Sunday, June 2, 2013

Characterisation of an Unusual TSE in a Goat by Transmission in Knock-in Transgenic Mice

Characterisation of an Unusual TSE in a Goat by Transmission in Knock-in Transgenic Mice


Rona Wilson, Declan King, Nora Hunter, Wilfred Goldmann and Rona M. Barron1 + Author Affiliations


Neurobiology Division, The Roslin Institute and R(D)SVS, University of Edinburgh, Roslin, Midlothian ↵1 E-mail: rona.barron@roslin.ed.ac.uk Received 18 January 2013. Accepted 24 May 2013.



Abstract



Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative disorder of cattle, and its transmission to humans through contaminated food is thought to be the cause of the variant form of Creutzfeldt-Jakob disease (vCJD). BSE is believed to have spread from the recycling in cattle of ruminant tissue in meat and bone meal (MBM), however during this time sheep and goats were also exposed to BSE-contaminated MBM. Both sheep and goats are experimentally susceptible to BSE, and while there have been no reported natural BSE cases in sheep, two goat BSE field cases have been documented. While cases of BSE are rare in small ruminants, the existence of scrapie in both sheep and goats is well established. In the UK, during 2006-2007, a serious outbreak of clinical scrapie was detected in a large dairy goat herd. Subsequently, 200 goats were selected for post-mortem examinations, one of which showed biochemical and immunohistochemical features of the disease associated prion protein (PrPTSE) which differed from all other infected goats. In the present study we investigated this unusual case by performing bioassays into a panel of mouse lines. Following characterisation, we found that strain properties such as the ability to transmit to different mouse lines, lesion profile pattern, degree of PrP deposition in the brain and biochemical features of this unusual goat case were neither consistent with goat BSE nor with a goat scrapie herdmate control. However our results suggest this unusual case has BSE-like properties and highlights the need for continued surveillance.












Published Date: 2012-01-04 17:44:07 Subject: PRO/AH/EDR> Prion Disease update 2012 (01) Archive Number: 20120104.0027




PRION DISEASE UPDATE 2012 (01) ******************************





[2] UK: caprine BSE



Date: Sat 3 Dec 2011



Source: Emerging Infectious Diseases 17(12) 12 [edited] http://wwwnc.cdc.gov/eid/article/17/12/11-0333_article.htm Isolation of prion with BSE properties from farmed goat



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



[Authors: Spiropoulos J, Lockey R, Sallis RE, Terry LA, Thorne L, Holder TM, et al. Animal Health and Veterinary Laboratories Agency, Weybridge, Surrey, UK]



Abstract



--------



Transmissible spongiform encephalopathies are fatal neurodegenerative diseases that include variant Creutzfeldt-Jakob disease in humans, scrapie in small ruminants, and bovine spongiform encephalopathy (BSE) in cattle. Scrapie is not considered a public health risk, but BSE has been linked to variant Creutzfeldt-Jakob disease. Small ruminants are susceptible to BSE, and in 2005 BSE was identified in a farmed goat in France. We confirm another BSE case in a goat in which scrapie was originally diagnosed and retrospectively identified as suspected BSE. The prion strain in this case was further characterized by mouse bioassay after extraction from formaldehyde-fixed brain tissue embedded in paraffin blocks. Our data show that BSE can infect small ruminants under natural conditions and could be misdiagnosed as scrapie. Surveillance should continue so that another outbreak of this zoonotic transmissible spongiform encephalopathy can be prevented and public health safeguarded.


Transmissible spongiform encephalopathies (TSEs) are fatal diseases characterized by neurodegenerative changes in the central nervous system that include vacuolation, gliosis, and accumulation of an abnormal isoform (PrPSc) of a naturally occurring host-encoded protein (PrPC) (1). According to the prion hypothesis, PrPSc is the major or the sole infectious agent (1). Although this hypothesis has not received universal acceptance, PrPScis ubiquitous in all known naturally occurring TSEs, and its detection is widely used for their diagnosis.


Bovine spongiform encephalopathy (BSE), a TSE of cattle, was first detected in 1986 (2) and has since been linked with emerging TSEs in other species (3,4) including humans (5,6). Because of its ability to cross species barriers and particularly its zoonotic potential, BSE is considered a public health risk, and extensive measures have been established to detect and eliminate the disease.


