Human prion protein sequence elements impede cross-species chronic wasting disease transmission
Human prion protein sequence elements impede cross-species chronic wasting
disease transmission
Timothy D. Kurt,1 Lin Jiang,2 Natalia Fernández-Borges,3 Cyrus Bett,1 Jun
Liu,1 Tom Yang,1 Terry R. Spraker,4 Joaquín Castilla,3,5 David Eisenberg,2
Qingzhong Kong,6 and Christina J. Sigurdson1,7
1Departments of Pathology and Medicine, UCSD, La Jolla, California, USA.
2UCLA-DOE Institute, Howard Hughes Medical Institute, and Molecular Biology
Institute, UCLA, Los Angeles, California, USA. 3CIC bioGUNE, Derio, Spain.
4Department of Microbiology, Immunology and Pathology, Colorado State
University, Fort Collins, Colorado, USA. 5IKERBASQUE, Basque Foundation for
Science, Bilbao, Spain. 6Departments of Pathology and Neurology, and National
Center for Regenerative Medicine, Case Western Reserve University, Cleveland,
Ohio, USA. 7Department of Pathology, Microbiology, and Immunology, UCD, Davis,
California, USA.
Chronic wasting disease (CWD) is a fatal prion disease of North American
deer and elk and poses an unclear risk for transmission to humans. Human
exposure to CWD occurs through hunting activities and consumption of venison
from prioninfected animals. Although the amino acid residues of the prion
protein (PrP) that prevent or permit human CWD infection are unknown, NMR-based
structural studies suggest that the β2-α2 loop (residues 165–175) may impact
species barriers. Here we sought to define PrP sequence determinants that affect
CWD transmission to humans. We engineered transgenic mice that express human PrP
with four amino acid substitutions that result in expression of PrP with a β2-α2
loop (residues 165–175) that exactly matches that of elk PrP. Compared with
transgenic mice expressing unaltered human PrP, mice expressing the human-elk
chimeric PrP were highly susceptible to elk and deer CWD prions but were
concurrently less susceptible to human Creutzfeldt-Jakob disease prions. A
systematic in vitro survey of amino acid differences between humans and cervids
identified two additional residues that impacted CWD conversion of human PrP.
This work identifies amino acids that constitute a substantial structural
barrier for CWD transmission to humans and helps illuminate the molecular
requirements for cross-species prion transmission.
Elucidating the determinants of cross-species prion transmission. Prions
can transmit between different species; however, infection of a new species is
typically characterized by prolonged, variable incubation periods and low attack
rates (41, 42). Known determinants of interspecies prion conversion are (a) PrPC
and PrPSc sequence similarity and (b) the conformation of the infectious prion
(43, 44). Here we propose to add a third determinant, the presence of glutamines
or asparagines in host PrPC within key interaction segments. These key segments
will vary depending upon exposure in the PrPSc conformation. We found that human
PrP with the E168Q and S170N substitutions was readily converted by CWD, whereas
adding the N174T substitution, which increases homology with elk CWD but removes
an asparagine, paradoxically led to a massive decrease in conversion. These
results suggest that for CWD, the β2-α2 segment is accessible and interacts with
host PrPC. These data also indicate that the presence of N/Qs in the loop can be
a strong determinant for conversion that overrides certain sequence
differences.
Glutamine- and asparagine-rich protein segments are proposed to play a role
in protein aggregation due to side chain hydrogen bonding among amide groups
that stabilizes adjacent β-strands (45–47). Asparagine residues are prevalent in
the PrPC of bank voles, a species that is highly susceptible to CWD, sheep
scrapie, and CJD, despite having many PrPC sequence mismatches with these
infectious prions (48–51). Indeed, bank voles were recently designated the
“universal acceptor for prions” (36). Similar to the bank vole, hamsters are
susceptible to CWD and other prions (42, 52–54) and also have an N/Q-rich loop.
Thus, it is possible that the bank vole–like sequence in the human β2-α2 loop
creates a permissive host PrPC sequence that is converted by prions from other
species, despite sequence mismatches. Consistent with the observation that N/Q
residues lead to a lower species barrier, fewer N/Qs in key segments may be
protective, as polymorphisms that replace a single N/Q residue — for example,
Q168R in sheep PrPC (55, 56), Q219K in mouse PrPC (30), and Q219K in goat PrPC
(57) (all human numbering) — correlate with profound resistance to certain
prions in vivo.
