Sunday, August 26, 2012

Susceptibility of young sheep to oral infection with bovine spongiform encephalopathy decreases significantly after weaning

Susceptibility of young sheep to oral infection with bovine spongiform encephalopathy decreases significantly after weaning.



Nora Hunter1,#, Fiona Houston2, James Foster1, Wilfred Goldmann1, Dawn Drummond1, David Parnham1, Iain Kennedy1, Andrew Green1, Paula Stewart1 and Angela Chong1


+ Author Affiliations


1Neurobiology Division, The Roslin Institute and R(D)SVS, University of Edinburgh, Roslin, Midlothian, United Kingdom 2School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom


ABSTRACT


Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE or prion disease) which is readily transmissible to sheep by experimental infection and animals of ARQ/ARQ PRNP genotype (at codons 136, 154 and 171) have the shortest incubation period. Because it is possible that sheep in the UK could have been infected with BSE via feeding of contaminated meat and bone meal supplements at the same time as cattle, there is considerable interest in the responses of sheep to BSE inoculation. Epidemiological evidence suggests that very young individuals are more susceptible to TSE infection however this has never been properly tested in sheep. In the present study, low doses of BSE were fed to lambs of a range of ages (∼24 hours, 2-3 weeks, 3 months, 6 months) and adult sheep. The incidence of clinical BSE disease was high when unweaned lambs (∼24 hours and 2-3 weeks) were inoculated but older weaned animals were much less susceptible. Incubation period was also found to be influenced by genotype at codon 141 of the PRNP gene as LF heterozygotes had a longer mean incubation period than either homozygote. The results suggest that UK sheep would have been at high risk of BSE infection only if contaminated supplementary foodstuffs had inadvertently been ingested by neonatal animals.


FOOTNOTES


↵#corresponding author email: nora.hunter@roslin.ed.ac.uk Copyright © 2012, American Society for Microbiology. All Rights Reserved.






>>> The results suggest that UK sheep would have been at high risk of BSE infection only if contaminated supplementary foodstuffs had inadvertently been ingested by neonatal animals.





THE RISK OF TRANSMISSION OF BSE TO SHEEP VIA FEED


snip...









Wednesday, February 16, 2011


IN CONFIDENCE


SCRAPIE TRANSMISSION TO CHIMPANZEES


IN CONFIDENCE








Sunday, April 18, 2010



SCRAPIE AND ATYPICAL SCRAPIE TRANSMISSION STUDIES A REVIEW 2010








Monday, April 25, 2011



Experimental Oral Transmission of Atypical Scrapie to Sheep



Volume 17, Number 5-May 2011








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








12/10/76



AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE



Office Note CHAIRMAN: PROFESSOR PETER WILDY



snip...



A The Present Position with respect to Scrapie A] The Problem Scrapie is a natural disease of sheep and goats. It is a slow and inexorably progressive degenerative disorder of the nervous system and it ia fatal. It is enzootic in the United Kingdom but not in all countries. The field problem has been reviewed by a MAFF working group (ARC 35/77). It is difficult to assess the incidence in Britain for a variety of reasons but the disease causes serious financial loss; it is estimated that it cost Swaledale breeders alone $l.7 M during the five years 1971-1975. A further inestimable loss arises from the closure of certain export markets, in particular those of the United States, to British sheep. It is clear that scrapie in sheep is important commercially and for that reason alone effective measures to control it should be devised as quickly as possible. 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).









Sunday, March 28, 2010



Nor-98 atypical Scrapie, atypical BSE, spontaneous TSE, trade policy, sound science ?








Monday, November 30, 2009



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








I strenuously urge the USDA and the OIE et al to revoke the exemption of the legal global trading of atypical Nor-98 scrapie TSE. ...TSS





Friday, February 11, 2011



Atypical/Nor98 Scrapie Infectivity in Sheep Peripheral Tissues








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



Danielle Padilla1., Vincent Be´ringue2., Juan Carlos Espinosa1, Olivier Andreoletti3, Emilie Jaumain2, Fabienne Reine2, Laetitia Herzog2, Alfonso Gutierrez-Adan4, Belen Pintado4, Hubert Laude2, Juan Maria Torres1*



1 Centro de Investigacio´n en Sanidad Animal (CISA-INIA), Madrid, Spain, 2 INRA, UR892, Virologie Immunologie Mole´culaires, Jouy-en-Josas, France, 3UMR INRA-ENVT 1225, Interactions Hoˆ te Agent Pathoge`ne, Ecole Nationale Ve´te´ rinaire de Toulouse, Toulouse, France, 4 Departamento de Reproduccio´n Animal-INIA, Madrid, Spain