Scrapie, a naturally occurring TSE affecting small ruminants, has been known for centuries (7) and is not considered to pose a public health risk (8). Under experimental conditions, however, small ruminants are susceptible to BSE, with pathogenesis and clinical signs that are not readily distinguishable from scrapie (9-12). Additionally, the fact that small ruminants were exposed to BSE-contaminated food before the exclusion of meat and bone meal from ruminant feedstuffs led to the possibility that sheep and goats on commercial farms could be affected by BSE that could be misdiagnosed as scrapie (13,14). The response to this potential risk was the implementation of extensive statutory active surveillance, elimination, and breeding for resistance programs in the European Union (EU).


In 2005, as part of a review of historical TSE-positive cases of sheep and goats in France, a specimen from a goat slaughtered for human consumption in 2002 was reported to be "indistinguishable from a BSE isolate on the basis of all identification criteria available." (15). In response to this report, 2 retrospective studies were initiated in the United Kingdom to analyze archived samples from goat cases that were initially diagnosed as scrapie (16,17). Because only fixed material was available, both studies had to use differential immunohistochemical analysis (D-IHC), a technique that can discriminate scrapie from experimentally induced BSE in sheep (18). These studies identified a single case, originally diagnosed in 1990 as scrapie, that had a D-IHC signature indistinguishable from BSE (16).


Given the wide phenotypic variance of scrapie in sheep and our limited knowledge of this variance in goats, the D-IHC result on its own was insufficient for an unequivocal diagnosis. In accordance with EU regulation 36/2005 (19), the case was referred to the EU Reference Laboratory Strain Typing Expert Group, which recommended further investigation by bioassay.


Bioassay is conventionally undertaken by using unfixed tissues to prepare inocula. Much historical tissue is available only as formalin fixed or formalin fixed and paraffin wax embedded. TSE infectivity persists in such material but with a lower infectious titer than with unfixed frozen tissue (20). However, the potential effects on biological activity, and therefore strain characterization, of fixation and processing are unknown. Thus, further investigation of this case required an extensive panel of controls. We report the results of the bioassay analysis and confirm the diagnosis of BSE in a goat in the United Kingdom.



-- Communicated by: Terry S Singeltary Sr flounder9@verizon.net



[Interested readers should access the original text via the source URL above to view the full text an the references cited. The following has been extracted from the Discussion.


"The 2 cases of naturally occurring BSE in small ruminants, the one reported here and the one identified in France (15), occurred in different countries, during different time periods, and before strict BSE control measures were fully implemented. Therefore, the most likely origin of these 2 cases would be exposure to BSE-contaminated food supplements. Although in France goats constitute 14.3 percent of the small ruminant population, in the United Kingdom they account for only 0.3 percent of small ruminants. It is intriguing, therefore, that the only naturally occurring BSE cases in small ruminants in France and particularly in the United Kingdom were detected in goats and not in sheep, although they have also been exposed to contaminated food supplements. A possible explanation could be that goats are generally managed more intensively than sheep and thus might have been exposed to higher doses of the infectious agent because of the more frequent use of concentrates in intensive dairy farming. Similar observations have been reported in cattle, in which the incidence of BSE was significantly higher in dairy herds and in which management is much more intensive than in beef herds (34). In the United Kingdom, most of the commercial goat herds are kept for milk production in a typically intensive production system, similar to dairy cattle.


The BSE case we have confirmed was 1 of 26 historic goat samples examined in the United Kingdom collected during 1984-2002 (16,17). Since 1993, scrapie in goats has been a notifiable disease in the United Kingdom, and since 2005, samples from all suspected cases of TSE in small ruminants are required to be tested for BSE-like features by using Western blotting (WB) (19). No BSE cases have been identified, although an intermediate case in a goat was reported and is under investigation by bioassay for final resolution (35,36). This screening of brain samples from all small ruminant cases offers reassurance that BSE is not present in the contemporary small ruminant population. However, application of WB to sheep experimentally co-infected with BSE and scrapie detected only the scrapie agent (37). Also, in contrast to BSE, where infectivity is mainly confined to the nervous system, in small ruminants the BSE agent is widely distributed in peripheral tissues and can be transmitted horizontally (11,38). Therefore, feed ban measures alone would be inadequate to control a BSE outbreak in small ruminants. Also, it would be impossible to prevent BSE from entering the human food chain through consumption of food products derived from small ruminants.