Accumulating evidence suggests that the β2-α2 loop governs certain prion
transmission barriers and conformational properties, reminiscent of Sup35 yeast
prion segments, also shown to govern species barriers and strains (58). In
transgenic mice, S170N and N174T loop substitutions increased susceptibility to
CWD and hamster prions, led to resistance to sheep or cattle prions, and altered
the RML mouse prion conformation (59). Here we show that replacing four human
amino acids in the β2-α2 loop enabled infection with elk CWD and created a
partial barrier for human CJD, as evidenced by the delayed infection kinetics.
Additionally, HuPrPelk166–174-CJD showed a different glycosylation pattern as
compared with human CJD prions, suggesting the emergence of a new CJD
conformation. Surprisingly, passage of HuPrPelk166–174-CWD prions revealed
efficient infection of all Tg(HuPrPelk166–174) mice, but not Tg(HuPrP) mice,
despite only four amino acid differences in PrP.
snip...
In conclusion, we have identified the β2-α2 loop sequence of human PrPC as
a major barrier to PrP conversion by CWD prions. The human-specific residues in
the β2-α2 loop, particularly E168 and S170, appear to substantially raise the
energetic barrier for conversion of human PrP by CWD prions, making conversion
of sarhuman PrP highly unfavorable. Thus we propose the β2-α2 loop as a critical
initial PrPC-PrPSc interaction site during the templating of human PrPC by
either CWD or CJD prions. Although we cannot exclude the involvement of
additional PrP segments that include 143 and 155, the β2-α2 loop may act as an
important gatekeeper that promotes or impairs conversion, depending on the
sequence (58). Since the loop substitutions in human PrP also markedly delayed
infection with CJD, the β2-α2 loop segment may also be a key site for PrPC-CJD
prion interaction and may indicate a potential therapeutic target for rationally
designed stable peptides (63, 64) or inhibitors that block PrPC-PrPSc
interaction and impede the progression of prion disease.
snip...
Discussion In 1996, ten cases of new variant CJD were reported in the UK
with suspected links to the BSE epidemic (37, 38), and extensive evidence now
supports that cattle BSE crossed the species barrier and infected humans (39,
40). With the realization that animal prions could transmit to humans, concerns
arose that CWD in cervids may lead to cases of a novel form of CJD.
Nevertheless, four laboratories have independently reported that transgenic mice
expressing human PrP resist CWD infection, suggestive of a strong barrier to
infection (9–12). Here we have identified the specific residues in human PrP
that modulate CWD transmission. We report that CWD transmits to mice expressing
a human-elk chimeric PrPC and show that the CWD-human species barrier is largely
maintained by the humanspecific amino acids within the β2-α2 loop. Within the
loop, human residues E168 and S170 are significant inhibitors of CWD conversion,
as evidenced by in vitro conversion experiments. Human residues S143 and H155
likely also contribute to the CWD barrier. Collectively, these results help
define the structural barriers that limit CWD transmission to humans.
snip...
In conclusion, we have identified the β2-α2 loop sequence of human PrPC as
a major barrier to PrP conversion by CWD prions. The human-specific residues in
the β2-α2 loop, particularly E168 and S170, appear to substantially raise the
energetic barrier for conversion of human PrP by CWD prions, making conversion
of sarhuman PrP highly unfavorable. Thus we propose the β2-α2 loop as a critical
initial PrPC-PrPSc interaction site during the templating of human PrPC by
either CWD or CJD prions. Although we cannot exclude the involvement of
additional PrP segments that include 143 and 155, the β2-α2 loop may act as an
important gatekeeper that promotes or impairs conversion, depending on the
sequence (58). Since the loop substitutions in human PrP also markedly delayed
infection with CJD, the β2-α2 loop segment may also be a key site for PrPC-CJD
prion interaction and may indicate a potential therapeutic target for rationally
designed stable peptides (63, 64) or inhibitors that block PrPC-PrPSc
interaction and impede the progression of prion disease.
snip...see full text ;
with TSE Prions, never say never...tss
every time some scientist claims an absolute about a TSE prion, it mutates,
or science evolves further, and proves them wrong again.
like old typical scrapie would not, has not, transmitted to humans, when
most science was saying otherwise, and now we have another study showing that
indeed the potential for typical scrapie to transmit to man has been here all
along. i am also, reminded of what one of the prion Gods said long ago about
Scrapie and TSE prion, and also the myth that Scrapie genotypes ARR/ARQ and
ARR/ARR are resistant.