Abstract



A new variant of Creutzfeldt Jacob Disease (vCJD) was identified in humans and linked to the consumption of Bovine Spongiform Encephalopathy (BSE)-infected meat products. Recycling of ruminant tissue in meat and bone meal (MBM) has been proposed as origin of the BSE epidemic. During this epidemic, sheep and goats have been exposed to BSEcontaminated MBM. It is well known that sheep can be experimentally infected with BSE and two field BSE-like cases have been reported in goats. In this work we evaluated the human susceptibility to small ruminants-passaged BSE prions by inoculating two different transgenic mouse lines expressing the methionine (Met) allele of human PrP at codon 129 (tg650 and tg340) with several sheep and goat BSE isolates and compared their transmission characteristics with those of cattle BSE. While the molecular and neuropathological transmission features were undistinguishable and similar to those obtained after transmission of vCJD in both transgenic mouse lines, sheep and goat BSE isolates showed higher transmission efficiency on serial passaging compared to cattle BSE. We found that this higher transmission efficiency was strongly influenced by the ovine PrP sequence, rather than by other host species-specific factors. Although extrapolation of results from prion transmission studies by using transgenic mice has to be done very carefully, especially when human susceptibility to prions is analyzed, our results clearly indicate that Met129 homozygous individuals might be susceptible to a sheep or goat BSE agent at a higher degree than to cattle BSE, and that these agents might transmit with molecular and neuropathological properties indistinguishable from those of vCJD. Our results suggest that the possibility of a small ruminant BSE prion as vCJD causal agent could not be ruled out, and that the risk for humans of a potential goat and/or sheep BSE agent should not be underestimated.



Citation: Padilla D, Be´ringue V, Espinosa JC, Andreoletti O, Jaumain E, et al. (2011) Sheep and Goat BSE Propagate More Efficiently than Cattle BSE in Human PrP Transgenic Mice. PLoS Pathog 7(3): e1001319. doi:10.1371/journal.ppat.1001319


Editor: Umberto Agrimi, Istituto Superiore di Sanita` , Italy


Received August 24, 2010; Accepted February 15, 2011; Published March 17, 2011


Copyright: 2011 Padilla et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Funding: This work was supported by grants from European Union (CT-2001-01309, CT2004-023183 and CT2005-036353), Spanish Ministerio de Ciencia e Inovacion (RTA2006-00091) and from UK Food Standards Agency (M03043). D.P. was supported by a fellowship from the Alban Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Competing Interests: The authors have declared that no competing interests exist.


* E-mail: jmtorres@inia.es


. These authors contributed equally to this work.




snip...




Whatever the mechanism, the notion that a passage through an intermediate species can profoundly alter prion virulence for the human species has important public-health issues, regarding emerging and/or expanding TSEs, like atypical scrapie or CWD.





Although extrapolation of results from prion transmission studies by using transgenic mice has to be done very carefully, especially when human susceptibility to prions is analyzed, our results clearly indicate that Met129 homozygous individuals might be susceptible to a sheep or goat BSE agent at a higher degree than to cattle BSE, and that these agents might transmit with molecular and neuropathological properties indistinguishable from those of vCJD. Although no vCJD cases have been described in Val129 homozygous individuals so far it is relevant to analyze if similar results will be observed in this genotype. This issue is currently being addressed in transmission experiments using transgenic mice expressing Val129 human PrP.





Taken all together, our results suggest that the possibility of a small ruminant BSE prion as vCJD causal agent could not be ruled out, which has important implications on public and animal health policies. On one hand, although the exact magnitude and characteristic of the vCJD epidemic is still unclear, its link with cattle BSE is supported by strong epidemiological ground and several experimental data. On the other hand, the molecular typing performed in our studies, indicates that the biochemical characteristics of the PrPres detected in brains of our sheep and goat BSE-inoculated mice seem to be indistinguishable from that observed in vCJD. Considering the similarity in clinical manifestation of BSE- and scrapie-affected sheep [48], a masker effect of scrapie over BSE, as well as a potential adaptation of the BSE agent through subsequent passages, could not be ruled out. As BSE infected sheep PrPSc have been detected in many peripheral organs, small ruminant-passaged BSE prions might be a more widespread source of BSE infectivity compared to cattle [19], [49], [50]. This fact is even more worrying since our transmission studies suggest that apparently Met129 human PrP favours a BSE agent with ovine rather than a bovine sequence. Finally, it is evident that, although few natural cases have been described and so far we cannot draw any definitive conclusion about the origin of vCJD, we can not underestimate the risk of a potential goat and/or sheep BSE agent.