Because TSEs in goats are still a problem, particularly in Mediterranean countries, our data suggest that extensive surveillance and breeding schemes must remain in place to prevent a BSE outbreak in small ruminants and to safeguard public health. This report also highlights several issues regarding the use of mouse bioassay to identify TSE strains. As governing bodies seek confirmation of equivocal cases that are identified worldwide, they must be aware of the limitations, cost, and timescale demands of confirming such cases." - Mod.CP]


[See http://healthmap.org/r/1lNY for the interactive HealthMap/ProMED map of the United Kingdom. - Mod.MPP]




******


snip...


******


[5]


Switzerland: BSE Date: Fri 16 Dec 2011 Source: Prionics AG, e-scope newsletter [edited] http://escope.prionics.com/issue/2011-december-4/


In spring 2011, 2 new cases of BSE were discovered in Switzerland [see ProMED-mail posting Prion disease update 2011 (10) 20111107.3317]. Both cases were detected using the Prionics(R)-Check BSE tests. A report has now been published showing that these cases represent a novel type of BSE. What are the consequences of these new BSE cases?


After a period of 4 years without BSE positive cows, in spring this year [2011] Switzerland was shaken by the discovery of 2 new BSE cases detected only one month apart from each other. The cases appeared in different areas of Switzerland and involved animals aged 8 and 15 years, which were tested with the Prionics(R)-Check BSE tests as part of the active disease surveillance program. Bettina Bernhard, Head of the Prionics diagnostic laboratory reported that: "It was the 1st time in 4.5 years that we had found a BSE positive sample in our laboratory. Based on the results from the Prionics(R)-Check WESTERN, we immediately saw that the fingerprint of the prion protein was not that of the classical BSE cases we have detected before. We then informed the Swiss National Reference Laboratory and veterinary authorities and the positive result was confirmed with the Prionics(R)-Check PrioSTRIP."


Novel type of BSE?


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


BSE cases that differ from the classical BSE strain have been detected before, however, with low incidence. These atypical strains, designated BASE/L-BSE and H-BSE, were first reported in 2004 in Italy and France. Both strains were detected as part of routine surveillance using the Prionics(R)-Check WESTERN and ELISA tests. The recent publication by Torsten Seuberlich of the Swiss National and OIE [World Organisation for Animal Health] Reference Laboratories for BSE and Scrapie and his colleagues, is showing that these 2 Swiss cases not only differ from classical BSE, but also from the atypical BSE cases found in other countries. It appears that the 2 BSE cases detected in Switzerland seem to represent a novel type of atypical BSE. Dr Seuberlich explains: "We are now undertaking further investigations into these 2 cases and until there is more clarity, surveillance should continue to be carried out at a high level and disease awareness should be increased. Furthermore, we have to ensure that diagnostic techniques are applied that identify such cases."


Continued vigilance needed


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


Whereas consumption of meat from cows affected by classical BSE has been associated with vCJD, the public health hazard from atypical BSE is unclear. Little is known about its origin and whether it can be transmitted to other animals. These cases show, however, that BSE has not been completely eradicated and that the disease can continue to occur even with current preventive measures (such as the meat-and-bone meal ban) in place. The appearance of new strains of the prion protein could also indicate that BSE is still evolving. Continuous monitoring will be needed to keep these new strains under surveillance.


-- Communicated by: Terry S Singeltary Sr flounder9@verizon.net


[[See http://healthmap.org/r/1AFv for the interactive HealthMap/ProMED map of Switzerland. - Mod.MPP]









Wednesday, January 18, 2012


BSE IN GOATS CAN BE MISTAKEN FOR SCRAPIE February 1, 2012








Saturday, December 3, 2011


Isolation of Prion with BSE Properties from Farmed Goat Volume 17, Number


12—December 2011








Sunday, October 3, 2010


Scrapie, Nor-98 atypical Scrapie, and BSE in sheep and goats North America, who's looking ?








Tuesday, February 01, 2011


Sparse PrP-Sc accumulation in the placentas of goats with naturally acquired scrapie


Research article








Thursday, June 2, 2011


USDA scrapie report for April 2011 NEW ATYPICAL NOR-98 SCRAPIE CASES Pennsylvania AND California








UPDATE PLEASE NOTE ;




AS of June 30, 2011,


snip...