Tuesday, December 16, 2014
Evidence for zoonotic potential of ovine scrapie prions
Hervé Cassard,1, n1 Juan-Maria Torres,2, n1 Caroline Lacroux,1, Jean-Yves
Douet,1, Sylvie L. Benestad,3, Frédéric Lantier,4, Séverine Lugan,1, Isabelle
Lantier,4, Pierrette Costes,1, Naima Aron,1, Fabienne Reine,5, Laetitia
Herzog,5, Juan-Carlos Espinosa,2, Vincent Beringue5, & Olivier Andréoletti1,
Affiliations Contributions Corresponding author Journal name: Nature
Communications Volume: 5, Article number: 5821 DOI: doi:10.1038/ncomms6821
Received 07 August 2014 Accepted 10 November 2014 Published 16 December 2014
Article tools Citation Reprints Rights & permissions Article metrics
Abstract
Although Bovine Spongiform Encephalopathy (BSE) is the cause of variant
Creutzfeldt Jakob disease (vCJD) in humans, the zoonotic potential of scrapie
prions remains unknown. Mice genetically engineered to overexpress the human
prion protein (tgHu) have emerged as highly relevant models for gauging the
capacity of prions to transmit to humans. These models can propagate human
prions without any apparent transmission barrier and have been used used to
confirm the zoonotic ability of BSE. Here we show that a panel of sheep scrapie
prions transmit to several tgHu mice models with an efficiency comparable to
that of cattle BSE. The serial transmission of different scrapie isolates in
these mice led to the propagation of prions that are phenotypically identical to
those causing sporadic CJD (sCJD) in humans. These results demonstrate that
scrapie prions have a zoonotic potential and raise new questions about the
possible link between animal and human prions.
Subject terms: Biological sciences• Medical research At a glance
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
Suspect symptoms
What if you can catch old-fashioned CJD by eating meat from a sheep
infected with scrapie?
28 Mar 01 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...
2001
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.
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.
Friday, January 30, 2015
*** Scrapie: a particularly persistent pathogen ***
>>> genotypes ARR/ARQ and ARR/ARR are resistant
Resistance to scrapie in PrP ARR/ARQ heterozygous sheep is not caused by
preferential allelic use
P A Caplazi, K I O’Rourke, T V Baszler
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . .
J Clin Pathol 2004;57:647–650. doi: 10.1136/jcp.2003.012203
Background: In sheep, susceptibility to scrapie, which is similar to human
prion diseases such as Kuru and variant Creutzfeldt-Jakob disease (vCJD), is
determined by prion protein (PrP) gene (Prnp) polymorphisms. Sheep with genotype
ARQ/ARQ, denoting polymorphisms at codons 136, 154, and 171, are susceptible,
whereas those with genotypes ARR/ARQ and ARR/ARR are resistant, indicating
dominance of ARR over the ARQ allele.
Aims: Based on familial CJD E200K, 129V, where preferential use of the 200E
allele in EK heterozygous individuals confers resistance, heterozygous ARR/ARQ
sheep were used to test the hypothesis that resistance is caused by preferential
use of the ARR allele.
Methods: After assessment of equivalent PrP expression across genotypes,
allele use was analysed by sequencing reverse transcription polymerase chain
reaction derived DNA clones containing the Prnp gene coding sequence. Results:
The ARR to ARQ ratio was 1.1 in 133 clones, representing Prnp mRNA from three
ARR/ARQ sheep, indicating equal use of both alleles.
Conclusions: Dominance of the resistant associated allele in sheep scrapie
involves mechanisms other than the absence of PrP derived from the disease
associated ARQ allele.
>>>We report here the identification and characterization of 2
natural classic scrapie cases in sheep of the ARR/ARR genotype, which are
clearly different from BSE and atypical scrapie.
Classic Scrapie in Sheep with the ARR/ARR Prion Genotype in Germany and
France
Martin H. Groschup,*1 Caroline Lacroux,†1 Anne Buschmann,* Gesine Lühken,‡
Jacinthe Mathey,† Martin Eiden,* Séverine Lugan,† Christine Hoffmann,* Juan
Carlos Espinosa,§ Thierry Baron,¶ Juan Maria Torres,§ Georg Erhardt,‡ and
Olivier Andreoletti†
In the past, natural scrapie and bovine spongiform encephalopathy (BSE)
infections have essentially not been diagnosed in sheep homozygous for the
A136R154R171 haplotype of the prion protein. This genotype was therefore assumed
to confer resistance to BSE and classic scrapie under natural exposure
conditions. Hence, to exclude prions from the human food chain, massive breeding
efforts have been undertaken in the European Union to amplify this gene. We
report the identifi cation of 2 natural scrapie cases in ARR/ARR sheep that have
biochemical and transmission characteristics similar to cases of classic
scrapie, although the abnormally folded prion protein (PrPSc) was associated
with a lower proteinase-K resistance. PrPSc was clearly distinct from BSE prions
passaged in sheep and from atypical scrapie prions. These findings strongly
support the idea that scrapie prions are a mosaic of agents, which harbor
different biologic properties, rather than a unique entity.
snip...
