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
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
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 HoĖ 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