INCLUDING 10 POSITIVE GOATS FROM THE SAME HERD (FIGURE 7).


snip...


see updated APHIS scrapie report ;








Tuesday, February 01, 2011


Sparse PrP-Sc accumulation in the placentas of goats with naturally acquired scrapie


Research article


snip...


Date: Tuesday, February 01, 2011 5:03 PM


To: Mr Terry Singeltary


Subject: Your comment on BMC Veterinary Research 2011, 7:7


Dear Mr Singeltary


Thank you for contributing to the discussion of BMC Veterinary Research 2011, 7:7 .


Your comment will be posted within 2 working days, as long as it contributes to the topic under discussion and does not breach patients' confidentiality or libel anyone. You will receive a further notification by email when the posting appears on the site or if it is rejected by the moderator.


Your posting will read:


Mr Terry Singeltary,


retired


Scrapie cases Goats from same herd USA Michigan


Comment: " In spite of the poorly defined effects of PRNP genetics, scrapie strain, dose, route and source of infection, the caprine placenta may represent a source of infection to progeny and herd mates as well as a source of persistent environmental contamination. "


Could this route of infection be the cause of the many cases of Goat scrapie from the same herd in Michigan USA ?


Has this been investigated ?


(Figure 6) including five goat cases in FY 2008 that originated from the same herd in Michigan. This is highly unusual for goats, and I strenuously urge that there should be an independent investigation into finding the common denominator for these 5 goats in the same herd in Michigan with Scrapie. ...


Kind Regards, Terry






Thursday, January 07, 2010


Scrapie and Nor-98 Scrapie November 2009 Monthly Report Fiscal Year 2010 and FISCAL YEAR 2008








In FY 2010, 72 cases of classical Scrapie and 5 cases of Nor-98 like Scrapie were confirmed...








Scrapie Nor-98 like case in California FY 2011 AS of December 31, 2010.


Scrapie cases in goats FY 2002 - 2011 AS of December 31, 2010 Total goat cases = 21 Scrapie cases, 0 Nor-98 like Scrapie cases (21 field cases, 0 RSSS cases)


Last herd with infected goats disignated in FY 2008 Michigan 8 cases








Tuesday, February 01, 2011


Sparse PrP-Sc accumulation in the placentas of goats with naturally acquired scrapie


Research article











"In spite of the poorly defined effects of PRNP genetics, scrapie strain, dose, route and source of infection, the caprine placenta may represent a source of infection to progeny and herd mates as well as a source of persistent environmental contamination."


Could this route of infection be the cause of the many cases of Goat scrapie from the same herd in Michigan USA ?


Has this been investigated ?


(Figure 6) including five goat cases in FY 2008 that originated from the same herd in Michigan. This is highly unusual for goats, and I strenuously urge that there should be an independent investigation into finding the common denominator for these 5 goats in the same herd in Michigan with Scrapie. ...


Kind Regards, Terry




SNIP...




Scrapie Nor-98 like case in California FY 2011 AS of December 31, 2010.


Scrapie cases in goats FY 2002 - 2011 AS of December 31, 2010 Total goat cases = 21 Scrapie cases, 0 Nor-98 like Scrapie cases (21 field cases, 0 RSSS cases)


Last herd with infected goats disignated in FY 2008 Michigan 8 cases









UPDATED RESPONSE ON MY CONCERNS OF GOAT SCRAPIE IN MICHIGAN ;






----- Original Message -----



From: "BioMed Central Comments"


To:


Sent: Wednesday, February 16, 2011 4:13 AM


Subject: Your comment on BMC Veterinary Research 2011, 7:7


Your discussion posting "Scrapie cases Goats from same herd USA Michigan" has been rejected by the moderator as not being appropriate for inclusion on the site.


Dear Mr Singeltary,


Thank you for submitting your comment on BMC Veterinary Research article (2011, 7:7). We have read your comment with interest but we feel that only the authors of the article can answer your question about further investigation of the route of infection of the five goats in Michigan. We advise that you contact the authors directly rather than post a comment on the article.