However, the successful transmission of BSE prions to ARR/ARR sheep showed
that the resistance of this genotype toward the TSE agent was not absolute (11).
Recently, the identification of previously unrecognized so-called atypical
scrapie in sheep of various genotypes, including ARR/ARR, has reinforced this
statement (4).
***We report here the identification and characterization of 2 natural
classic scrapie cases in sheep of the ARR/ARR genotype, which are clearly
different from BSE and atypical scrapie.
snip...
see full text ;
2011-06-16-110 Prion disease update 2011 (06) To: (06) Transmissible
spongiform encephalopathies *************************************************
PRION DISEASE UPDATE 2011 (06) ****************************** A ProMED-mail post
<http://www.promedmail.org>
Archive Number 20100312.0803 Published Date 12-MAR-2010 Subject
PRO/AH/EDR> Scrapie, atypical, ovine - Australia: (WA) susp
SCRAPIE, ATYPICAL, OVINE - AUSTRALIA: (WESTERN AUSTRALIA) SUSPECTED
*******************************************************************
A ProMED-mail post
ProMED-mail is a program of the International Society for Infectious
Diseases
[1] Date: Fri 12 Mar 2010 Source: The Australian [edited]
A West Australian sheep has been found to have signs characteristic of the
fatal brain disease atypical scrapie. It comes as Australia faces growing anger
from its trade partners over the Rudd government's surprise decision to extend a
ban on the importation of beef from countries exposed to mad cow disease for a
further 2 years.
Australia's chief veterinarian, Andy Carroll, told the ABC an indicative
case of the atypical scrapie had been confirmed but said it posed no risk to
human or animal health or the safety of eating meat and animal products.
Nor does atypical scrapie carry the dire trade consequences associated with
classical scrapie.
Classical scrapie is in the same transmissible spongiform encephalopathies
(TSE) family as BSE, better known as mad cow disease, from which humans can be
fatally infected.
Dr Carroll said samples from the sheep's brain were being sent to the World
Reference Laboratory in Britain.
Neither atypical scrapie nor classical scrapie has been seen in Australia
before, but a sheep in New Zealand tested positive to the atypical form last
year [2009].
Atypical scrapie is a relatively recently discovered disease and the common
scientific view is that it occurs spontaneously or naturally in very small
numbers of older sheep in countries all over the world.
[Byline: Jodie Minus]
-- Communicated by: Sabine Zentis Castleview Pedigree English Longhorns Gut
Laach 52385 Nideggen Germany
****** [2] Date: Wed 10 Mar 2010 Source: ABC News (Australian Broadcasting
Corporation) [edited]
Animal health authorities are testing a sheep's brain for what could be
Australia's 1st case of the disease atypical scrapie.
Although not confirmed, the sheep is thought to be from Western
Australia.
This type of scrapie is described as a sporadic degenerative brain
condition affecting older sheep, and is not contagious.
Ed Klim, from national advisory group SafeMeat, says a 2nd round of testing
is now taking place. "We've been made aware that the Australian Animal Health
Laboratory is conducting further routine testing on a sheep sample," he
says.
"The disease isn't considered a health risk nor should have any impact on
food safety or export markets for sheep meat of live sheep."
Australia's chief veterinarian and WA's Department of Agriculture of Food
are both aware of the testing but will not comment.
-- Communicated by: Terry S Singeltary Sr
[Although atypical scrapie is not yet ruled out, it is important to realize
this is a type of scrapie that thus far has only tended to appear as a sporadic
condition in older animals. Currently it has not been shown to follow the same
genetic tendencies for propagation as the usual scrapie.
However, the atypical phenotypic appearance has been shown to be preserved
on experimental passage.
Atypical scrapie was first identified in Norwegian sheep in 1998 and has
subsequently been identified in many countries, as Australia may join that list.
It is likely that this case will be sent to the UK for definitive
conformation.
[Ref: M Simmons, T Konold, L Thurston, et al. BMC Veterinary Research 2010,
6:14 [provisional abstract available at ]
"Background ----------- "Retrospective studies have identified cases
predating the initial identification of this form of scrapie, and
epidemiological studies have indicated that it does not conform to the behaviour
of an infectious disease, giving rise to the hypothesis that it represents
spontaneous disease. However, atypical scrapie isolates have been shown to be
infectious experimentally, through intracerebral inoculation in transgenic mice
and sheep. [Many of the neurological diseases can be transmitted by
intracerebral inoculation, which causes this moderator to approach intracerebral
studies as a tool for study, but not necessarily as a direct indication of
transmissibility of natural diseases. - Mod.TG]
"The 1st successful challenge of a sheep with 'field' atypical scrapie from
an homologous donor sheep was reported in 2007.
