Western blot and showing a characteristic banding pattern that reflects the 3 PrPres glycoforms. The apparent molecular masses and relative quantities of these glycoforms are used in biochemical PrPres typing as the criteria to differentiate between prion diseases.
BSE is a prion epidemic that has caused the deaths of ˜200,000 cattle in Europe, mainly in the United Kingdom, since it emerged in 1985. Although multiple agent strains have been identified in sheep scrapie (1,2) and human CJD (3,4), early evidence showed that BSE was caused by a single major strain (5,6) with the ability to efficiently cross the species barriers and showing stable features even when transmitted to other species. Transmission of BSE to humans through contaminated food is believed to be responsible for variant CJD (vCJD) (7,8). Several authors reported that BSE and vCJD prions share similar strain-specific features, including a unique PrPres molecular signature (6,9,10), after transmission to mice or macaques. However, other studies described the production of different PrPres molecular signature after BSE and vCJD prions transmission in wild-type (11) and human PrP transgenic mice (12,13).
Epidemiologic investigations identified contaminated meat and bone meal as the vehicle that recycled the BSE agent in the cattle population (14). However, the origin of BSE remains under debate, and the disease has been hypothesized to have derived either from sheep scrapie or from a spontaneous bovine prion disease analogous to sporadic forms of CJD in human (15) or even from human transmissible spongiform encephalopathy (16).
More recently, 2 atypical forms of BSE have been identified in several European countries (17), Japan (18,19), the United States (20), and Canada (21). Several studies suggest that these atypical disorders are associated with 2 distinct prion strains that are mainly characterized by distinct PrPres profiles, named high-type (H-type) and low-type (L-type) according to the electrophoretic migration of the unglycosylated PrPres, which is higher (BSE-H) or lower (BSE-L) than classical BSE (BSE-C) (22). An additional distinctive signature of H-type and L-type PrPres is the smaller proportion of the diglycosylated PrPres compared with the classical-type (C-type) PrPres, more obvious in L-type BSE (23–25).
All epidemiologic and biologic evidence strongly suggests that BSE-H and BSE-L represent sporadic forms of BSE (23,24) associated with 2 distinct prion strains. Transmission experiments in different mouse models, including transgenic mice expressing bovine PrP, showed that BSE-H and BSE-L exhibited strain-specific features clearly distinct between each other that also differed from BSE-C (13,25–28). However, BSE-L isolates unexpectedly showed transmission of a disease with some phenotypic features that resembled those of the BSE-C agent when inoculated in either transgenic mice expressing ovine PrP (28) or inbred wild-type mouse lines (25), suggesting that atypical bovine strains can modify their properties, at least after species barrier passages, converging with those of BSE-C.
We show that the transmission of atypical BSE-H isolates in transgenic mice expressing homologous bovine prion protein (PrP) led to emergence of a clearly distinct prion with strain features similar to those of the BSE-C agent and that such similarities were maintained on subsequent passages. These observations provide new insights into the nature of the events that could have led to the BSE epizootic.
Materials and Methods
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Discussion
We studied the behavior and stability of the atypical BSE-H during propagation into a bovine PrP background, thus in the absence of a species barrier. We used Tg110 mice (29,36) because they express a PrPC homologous to that of the donors, thus providing a relevant context for comparing atypical BSE-H and epizootic BSE-C isolates.
Our results showed that all BSE-H isolates induced a typical neurologic disease on primary transmission, with a 100% attack rate and survival times similar to those produced by several BSE-C isolates in this mouse line (29,36) (Figure 1). The longer survival times for some mice infected with BSE-H isolates could reflect a lower infectivity of this isolate consistent with the reduction of survival time observed on subpassages, approaching that for BSE-C or BSE-H isolates of presumably higher titer (i.e., producing no substantial reduction of survival time on subpassage). These results are also consistent with another comparative study of BSE-H and BSE-C transmissions in a different bovine PrP mouse line (27). These data suggest that atypical BSE-H and BSE-C agents have similar transmission features into Tg110 mice.