With best wishes,


Maria


Maria Kowalczuk, PhD Deputy Biology Editor BMC-series Journals


BioMed Central 236 Gray's Inn Road London, WC1X 8HB


+44 20 3192 2000 (tel) +44 20 3192 2010 (fax)


W: www.biomedcentral.com E: Maria.Kowalczuk@biomedcentral.com


Any queries about this decision should be sent to comments@biomedcentral.com


Regards


BMC Veterinary Research


SNIP...PLEASE SEE FULL TEXT ;




Tuesday, February 01, 2011


Sparse PrP-Sc accumulation in the placentas of goats with naturally acquired scrapie


Research article








Scrapie Nor-98 like case in California FY 2011 AS of December 31, 2010.


Scrapie cases in goats FY 2002 - 2011 AS of December 31, 2010 Total goat cases = 21 Scrapie cases, 0 Nor-98 like Scrapie cases (21 field cases, 0 RSSS cases)


Last herd with infected goats disignated in FY 2008 Michigan 8 cases







Thursday, November 18, 2010


Increased susceptibility of human-PrP transgenic mice to bovine spongiform encephalopathy following passage in sheep








Monday, March 21, 2011


Sheep and Goat BSE Propagate More Efficiently than Cattle BSE in Human PrP Transgenic Mice









*** Most recent positive goat confirmed in April 2013.





Scrapie Cases in Goats FY 2002 – FY 2013 As of April 30, 2013




***SCRAPIE GOATS CALIFORNIA 13 CASES TO DATE ! ***




(an unusually high amount of scrapie documented in goats for a happenstance of bad luck, or spontaneous event, THAT DOES NOT HAPPEN IN OTHER STATES ??? )










Thursday, November 18, 2010


Increased susceptibility of human-PrP transgenic mice to bovine spongiform encephalopathy following passage in sheep







Monday, November 30, 2009


USDA AND OIE COLLABORATE TO EXCLUDE ATYPICAL SCRAPIE NOR-98 ANIMAL HEALTH CODE








Thursday, December 20, 2012


OIE GROUP RECOMMENDS THAT SCRAPE PRION DISEASE BE DELISTED AND SAME OLD BSe WITH BOVINE MAD COW DISEASE








*** The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.






Tuesday, April 30, 2013


Transmission of classical scrapie via goat milk


Veterinary Record2013;172:455 doi:10.1136/vr.f2613








ALSO, SEE CALIFORNIA AND MICHIGAN FOR THE HIGH SCRAPIE RATE IN GOATS ???


THIS needs to be addressed immediately, as to find the source, route, cause, from this unusual event...tss








Wednesday, November 28, 2012


Scientific and technical assistance on the provisional results of the study on genetic resistance to Classical scrapie in goats in Cyprus 1


SCIENTIFIC REPORT OF EFSA









Thursday, March 29, 2012


atypical Nor-98 Scrapie has spread from coast to coast in the USA 2012


NIAA Annual Conference April 11-14, 2011San Antonio, Texas









*** The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.


OR-10: Variably protease-sensitive prionopathy is transmissible in bank voles


Romolo Nonno,1 Michele Di Bari,1 Laura Pirisinu,1 Claudia D’Agostino,1 Stefano Marcon,1 Geraldina Riccardi,1 Gabriele Vaccari,1 Piero Parchi,2 Wenquan Zou,3 Pierluigi Gambetti,3 Umberto Agrimi1 1Istituto Superiore di Sanità; Rome, Italy; 2Dipartimento di Scienze Neurologiche, Università di Bologna; Bologna, Italy; 3Case Western Reserve University; Cleveland, OH USA


Background. Variably protease-sensitive prionopathy (VPSPr) is a recently described “sporadic”neurodegenerative disease involving prion protein aggregation, which has clinical similarities with non-Alzheimer dementias, such as fronto-temporal dementia. Currently, 30 cases of VPSPr have been reported in Europe and USA, of which 19 cases were homozygous for valine at codon 129 of the prion protein (VV), 8 were MV and 3 were MM. A distinctive feature of VPSPr is the electrophoretic pattern of PrPSc after digestion with proteinase K (PK). After PK-treatment, PrP from VPSPr forms a ladder-like electrophoretic pattern similar to that described in GSS cases. The clinical and pathological features of VPSPr raised the question of the correct classification of VPSPr among prion diseases or other forms of neurodegenerative disorders. Here we report preliminary data on the transmissibility and pathological features of VPSPr cases in bank voles.