"Results -------- "This study demonstrates that atypical scrapie has
distinct clinical, pathological, and biochemical characteristics which are
maintained on transmission and sub-passage, and which are distinct from other
strains of transmissible spongiform encephalopathies in the same host
genotype.
"Conclusions ------------ Atypical scrapie is consistently transmissible
within AHQ homozygous sheep, and the disease phenotype is preserved on
sub-passage."
Lastly, this moderator wishes to thank Terry Singletary for some of his
behind the scenes work of providing citations and references for this posting. -
Mod.TG]
The HealthMap/ProMED-mail interactive map of Australia is available at . -
Sr.Tech.Ed.MJ]
Worryingly, a substantial proportion of such cases involved sheep with PrP
genotypes known until now to confer natural resistance to conventional scrapie.
Here we report that both Nor98 and discordant cases, including three sheep
homozygous for the resistant PrPARR allele (A136R154R171), efficiently
transmitted the disease to transgenic mice expressing ovine PrP, and that they
shared unique biological and biochemical features upon propagation in mice.
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.
snip...
Sunday, August 19, 2012
Susceptibility of cattle to the agent of chronic wasting disease from elk
after intracranial inoculation 2012
Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES Location: Virus and Prion Research
Unit
Thursday, November 21, 2013
*** Assessing the susceptibility of transgenic mice over-expressing deer
prion protein to bovine spongiform encephalopathy
The present study was designed to assess the susceptibility of the
prototypic mouse line, Tg(CerPrP)1536+/- to bovine spongiform encephalopathy
(BSE) prions, which have the ability to overcome species barriers.
Tg(CerPrP)1536+/- mice challenged with red deer-adapted BSE resulted in a
90-100% attack rates, BSE from cattle failed to transmit, indicating agent
adaptation in the deer.
*** The potential impact of prion diseases on human health was greatly
magnified by the recognition that interspecies transfer of BSE to humans by beef
ingestion resulted in vCJD. While changes in animal feed constituents and
slaughter practices appear to have curtailed vCJD, there is concern that CWD of
free-ranging deer and elk in the U.S. might also cross the species barrier.
Thus, consuming venison could be a source of human prion disease. Whether BSE
and CWD represent interspecies scrapie transfer or are newly arisen prion
diseases is unknown. Therefore, the possibility of transmission of prion disease
through other food animals cannot be ruled out. There is evidence that vCJD can
be transmitted through blood transfusion. There is likely a pool of unknown size
of asymptomatic individuals infected with vCJD, and there may be asymptomatic
individuals infected with the CWD equivalent. These circumstances represent a
potential threat to blood, blood products, and plasma supplies.
NOW, what is the latest on human risk factors to CWD strains ???
*** PPo3-7: Prion Transmission from Cervids to Humans is Strain-dependent
*** Here we report that a human prion strain that had adopted the cervid
prion protein (PrP) sequence through passage in cervidized transgenic mice
efficiently infected transgenic mice expressing human PrP,
*** indicating that the species barrier from cervid to humans is prion
strain-dependent and humans can be vulnerable to novel cervid prion strains.
PPo2-27:
Generation of a Novel form of Human PrPSc by Inter-species Transmission of
Cervid Prions
*** Our findings suggest that CWD prions have the capability to infect
humans, and that this ability depends on CWD strain adaptation, implying that
the risk for human health progressively increases with the spread of CWD among
cervids.
PPo2-7:
Biochemical and Biophysical Characterization of Different CWD Isolates
*** The data presented here substantiate and expand previous reports on the
existence of different CWD strains.
Envt.07:
Pathological Prion Protein (PrPTSE) in Skeletal Muscles of Farmed and Free
Ranging White-Tailed Deer Infected with Chronic Wasting Disease
***The presence and seeding activity of PrPTSE in skeletal muscle from
CWD-infected cervids suggests prevention of such tissue in the human diet as a
precautionary measure for food safety, pending on further clarification of
whether CWD may be transmissible to humans.
>>>CHRONIC WASTING DISEASE , THERE WAS NO ABSOLUTE BARRIER TO
CONVERSION OF THE HUMAN PRION PROTEIN<<<
*** PRICE OF CWD TSE PRION POKER GOES UP 2014 ***
Transmissible Spongiform Encephalopathy TSE PRION update January 2, 2014
Wednesday, January 01, 2014
Molecular Barriers to Zoonotic Transmission of Prions
*** chronic wasting disease, there was no absolute barrier to conversion of
the human prion protein.