Although all BSE-H–inoculated mice showed homogeneous survival times, a phenotypic divergence was observed in a few animals infected with 2 of the BSE-H isolates. Surprisingly, these few mice showed phenotypic features clearly distinct from those in most of the BSE-H–infected mice but similar to those of BSE-C propagated onto the same mice, according to various criteria. First, a PrPres profile indistinguishable from that produced by BSE-C agent in these mice but clearly distinct from that of BSE-H in cattle, in terms of 1) apparent molecular mass of PrPres, 2) PrPres glycosylation pattern, 3) immunoreactivity with 12B2 mAb, and 4) pattern of labeling with Saf84 antibody. Second, the vacuolation profile essentially overlapped that in mice infected with BSE-C, with slight differences only in the mesencephalic tegmentum area. Third, the spatial distribution of PrPres in the brain was clearly similar to that of mice infected with BSE-C. Fourth, PrPSc was consistently detected in the spleen, similar to mice infected with BSE-C. These similarities with BSE-C were fully retained after a second passage by using brain homogenate from mice with C-like features, whereas a BSE-H strain phenotype was maintained in mice inoculated with mouse brains homogenates containing H-type PrPres.
However, C-like features emerged in only 2 of the 5 isolates tested. Because only a low proportion of the mice inoculated with these 2 isolates exhibited these novel features (3/12 and 2/10, respectively), the lack of such observation in the other 3 isolates, and in 2 other independent studies of 3 BSE-H isolates in different bovine transgenic mouse lines (27), could be due to the low number of inoculated mice (6 per isolate), which could be statistically insufficient for such an event. No variability was ever observed in the PrPres profiles of >100 Tg110 mice inoculated with 4 different BSE-C isolates (29,36) (Figure 1). However, a divergent evolution of the BSE agent has been reported after trans-species transmission in both wild-type (11) and human PrP transgenic mice (12,39,40).
Although further studies are required to clarify the mechanisms associated with the emergence of distinct phenotypes among individual mice, several factors would be expected to influence the probability of detecting such a variant through mouse bioassay. These factors are 1) amount or regions of cattle brain tissue taken for inoculum preparation, 2) physicochemical treatment during inoculum preparation (e.g., temperature, homogenization buffer), 3) the precise site of mouse inoculation, 4) the infectious titer of the inoculum, and 5) others unknown mouse factor affecting prion propagation and disease evolution. Because samples used in this study were prepared from the same region (brainstem) following the same precise protocol and under identical conditions, differences in inoculum preparation and conditions are unlikely. However, the possibility that the observations might be influenced by the precise neuroanatomic origin of the inoculated bovine brainstem homogenate or by other mouse bioassay–related factors cannot be excluded.
The possible cross-contamination of the BSE-H isolates material (02-2695 and 45 from 2 laboratories in different countries) by a BSE-C infectious source was judged highly improbable for several reasons. These reasons are 1) the strict biosafety procedures followed for sample collection, preparation of the inocula, inoculation scheme, and care of mice; 2) the absence of C-type PrPSc in the BSE-H inocula used for transmissions as deduced by Western blot analysis; and 3) 2 independent transmission experiments, involving separate batches of both incriminated isolates, all produced consistent results.
Together, these observations support 2 possible hypotheses. First, a minor strain component might be present in BSE-H isolates that could emerge on subsequent transmission in Tg110 mice. Second, a new strain component has been generated during propagation of BSE-H agent in Tg110. In both instances, emergence of the new strain, either in the original cattle or during propagation in Tg110 mice, could be promoted by specific propagation conditions or by physicochemical treatment of the inoculum. In this regard, acquisition of novel properties by a sporadic cattle transmissible spongiform encephalopathy agent by a physicochemical treatment, such as that applied to carcass-derived products, has been invoked as a possible origin for the BSE epidemic (7).