Materials and Methods. Seven VPSPr cases were inoculated in two genetic lines of bank voles, carrying either methionine or isoleucine at codon 109 of the prion protein (named BvM109 and BvI109, respectively). Among the VPSPr cases selected, 2 were VV at PrP codon 129, 3 were MV and 2 were MM. Clinical diagnosis in voles was confirmed by brain pathological assessment and western blot for PK-resistant PrPSc (PrPres) with mAbs SAF32, SAF84, 12B2 and 9A2.


Results. To date, 2 VPSPr cases (1 MV and 1 MM) gave positive transmission in BvM109. Overall, 3 voles were positive with survival time between 290 and 588 d post inoculation (d.p.i.). All positive voles accumulated PrPres in the form of the typical PrP27–30, which was indistinguishable to that previously observed in BvM109 inoculated with sCJDMM1 cases.


In BvI109, 3 VPSPr cases (2 VV and 1 MM) showed positive transmission until now. Overall, 5 voles were positive with survival time between 281 and 596 d.p.i.. In contrast to what observed in BvM109, all BvI109 showed a GSS-like PrPSc electrophoretic pattern, characterized by low molecular weight PrPres. These PrPres fragments were positive with mAb 9A2 and 12B2, while being negative with SAF32 and SAF84, suggesting that they are cleaved at both the C-terminus and the N-terminus. Second passages are in progress from these first successful transmissions.


Conclusions. Preliminary results from transmission studies in bank voles strongly support the notion that VPSPr is a transmissible prion disease. Interestingly, VPSPr undergoes divergent evolution in the two genetic lines of voles, with sCJD-like features in BvM109 and GSS-like properties in BvI109.


The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.








Wednesday, March 28, 2012


VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE, price of prion poker goes up again $








*** The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.


Increased Atypical Scrapie Detections


Press reports indicate that increased surveillance is catching what otherwise would have been unreported findings of atypical scrapie in sheep. In 2009, five new cases have been reported in Quebec, Ontario, Alberta, and Saskatchewan. With the exception of Quebec, all cases have been diagnosed as being the atypical form found in older animals. Canada encourages producers to join its voluntary surveillance program in order to gain scrapie-free status. The World Animal Health will not classify Canada as scrapie-free until no new cases are reported for seven years. The Canadian Sheep Federation is calling on the government to fund a wider surveillance program in order to establish the level of prevalence prior to setting an eradication date. Besides long-term testing, industry is calling for a compensation program for farmers who report unusual deaths in their flocks.








Thursday, March 29, 2012


atypical Nor-98 Scrapie has spread from coast to coast in the USA 2012


NIAA Annual Conference April 11-14, 2011San Antonio, Texas








Monday, April 25, 2011


Experimental Oral Transmission of Atypical Scrapie to Sheep


Volume 17, Number 5-May 2011 However, work with transgenic mice has demonstrated the potential susceptibility of pigs, with the disturbing finding that the biochemical properties of the resulting PrPSc have changed on transmission (40).








***The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.








*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.


119








*** These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health.








Surprisingly the TSE agent characteristics were dramatically different v/hen passaged into Tg bovine mice. The recovered TSE agent had biological and biochemical characteristics similar to those of atypical BSE L in the same mouse model. Moreover, whereas no other TSE agent than BSE were shown to transmit into Tg porcine mice, atypical scrapie was able to develop into this model, albeit with low attack rate on first passage.


Furthermore, after adaptation in the porcine mouse model this prion showed similar biological and biochemical characteristics than BSE adapted to this porcine mouse model. Altogether these data indicate.


(i) the unsuspected potential abilities of atypical scrapie to cross species barriers


(ii) the possible capacity of this agent to acquire new characteristics when crossing species barrier


These findings raise some interrogation on the concept of TSE strain and on the origin of the diversity of the TSE agents and could have consequences on field TSE control measures.