*** Furthermore, the form of human PrPres produced in this in vitro assay
when seeded with CWD, resembles that found in the most common human prion
disease, namely sCJD of the MM1 subtype.
PRION2013 CONGRESSIONAL ABSTRACTS CWD
Sunday, August 25, 2013
HD.13: CWD infection in the spleen of humanized transgenic mice
***These results indicate that the CWD prion may have the potential to
infect human peripheral lymphoid tissues.
Oral.15: Molecular barriers to zoonotic prion transmission: Comparison of
the ability of sheep, cattle and deer prion disease isolates to convert normal
human prion protein to its pathological isoform in a cell-free system
***However, they also show that there is no absolute barrier to conversion of
human prion protein in the case of chronic wasting disease.
PRION2013 CONGRESSIONAL ABSTRACTS CWD
Sunday, August 25, 2013
***Chronic Wasting Disease CWD risk factors, humans, domestic cats, blood,
and mother to offspring transmission
there is in fact evidence that the potential for cwd transmission to humans
can NOT be ruled out.
I thought your readers and hunters and those that consume the venison,
should have all the scientific facts, personally, I don’t care what you eat, but
if it effects me and my family down the road, it should then concern everyone,
and the potential of iatrogenic transmission of the TSE prion is real i.e.
‘friendly fire’, medical, surgical, dental, blood, tissue, and or products there
from...like deer antler velvet and TSE prions and nutritional supplements there
from, all a potential risk factor that should not be ignored or silenced. ...
the prion gods at the cdc state that there is ;
''no strong evidence''
but let's see exactly what the authors of this cwd to human at the cdc
state ;
now, let’s see what the authors said about this casual link, personal
communications years ago. see where it is stated NO STRONG evidence. so, does
this mean there IS casual evidence ????
“Our conclusion stating that we found no strong evidence of CWD
transmission to humans”
From: TSS (216-119-163-189.ipset45.wt.net)
Subject: CWD aka MAD DEER/ELK TO HUMANS ???
Date: September 30, 2002 at 7:06 am PST
From: "Belay, Ermias"
To:
Cc: "Race, Richard (NIH)" ; ; "Belay, Ermias"
Sent: Monday, September 30, 2002 9:22 AM
Subject: RE: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Dear Sir/Madam,
In the Archives of Neurology you quoted (the abstract of which was attached
to your email), we did not say CWD in humans will present like variant CJD.
That assumption would be wrong. I encourage you to read the whole article
and call me if you have questions or need more clarification (phone:
404-639-3091). Also, we do not claim that "no-one has ever been infected with
prion disease from eating venison." Our conclusion stating that we found no
strong evidence of CWD transmission to humans in the article you quoted or in
any other forum is limited to the patients we investigated.
Ermias Belay, M.D. Centers for Disease Control and Prevention
-----Original Message-----
From:
Sent: Sunday, September 29, 2002 10:15 AM
To: rr26k@nih.gov; rrace@niaid.nih.gov; ebb8@CDC.GOV
Subject: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Sunday, November 10, 2002 6:26 PM ......snip........end..............TSS
Thursday, April 03, 2008
A prion disease of cervids: Chronic wasting disease
2008 1: Vet Res. 2008 Apr 3;39(4):41
A prion disease of cervids: Chronic wasting disease
Sigurdson CJ.
snip...
*** twenty-seven CJD patients who regularly consumed venison were reported
to the Surveillance Center***,
snip...
full text ;
***********CJD REPORT 1994 increased risk for consumption of veal and
venison and lamb***********
CREUTZFELDT JAKOB DISEASE SURVEILLANCE IN THE UNITED KINGDOM THIRD ANNUAL
REPORT AUGUST 1994
Consumption of venison and veal was much less widespread among both cases
and controls. For both of these meats there was evidence of a trend with
increasing frequency of consumption being associated with increasing risk of
CJD. (not nvCJD, but sporadic CJD...tss)
These associations were largely unchanged when attention was restricted to
pairs with data obtained from relatives. ...
Table 9 presents the results of an analysis of these data.
There is STRONG evidence of an association between ‘’regular’’ veal eating
and risk of CJD (p = .0.01).
Individuals reported to eat veal on average at least once a year appear to
be at 13 TIMES THE RISK of individuals who have never eaten veal.
There is, however, a very wide confidence interval around this estimate.
There is no strong evidence that eating veal less than once per year is
associated with increased risk of CJD (p = 0.51).
The association between venison eating and risk of CJD shows similar
pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK
OF CJD (p = 0.04).
There is some evidence that risk of CJD INCREASES WITH INCREASING FREQUENCY
OF LAMB EATING (p = 0.02).