Contrary to BSE-H, the atypical BSE-L agent retained unique and distinct phenotypic features, compared with BSE-C agent, on transmission to both bovine and human PrP transgenic mice (26–28). This agent, however, acquired phenotypic traits intriguingly similar to those of the BSE agent during trans-species transmission in either transgenic mice expressing ovine PrP (28) or inbred mouse lines. On the basis of these observations, the BSE-C agent already has been speculated to have originated from atypical BSE-L after conversion in an intermediate host such as a sheep. However, the capacity of these BSE-L–derived agents to retain BSE phenotypic traits after reinoculation to bovine PrP transgenic mice is a key question, remaining to be demonstrated, to show whether the observed convergence truly reflects a permanent strain shift of the BSE-L agent rather than a phenotypic convergence in an experimental model.
In contrast, our results suggest that prion strain divergence might occur on propagation of atypical BSE-H in a homologous bovine PrP context and that this strain divergence could result from a permanent strain shift of the BSE-H agent toward a C-like agent that is stable in subsequent passages. These findings emphasize the potential capacity of prion diversification during propagation, even in the absence of any species barrier, and represent an experimental demonstration of the capability of an atypical, presumably sporadic, bovine prion to acquire C-like properties during propagation in a homologous bovine PrP context.
Results in transgenic mouse models cannot be directly extrapolated to the natural host. However, our observations are consistent with the view that the BSE agent could have originated from a cattle prion, such as BSE-H, and provide new insights into the nature of the events that could have led to the appearance of this agent.
This study was supported by grants from the European Union (CT2004-50657 and CT2004-023183) and from UK Food Standards Agency (M03043).
Dr Torres is the lead researcher scientist of the Prions Group at the Centro de Investigación en Sanidad Animal–Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Madrid, Spain. His research interests include prion strain characterization and evolution and the pathogenesis of prion diseases and their effects on human and animal health.
http://www.cdc.gov/eid/content/17/9/101403.htm
The EMBO Journal (2002) 21, 6358 - 6366 doi:10.1093/emboj/cdf653
Subject Categories: Neuroscience | Molecular Biology of Disease
BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein
Emmanuel A. Asante1, Jacqueline M. Linehan1, Melanie Desbruslais1, Susan Joiner1, Ian Gowland1, Andrew L. Wood1, Julie Welch1, Andrew F. Hill1, Sarah E. Lloyd1, Jonathan D.F. Wadsworth1 and John Collinge1 1.MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College, Queen Square, London WC1N 3BG, UK
Correspondence to:
John Collinge, E-mail: j.collinge@prion.ucl.ac.uk
Received 1 August 2002; Accepted 17 October 2002; Revised 24 September 2002
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Abstract
Variant Creutzfeldt–Jakob disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a disease arising from BSE exposure.
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Keywords: BSE, Creutzfeldt–Jakob disease, prion, transgenic
http://www.nature.com/emboj/journal/v21/n23/full/7594869a.html
Tuesday, November 02, 2010
BSE - ATYPICAL LESION DISTRIBUTION (RBSE 92-21367) statutory (obex only) diagnostic criteria CVL 1992
http://bse-atypical.blogspot.com/2010/11/bse-atypical-lesion-distribution-rbse.html
Saturday, June 25, 2011
Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque
"BSE-L in North America may have existed for decades"
http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/transmissibility-of-bse-l-and-cattle.html
Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME.
snip...
The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle...