J Virol. 2011 February; 85(3): 1174–1181. Published online 2010 November 17. doi: 10.1128/JVI.01578-10 PMCID: PMC3020518




Increased Susceptibility of Human-PrP Transgenic Mice to Bovine Spongiform Encephalopathy Infection following Passage in Sheep †




Chris Plinston,1 Patricia Hart,1 Angela Chong,1 Nora Hunter,1 James Foster,1 Pedro Piccardo,1,2 Jean C. Manson,1 and Rona M. Barron1,* Neuropathogenesis Division, The Roslin Institute, and R(D)SVS, University of Edinburgh, Roslin, Midlothian, United Kingdom,1 Laboratory of Bacterial and TSE Agents, Food and Drug Administration, Rockville, Maryland2 *Corresponding author. Mailing address: Neuropathogenesis Division, The Roslin Institute and R(D)SVS, University of Edinburgh, Roslin, Midlothian EH25 9PS, United Kingdom. Phone: 0131 527 4200. Fax: 0131 440 0434. E-mail: rona.barron@roslin.ed.ac.uk




Author information ► Article notes ► Copyright and License information ►




Received July 28, 2010; Accepted November 9, 2010. Copyright © 2011, American Society for Microbiology This article has been cited by other articles in PMC.






Abstract


The risk of the transmission of ruminant transmissible spongiform encephalopathy (TSE) to humans was thought to be low due to the lack of association between sheep scrapie and the incidence of human TSE. However, a single TSE agent strain has been shown to cause both bovine spongiform encephalopathy (BSE) and human vCJD, indicating that some ruminant TSEs are transmissible to humans. While the transmission of cattle BSE to humans in transgenic mouse models has been inefficient, indicating the presence of a significant transmission barrier between cattle and humans, BSE has been transmitted to a number of other species. Here, we aimed to further investigate the human transmission barrier following the passage of BSE in a sheep. Following inoculation with cattle BSE, gene-targeted transgenic mice expressing human PrP showed no clinical or pathological signs of TSE disease. However, following inoculation with an isolate of BSE that had been passaged through a sheep, TSE-associated vacuolation and proteinase K-resistant PrP deposition were observed in mice homozygous for the codon 129-methionine PRNP gene. This observation may be due to higher titers of the BSE agent in sheep or an increased susceptibility of humans to BSE prions following passage through a sheep. However, these data confirm that, contrary to previous predictions, it is possible that a sheep prion is transmissible to humans and that BSE from other species is a public health risk.




snip...




Although sheep can be experimentally infected with BSE by oral, intravenous, or intracerebral exposure (18), no cases of sheep BSE have been reported in the field. The possible increased risk of disease transmission identified in these studies thus is not of major concern to the public at present. Natural BSE infection has, however, been identified in goats (14, 25), indicating that small ruminants have been exposed to sources of contamination. We cannot rule out the possibility that sheep have been infected with BSE during the height of the BSE epidemic, as these animals undoubtedly were exposed to similar feed sources (although with different levels of exposure compared to those of cattle). Such infection may have been limited and/or localized and resolved very quickly. BSE in small ruminants may, however, represent an increased risk to humans due to the wider distribution of BSE infectivity identified in peripheral sheep tissues (2, 17, 19, 29) compared to that of BSE in cattle, mainly which is restricted to the CNS (10). While TSEs remain in the environment and continue to infect animals (even at low prevalence), there remains the potential for cross-species transmission and the emergence of TSE isolates with altered strain properties or host ranges. Our data therefore emphasize the need for continued surveillance to identify, monitor, and characterize any new emerging TSE agents that are identified in ruminants and the assessment of the potential risks posed to other species.












*** CONFIDENTIAL ***



DRAFT



SHEEP AND BSE



A. The experimental transmission of BSE to sheep.



http://web.archive.org/web/20060517080024/http://www.bseinquiry.gov.uk/files/sc/seac33/tab02.pdf



http://web.archive.org/web/20060517075652/http://www.bseinquiry.gov.uk/files/sc/seac33/tab03.pdf






The only circumstance in which infection with the natural isolate produces an higher incidence of disease compared to BSE, is in intracerebrally (and possibly orally) challenged ''positive'' line sheep. Notwithstanding the possibility of indigenous natural scrapie in some of these sheep, there are still sufficient numbers of transmission cases with PrP genotypes which preclude the natural disease developing i.e. those typed as VA136/RR154/QR171.


As an extension to this study, it has been possible to recover BSE by passage in mice from brain and spleen taken from ''negative'' line sheep infected with BSAE by ic and oral challenge (Foster and others 1996). The close similarity of incubation periods and pathology from the passage of these tissues in mice to those seen in direct BSE transmission studies from cattle to mice suggests that passaging BSE in sheep does not alter its bilogical properties (Bruce and others 1994). IN FACT, because it has been possible to isolate BSE infectivity from ovine spleens, when this proved impossible from the spleens of naturally infected BSE cows (Fraser and Foster 1993), experimentally-induced BSE in sheep appears to behave more like the natural disease of scrapie.Whether this putative similarity to natural scrapie extends to the possibility of maternal transmission of experimentally-induced BSE in sheep, has till to be elucidated...







http://web.archive.org/web/20060517075749/http://www.bseinquiry.gov.uk/files/mb/m09/tab01.pdf











TSS

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