The evidence for such an association between beef eating and CJD is weaker
(p = 0.14). When only controls for whom a relative was interviewed are included,
this evidence becomes a little STRONGER (p = 0.08).
snip...
It was found that when veal was included in the model with another
exposure, the association between veal and CJD remained statistically
significant (p = < 0.05 for all exposures), while the other exposures ceased
to be statistically significant (p = > 0.05).
snip...
In conclusion, an analysis of dietary histories revealed statistical
associations between various meats/animal products and INCREASED RISK OF CJD.
When some account was taken of possible confounding, the association between
VEAL EATING AND RISK OF CJD EMERGED AS THE STRONGEST OF THESE ASSOCIATIONS
STATISTICALLY. ...
snip...
In the study in the USA, a range of foodstuffs were associated with an
increased risk of CJD, including liver consumption which was associated with an
apparent SIX-FOLD INCREASE IN THE RISK OF CJD. By comparing the data from 3
studies in relation to this particular dietary factor, the risk of liver
consumption became non-significant with an odds ratio of 1.2 (PERSONAL
COMMUNICATION, PROFESSOR A. HOFMAN. ERASMUS UNIVERSITY, ROTTERDAM). (???...TSS)
snip...see full report ;
Thursday, October 10, 2013
*************CJD REPORT 1994 increased risk for consumption of veal and
venison and lamb**************
CJD9/10022
October 1994
Mr R.N. Elmhirst Chairman British Deer Farmers Association Holly Lodge
Spencers Lane BerksWell Coventry CV7 7BZ
Dear Mr Elmhirst,
CREUTZFELDT-JAKOB DISEASE (CJD) SURVEILLANCE UNIT REPORT
Thank you for your recent letter concerning the publication of the third
annual report from the CJD Surveillance Unit. I am sorry that you are
dissatisfied with the way in which this report was published.
The Surveillance Unit is a completely independant outside body and the
Department of Health is committed to publishing their reports as soon as they
become available. In the circumstances it is not the practice to circulate the
report for comment since the findings of the report would not be amended. In
future we can ensure that the British Deer Farmers Association receives a copy
of the report in advance of publication.
The Chief Medical Officer has undertaken to keep the public fully informed
of the results of any research in respect of CJD. This report was entirely the
work of the unit and was produced completely independantly of the the
Department.
The statistical results reqarding the consumption of venison was put into
perspective in the body of the report and was not mentioned at all in the press
release. Media attention regarding this report was low key but gave a realistic
presentation of the statistical findings of the Unit. This approach to
publication was successful in that consumption of venison was highlighted only
once by the media ie. in the News at one television proqramme.
I believe that a further statement about the report, or indeed statistical
links between CJD and consumption of venison, would increase, and quite possibly
give damaging credence, to the whole issue. From the low key media reports of
which I am aware it seems unlikely that venison consumption will suffer
adversely, if at all.
http://web.archive.org/web/20030511010117/http://www.bseinquiry.gov.uk/files/yb/1994/10/00003001.pdf
*** our results raise the possibility that CJD cases classified as VV1 may
include cases caused by iatrogenic transmission of sCJD-MM1 prions or food-borne
infection by type 1 prions from animals, e.g., chronic wasting disease prions in
cervid. In fact, two CJD-VV1 patients who hunted deer or consumed venison have
been reported (40, 41). The results of the present study emphasize the need for
traceback studies and careful re-examination of the biochemical properties of
sCJD-VV1 prions. ***
snip...see full text ;
Thursday, January 2, 2014
*** CWD TSE Prion in cervids to hTGmice, Heidenhain Variant
Creutzfeldt-Jacob Disease MM1 genotype, and iatrogenic CJD ??? ***
*** We hypothesize that both BSE prions and CWD prions passaged through
felines will seed human recPrP more efficiently than BSE or CWD from the
original hosts, evidence that the new host will dampen the species barrier
between humans and BSE or CWD. The new host effect is particularly relevant as
we investigate potential means of trans-species transmission of prion disease.
Monday, August 8, 2011
*** Susceptibility of Domestic Cats to CWD Infection ***
Oral.29: Susceptibility of Domestic Cats to CWD Infection
Amy Nalls, Nicholas J. Haley, Jeanette Hayes-Klug, Kelly Anderson, Davis M.
Seelig, Dan S. Bucy, Susan L. Kraft, Edward A. Hoover and Candace K.
Mathiason†
Colorado State University; Fort Collins, CO USA†Presenting author; Email:
ckm@lamar.colostate.edu
Domestic and non-domestic cats have been shown to be susceptible to one
prion disease, feline spongiform encephalopathy (FSE), thought to be transmitted
through consumption of bovine spongiform encephalopathy (BSE) contaminated meat.