http://web.archive.org/web/20030516051623/http://www.bseinquiry.gov.uk/files/mb/m09/tab05.pdf
Sunday, June 26, 2011
Risk Analysis of Low-Dose Prion Exposures in Cynomolgus Macaque
http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/risk-analysis-of-low-dose-prion.html
Thursday, June 23, 2011
Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits
http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/experimental-h-type-bovine-spongiform.html
Thursday, July 21, 2011
A Second Case of Gerstmann-Sträussler-Scheinker Disease Linked to the G131V Mutation in the Prion Protein Gene in a Dutch Patient Journal of Neuropathology & Experimental Neurology:
August 2011 - Volume 70 - Issue 8 - pp 698-702
http://transmissiblespongiformencephalopathy.blogspot.com/2011/07/second-case-of-gerstmann-straussler.html
Saturday, August 14, 2010
BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY
(see mad cow feed in COMMERCE IN ALABAMA...TSS)
http://prionpathy.blogspot.com/2010/08/bse-case-associated-with-prion-protein.html
Wednesday, June 15, 2011
Galveston, Texas - Isle port moves through thousands of heifers headed to Russia, none from Texas, Alabama, or Washington, due to BSE risk factor
http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/galveston-texas-isle-port-moves-through.html
Saturday, July 23, 2011
CATTLE HEADS WITH TONSILS, BEEF TONGUES, SPINAL CORD, SPECIFIED RISK MATERIALS (SRM's) AND PRIONS, AKA MAD COW DISEASE
http://transmissiblespongiformencephalopathy.blogspot.com/2011/07/cattle-heads-with-tonsils-beef-tongues.html
Saturday, November 6, 2010
TAFS1 Position Paper on Position Paper on Relaxation of the Feed Ban in the EU Berne, 2010 TAFS
INTERNATIONAL FORUM FOR TRANSMISSIBLE ANIMAL DISEASES AND FOOD SAFETY a non-profit Swiss Foundation
http://madcowfeed.blogspot.com/2010/11/tafs1-position-paper-on-position-paper.html
Archive Number 20101206.4364 Published Date 06-DEC-2010 Subject PRO/AH/EDR> Prion disease update 2010 (11)
PRION DISEASE UPDATE 2010 (11)
http://www.promedmail.org/pls/apex/f?p=2400:1001:5492868805159684::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1000,86129
P.9.21
Molecular characterization of BSE in Canada
Jianmin Yang1, Sandor Dudas2, Catherine Graham2, Markus Czub3, Tim McAllister1, Stefanie Czub1 1Agriculture and Agri-Food Canada Research Centre, Canada; 2National and OIE BSE Reference Laboratory, Canada; 3University of Calgary, Canada
Background: Three BSE types (classical and two atypical) have been identified on the basis of molecular characteristics of the misfolded protein associated with the disease. To date, each of these three types have been detected in Canadian cattle.
Objectives: This study was conducted to further characterize the 16 Canadian BSE cases based on the biochemical properties of there associated PrPres. Methods: Immuno-reactivity, molecular weight, glycoform profiles and relative proteinase K sensitivity of the PrPres from each of the 16 confirmed Canadian BSE cases was determined using modified Western blot analysis.
Results: Fourteen of the 16 Canadian BSE cases were C type, 1 was H type and 1 was L type. The Canadian H and L-type BSE cases exhibited size shifts and changes in glycosylation similar to other atypical BSE cases. PK digestion under mild and stringent conditions revealed a reduced protease resistance of the atypical cases compared to the C-type cases. N terminal- specific antibodies bound to PrPres from H type but not from C or L type. The C-terminal-specific antibodies resulted in a shift in the glycoform profile and detected a fourth band in the Canadian H-type BSE.
Discussion: The C, L and H type BSE cases in Canada exhibit molecular characteristics similar to those described for classical and atypical BSE cases from Europe and Japan. This supports the theory that the importation of BSE contaminated feedstuff is the source of C-type BSE in Canada.
*** It also suggests a similar cause or source for atypical BSE in these countries.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf
STRICTLY PRIVATE AND CONFIDENTIAL 25, AUGUST 1995
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To minimise the risk of farmers' claims for compensation from feed compounders.
To minimise the potential damage to compound feed markets through adverse publicity.
To maximise freedom of action for feed compounders, notably by maintaining the availability of meat and bone meal as a raw material in animal feeds, and ensuring time is available to make any changes which may be required.
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THE FUTURE
4..........
MAFF remains under pressure in Brussels and is not skilled at handling potentially explosive issues.
5. Tests _may_ show that ruminant feeds have been sold which contain illegal traces of ruminant protein. More likely, a few positive test results will turn up but proof that a particular feed mill knowingly supplied it to a particular farm will be difficult if not impossible.