Friday, February 11, 2011


Atypical/Nor98 Scrapie Infectivity in Sheep Peripheral Tissues








RESEARCH


Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011


Experimental Oral Transmission of Atypical Scrapie to Sheep


Marion M. Simmons, S. Jo Moore,1 Timm Konold, Lisa Thurston, Linda A. Terry, Leigh Thorne, Richard Lockey, Chris Vickery, Stephen A.C. Hawkins, Melanie J. Chaplin, and John Spiropoulos


To investigate the possibility of oral transmission of atypical scrapie in sheep and determine the distribution of infectivity in the animals’ peripheral tissues, we challenged neonatal lambs orally with atypical scrapie; they were then killed at 12 or 24 months. Screening test results were negative for disease-specifi c prion protein in all but 2 recipients; they had positive results for examination of brain, but negative for peripheral tissues. Infectivity of brain, distal ileum, and spleen from all animals was assessed in mouse bioassays; positive results were obtained from tissues that had negative results on screening. These fi ndings demonstrate that atypical scrapie can be transmitted orally and indicate that it has the potential for natural transmission and iatrogenic spread through animal feed. Detection of infectivity in tissues negative by current surveillance methods indicates that diagnostic sensitivity is suboptimal for atypical scrapie, and potentially infectious material may be able to pass into the human food chain.


SNIP...


Although we do not have epidemiologic evidence that supports the effi cient spread of disease in the fi eld, these data imply that disease is potentially transmissible under fi eld situations and that spread through animal feed may be possible if the current feed restrictions were to be relaxed. Additionally, almost no data are available on the potential for atypical scrapie to transmit to other food animal species, certainly by the oral route. However, work with transgenic mice has demonstrated the potential susceptibility of pigs, with the disturbing fi nding that the biochemical properties of the resulting PrPSc have changed on transmission (40). The implications of this observation for subsequent transmission and host target range are currently unknown.


How reassuring is this absence of detectable PrPSc from a public health perspective? The bioassays performed in this study are not titrations, so the infectious load of the positive gut tissues cannot be quantifi ed, although infectivity has been shown unequivocally. No experimental data are currently available on the zoonotic potential of atypical scrapie, either through experimental challenge of humanized mice or any meaningful epidemiologic correlation with human forms of TSE. However, the detection of infectivity in the distal ileum of animals as young as 12 months, in which all the tissues tested were negative for PrPSc by the currently available screening and confi rmatory diagnostic tests, indicates that the diagnostic sensitivity of current surveillance methods is suboptimal for detecting atypical scrapie and that potentially infectious material may be able to pass into the human food chain undetected.


Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011








why do we not want to do TSE transmission studies on chimpanzees $





5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man. I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough. Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.


snip...


R. BRADLEY








1: J Infect Dis 1980 Aug;142(2):205-8


Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.


Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.


Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.


snip...


The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.


PMID: 6997404








Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias"


Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously.


snip...


76/10.12/4.6








Nature. 1972 Mar 10;236(5341):73-4.


Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis).


Gibbs CJ Jr, Gajdusek DC.


Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0


Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)


C. J. GIBBS jun. & D. C. GAJDUSEK


National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland


SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).











Suspect symptoms


What if you can catch old-fashioned CJD by eating meat from a sheep infected with scrapie?


28 Mar 01


Like lambs to the slaughter 31 March 2001 by Debora MacKenzie Magazine issue 2284. Subscribe and get 4 free issues. FOUR years ago, Terry Singeltary watched his mother die horribly from a degenerative brain disease. Doctors told him it was Alzheimer's, but Singeltary was suspicious. The diagnosis didn't fit her violent symptoms, and he demanded an autopsy. It showed she had died of sporadic Creutzfeldt-Jakob disease.


Most doctors believe that sCJD is caused by a prion protein deforming by chance into a killer. But Singeltary thinks otherwise. He is one of a number of campaigners who say that some sCJD, like the variant CJD related to BSE, is caused by eating meat from infected animals. Their suspicions have focused on sheep carrying scrapie, a BSE-like disease that is widespread in flocks across Europe and North America.


Now scientists in France have stumbled across new evidence that adds weight to the campaigners' fears. To their complete surprise, the researchers found that one strain of scrapie causes the same brain damage in mice as sCJD.


"This means we cannot rule out that at least some sCJD may be caused by some strains of scrapie," says team member Jean-Philippe Deslys of the French Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses, south-west of Paris. Hans Kretschmar of the University of Göttingen, who coordinates CJD surveillance in Germany, is so concerned by the findings that he now wants to trawl back through past sCJD cases to see if any might have been caused by eating infected mutton or lamb.