Because domestic and free ranging felids scavenge cervid carcasses, including
those in CWD affected areas, we evaluated the susceptibility of domestic cats to
CWD infection experimentally. Groups of n = 5 cats each were inoculated either
intracerebrally (IC) or orally (PO) with CWD deer brain homogenate. Between
40–43 months following IC inoculation, two cats developed mild but progressive
symptoms including weight loss, anorexia, polydipsia, patterned motor behaviors
and ataxia—ultimately mandating euthanasia. Magnetic resonance imaging (MRI) on
the brain of one of these animals (vs. two age-matched controls) performed just
before euthanasia revealed increased ventricular system volume, more prominent
sulci, and T2 hyperintensity deep in the white matter of the frontal hemisphere
and in cortical grey distributed through the brain, likely representing
inflammation or gliosis. PrPRES and widely distributed peri-neuronal vacuoles
were demonstrated in the brains of both animals by immunodetection assays. No
clinical signs of TSE have been detected in the remaining primary passage cats
after 80 months pi. Feline-adapted CWD was sub-passaged into groups (n=4 or 5)
of cats by IC, PO, and IP/SQ routes. Currently, at 22 months pi, all five IC
inoculated cats are demonstrating abnormal behavior including increasing
aggressiveness, pacing, and hyper responsiveness.
*** Two of these cats have developed rear limb ataxia. Although the limited
data from this ongoing study must be considered preliminary, they raise the
potential for cervid-to-feline transmission in nature.
AD.63:
Susceptibility of domestic cats to chronic wasting disease
Amy V.Nalls,1 Candace Mathiason,1 Davis Seelig,2 Susan Kraft,1 Kevin
Carnes,1 Kelly Anderson,1 Jeanette Hayes-Klug1 and Edward A. Hoover1 1Colorado
State University; Fort Collins, CO USA; 2University of Minnesota; Saint Paul, MN
USA
Domestic and nondomestic cats have been shown to be susceptible to feline
spongiform encephalopathy (FSE), almost certainly caused by consumption of
bovine spongiform encephalopathy (BSE)-contaminated meat. Because domestic and
free-ranging nondomestic felids scavenge cervid carcasses, including those in
areas affected by chronic wasting disease (CWD), we evaluated the susceptibility
of the domestic cat (Felis catus) to CWD infection experimentally. Cohorts of 5
cats each were inoculated either intracerebrally (IC) or orally (PO) with
CWD-infected deer brain. At 40 and 42 mo post-inoculation, two IC-inoculated
cats developed signs consistent with prion disease, including a stilted gait,
weight loss, anorexia, polydipsia, patterned motor behaviors, head and tail
tremors, and ataxia, and progressed to terminal disease within 5 mo. Brains from
these two cats were pooled and inoculated into cohorts of cats by IC, PO, and
intraperitoneal and subcutaneous (IP/SC) routes. Upon subpassage, feline-adapted
CWD (FelCWD) was transmitted to all IC-inoculated cats with a decreased
incubation period of 23 to 27 mo. FelCWD was detected in the brains of all the
symptomatic cats by western blotting and immunohistochemistry and abnormalities
were seen in magnetic resonance imaging, including multifocal T2 fluid
attenuated inversion recovery (FLAIR) signal hyper-intensities, ventricular size
increases, prominent sulci, and white matter tract cavitation. Currently, 3 of 4
IP/SQ and 2 of 4 PO inoculared cats have developed abnormal behavior patterns
consistent with the early stage of feline CWD.
*** These results demonstrate that CWD can be transmitted and adapted to
the domestic cat, thus raising the issue of potential cervid-to- feline
transmission in nature.
www.landesbioscience.com
PO-081: Chronic wasting disease in the cat— Similarities to feline
spongiform encephalopathy (FSE)
FELINE SPONGIFORM ENCEPHALOPATHY FSE
Saturday, January 31, 2015
European red deer (Cervus elaphus elaphus) are susceptible to Bovine
Spongiform Encephalopathy BSE by Oral Alimentary route
*** Singeltary reply ;
ruminant feed ban for cervids in the United States ?
31 Jan 2015 at 20:14 GMT
Friday, January 30, 2015
*** Scrapie: a particularly persistent pathogen ***
Tuesday, January 06, 2015
APHIS Provides Additional Information on Chronic Wasting Disease (CWD)
Indemnity Requests January 5, 2015 05:26 PM EST
TSS
posted by Terry S. Singeltary Sr. at
9:21 AM
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