6. The threat remains real and it will be some years before feed compounders are free of it. The longer we can avoid any direct linkage between feed milling _practices_ and actual BSE cases, the more likely it is that serious damage can be avoided. ...
SEE full text ;
http://web.archive.org/web/20060517074958/http://www.bseinquiry.gov.uk/files/yb/1995/08/24002001.pdf
Saturday, August 14, 2010
BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY
(see mad cow feed in COMMERCE IN ALABAMA...TSS)
http://prionpathy.blogspot.com/2010/08/bse-case-associated-with-prion-protein.html
Thursday, July 28, 2011
An Update on the Animal Disease Traceability Framework July 27, 2011
http://naiscoolyes.blogspot.com/2011/07/update-on-animal-disease-traceability.html
Monday, June 27, 2011
Zoonotic Potential of CWD: Experimental Transmissions to Non-Human Primates
http://chronic-wasting-disease.blogspot.com/2011/06/zoonotic-potential-of-cwd-experimental.html
Monday, August 8, 2011
Susceptibility of Domestic Cats to CWD Infection
http://felinespongiformencephalopathyfse.blogspot.com/2011/08/susceptibility-of-domestic-cats-to-cwd.html
Monday, June 27, 2011
Zoonotic Potential of CWD: Experimental Transmissions to Non-Human Primates
http://chronic-wasting-disease.blogspot.com/2011/06/zoonotic-potential-of-cwd-experimental.html
Please see the following warning from CDC about prion TSE consumption in North America ;
Thursday, May 26, 2011
Travel History, Hunting, and Venison Consumption Related to Prion Disease Exposure, 2006-2007 FoodNet Population Survey
Journal of the American Dietetic Association Volume 111, Issue 6 , Pages 858-863, June 2011.
http://transmissiblespongiformencephalopathy.blogspot.com/2011/05/travel-history-hunting-and-venison.html
Thursday, July 14, 2011
Histopathological Studies of "CH1641-Like" Scrapie Sources Versus Classical Scrapie and BSE Transmitted to Ovine Transgenic Mice (TgOvPrP4)
http://transmissiblespongiformencephalopathy.blogspot.com/2011/07/histopathological-studies-of-ch1641.html
Monday, June 20, 2011 2011
Annual Conference of the National Institute for Animal Agriculture ATYPICAL NOR-98 LIKE SCRAPIE UPDATE USA
http://nor-98.blogspot.com/2011/06/2011-annual-conference-of-national.html
Thursday, June 2, 2011
USDA scrapie report for April 2011 NEW ATYPICAL NOR-98 SCRAPIE CASES Pennsylvania AND California
http://nor-98.blogspot.com/2011/06/usda-scrapie-report-for-april-2011-new.html
Monday, June 27, 2011
Comparison of Sheep Nor98 with Human Variably Protease-Sensitive Prionopathy and Gerstmann-Sträussler-Scheinker Disease
http://prionopathy.blogspot.com/2011/06/comparison-of-sheep-nor98-with-human.html
Saturday, March 5, 2011
MAD COW ATYPICAL CJD PRION TSE CASES WITH CLASSIFICATIONS PENDING ON THE RISE IN NORTH AMERICA
http://transmissiblespongiformencephalopathy.blogspot.com/2011/03/mad-cow-atypical-cjd-prion-tse-cases.html
Friday, August 12, 2011
Creutzfeldt-Jakob disease (CJD) biannual update (2011/2), Incidents Panel, National Anonymous Tonsil Archive
http://transmissiblespongiformencephalopathy.blogspot.com/2011/08/creutzfeldt-jakob-disease-cjd-biannual.html
Wednesday, June 29, 2011
TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products
http://tseac.blogspot.com/2011/06/tseac-meeting-august-1-2011-donor.html
TSS
Showing posts with label cBSE lBSE hBSE atypical sCJD prion. Show all posts
Showing posts with label cBSE lBSE hBSE atypical sCJD prion. Show all posts
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