Scrapie has been around for centuries and until now there has been no evidence that it poses a risk to human health. But if the French finding means that scrapie can cause sCJD in people, countries around the world may have overlooked a CJD crisis to rival that caused by BSE.


Deslys and colleagues were originally studying vCJD, not sCJD. They injected the brains of macaque monkeys with brain from BSE cattle, and from French and British vCJD patients. The brain damage and clinical symptoms in the monkeys were the same for all three. Mice injected with the original sets of brain tissue or with infected monkey brain also developed the same symptoms.


As a control experiment, the team also injected mice with brain tissue from people and animals with other prion diseases: a French case of sCJD; a French patient who caught sCJD from human-derived growth hormone; sheep with a French strain of scrapie; and mice carrying a prion derived from an American scrapie strain. As expected, they all affected the brain in a different way from BSE and vCJD. But while the American strain of scrapie caused different damage from sCJD, the French strain produced exactly the same pathology.


"The main evidence that scrapie does not affect humans has been epidemiology," says Moira Bruce of the neuropathogenesis unit of the Institute for Animal Health in Edinburgh, who was a member of the same team as Deslys. "You see about the same incidence of the disease everywhere, whether or not there are many sheep, and in countries such as New Zealand with no scrapie." In the only previous comparisons of sCJD and scrapie in mice, Bruce found they were dissimilar.


But there are more than 20 strains of scrapie, and six of sCJD. "You would not necessarily see a relationship between the two with epidemiology if only some strains affect only some people," says Deslys. Bruce is cautious about the mouse results, but agrees they require further investigation. Other trials of scrapie and sCJD in mice, she says, are in progress.


People can have three different genetic variations of the human prion protein, and each type of protein can fold up two different ways. Kretschmar has found that these six combinations correspond to six clinical types of sCJD: each type of normal prion produces a particular pathology when it spontaneously deforms to produce sCJD.


But if these proteins deform because of infection with a disease-causing prion, the relationship between pathology and prion type should be different, as it is in vCJD. "If we look at brain samples from sporadic CJD cases and find some that do not fit the pattern," says Kretschmar, "that could mean they were caused by infection."


There are 250 deaths per year from sCJD in the US, and a similar incidence elsewhere. Singeltary and other US activists think that some of these people died after eating contaminated meat or "nutritional" pills containing dried animal brain. Governments will have a hard time facing activists like Singeltary if it turns out that some sCJD isn't as spontaneous as doctors have insisted.


Deslys's work on macaques also provides further proof that the human disease vCJD is caused by BSE. And the experiments showed that vCJD is much more virulent to primates than BSE, even when injected into the bloodstream rather than the brain. This, says Deslys, means that there is an even bigger risk than we thought that vCJD can be passed from one patient to another through contaminated blood transfusions and surgical instruments.







Monday, December 14, 2009


Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types


(hmmm, this is getting interesting now...TSS)


Sporadic CJD type 1 and atypical/ Nor98 scrapie are characterized by fine (reticular) deposits,


see also ;


All of the Heidenhain variants were of the methionine/ methionine type 1 molecular subtype.






see full text ;


Monday, December 14, 2009


Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types







Friday, March 09, 2012


Experimental H-type and L-type bovine spongiform encephalopathy in cattle: observation of two clinical syndromes and diagnostic challenges


Research article







Thursday, June 23, 2011


Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits








Thursday, February 14, 2013


*** The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE and TSE prion disease








Tuesday, March 5, 2013


Use of Materials Derived From Cattle in Human Food and Cosmetics; Reopening of the Comment Period FDA-2004-N-0188-0051 (TSS SUBMISSION)


FDA believes current regulation protects the public from BSE but reopens comment period due to new studies







Tuesday, March 05, 2013


A closer look at prion strains Characterization and important implications


Prion 7:2, 99–108; March/April 2013; © 2013 Landes Bioscience








Tuesday, May 28, 2013


Late-in-life surgery associated with Creutzfeldt-Jakob disease: a methodological outline for evidence-based guidance








Thursday, May 30, 2013


World Organization for Animal Health (OIE) has upgraded the United States' risk classification for mad cow disease to "negligible" from "controlled", and risk further exposing the globe to the TSE prion mad cow type disease


U.S. gets top mad-cow rating from international group and risk further exposing the globe to the TSE prion mad cow type disease































TSS





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