Chronic Wasting Disease CWD TSE prion and human animal risk factor there from
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.
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.
*** 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.
The most common Prnp genotype in deer, which is also the most susceptible
to CWD infection, is widely shared across cervid taxa, and the common elk
genotype differs from deer only at codon 226. None of the cervid Prnp genotypes
described are highly diverged from the known susceptible genotypes (Fig. 1),
suggesting that Prnp divergence alone is unlikely to provide a strong barrier to
CWD transmission between species and that complete resistance is unlikely for
any specific genotype.
snip...
In addition to variability in the agent and mode of infection, host
differences beyond genotype can have substantial impacts on CWD infection. Both
age and sex are important predictors of CWD infection rates in deer.79,80
Current evidence suggests that higher CWD prevalence in males is likely due to
differences in behavior and exposure, rather than innate susceptibility.79,80 In
both Odocoileus species infection rates increase with age, as is characteristic
of a chronic disease where cumulative risk increases with time of exposure.
Implications and Opportunities for Future Research Disease risk. There is much
debate over whether a partial genetic resistance to CWD infection, or delayed
progression, might have positive or negative effects on disease dynamics on the
landscape. On the one hand, CWD infection rates may be substantially lower in
some genotypes, reducing the prevalence of CWD and disease impacts on the
affected population. These less-susceptible genotypes may gain a survival
advantage over other genotypes.20 Yet, because the infectious state may be
prolonged, these animals could disproportionately contribute to environmental
contamination and transmission to susceptible animals.18,81 Future research is
needed to determine whether all genotypes shed infectious material at similar
rates. We currently understand little about the relative importance of direct
vs. environmental routes of transmission in wild cervid populations. It will be
important to understand the ways in which these routes interact with Prnp types
to influence CWD infection and progression of disease. In addition to the mode
of contact, the biological source of infectious material may have an impact on
infectivity. It is unknown whether cervid species have different sensitivities
to particular agent conformations, genotypes or strains. Additionally, though we
know that cross-species infection is possible between elk, mule deer and
white-tailed deer, we do not understand the level of transmissibility of agent
between these species, or to other mammals in the ecosystem.82 Newly developed
laboratory methods including PMCA,27,83 shaking assays,84 and cell-free
conversions32 may provide insights on this question.
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
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
PPo3-7:
Prion Transmission from Cervids to Humans is Strain-dependent
Qingzhong Kong, Shenghai Huang,*Fusong Chen, Michael Payne, Pierluigi
Gambetti and Liuting Qing Department of Pathology; Case western Reserve
University; Cleveland, OH USA *Current address: Nursing Informatics; Memorial
Sloan-Kettering Cancer Center; New York, NY USA
Key words: CWD, strain, human transmission
Chronic wasting disease (CWD) is a widespread prion disease in cervids
(deer and elk) in North America where significant human exposure to CWD is
likely and zoonotic transmission of CWD is a concern. Current evidence indicates
a strong barrier for transmission of the classical CWD strain to humans with the
PrP-129MM genotype. A few recent reports suggest the presence of two or more CWD
strains. What remain unknown is whether individuals with the PrP-129VV/MV
genotypes are also resistant to the classical CWD strain and whether humans are
resistant to all natural or adapted cervid prion strains. 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. Preliminary results on CWD transmission in transgenic mice
expressing human PrP-129V will also be discussed.
Acknowledgement Supported by NINDS NS052319 and NIA AG14359.
PPo2-27:
Generation of a Novel form of Human PrPSc by Inter-species Transmission of
Cervid Prions
Marcelo A. Barria,1 Glenn C. Telling,2 Pierluigi Gambetti,3 James A.
Mastrianni4 and Claudio Soto1 1Mitchell Center for Alzheimer’s disease and
related Brain disorders; Dept of Neurology; University of Texas Houston Medical
School; Houston, TX USA; 2Dept of Microbiology, Immunology & Molecular
Genetics and Neurology; Sanders Brown Center on Aging; University of Kentucky
Medical Center; Lexington, KY USA; 3Institute of Pathology; Case western Reserve
University; Cleveland, OH USA; 4Dept of Neurology; University of Chicago;
Chicago, IL USA
Prion diseases are infectious neurodegenerative disorders affecting humans
and animals that result from the conversion of normal prion protein (PrPC) into
the misfolded and infectious prion (PrPSc). Chronic wasting disease (CWD) of
cervids is a prion disorder of increasing prevalence within the United States
that affects a large population of wild and captive deer and elk. CWD is highly
contagious and its origin, mechanism of transmission and exact prevalence are
currently unclear. The risk of transmission of CWD to humans is unknown.
Defining that risk is of utmost importance, considering that people have been
infected by animal prions, resulting in new fatal diseases. To study the
possibility that human PrPC can be converted into the infectious form by CWD
PrPSc we performed experiments using the Protein Misfolding Cyclic Amplification
(PMCA) technique, which mimic in vitro the process of prion replication. Our
results show that cervid PrPSc can induce the pathological conversion of human
PrPC, but only after the CWD prion strain has been stabilized by successive
passages in vitro or in vivo. Interestingly, this newly generated human PrPSc
exhibits a distinct biochemical pattern that differs from any of the currently
known forms of human PrPSc, indicating that it corresponds to a novel human
prion strain. 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
Martin L. Daus and Michael Beekes Robert Koch Institute; Berlin,
Germany
Key words: CWD, strains, FT-IR, AFM
Chronic wasting disease (CWD) is one of three naturally occurring forms of
prion disease. The other two are Creutzfeldt-Jakob disease in humans and scrapie
in sheep. CWD is contagious and affects captive as well as free ranging cervids.
As long as there is no definite answer of whether CWD can breach the species
barrier to humans precautionary measures especially for the protection of
consumers need to be considered. In principle, different strains of CWD may be
associated with different risks of transmission to humans. Sophisticated strain
differentiation as accomplished for other prion diseases has not yet been
established for CWD. However, several different findings indicate that there
exists more than one strain of CWD agent in cervids. We have analysed a set of
CWD isolates from white-tailed deer and could detect at least two biochemically
different forms of disease-associated prion protein PrPTSE. Limited proteolysis
with different concentrations of proteinase K and/or after exposure of PrPTSE to
different pH-values or concentrations of Guanidinium hydrochloride resulted in
distinct isolate-specific digestion patterns. Our CWD isolates were also
examined in protein misfolding cyclic amplification studies. This showed
different conversion activities for those isolates that had displayed
significantly different sensitivities to limited proteolysis by PK in the
biochemical experiments described above. We further applied Fourier transform
infrared spectroscopy in combination with atomic force microscopy. This
confirmed structural differences in the PrPTSE of at least two disinct CWD
isolates. The data presented here substantiate and expand previous reports on
the existence of different CWD strains.
2012
Envt.06:
Zoonotic Potential of CWD: Experimental Transmissions to Non-Human Primates
Emmanuel Comoy,1,† Valérie Durand,1 Evelyne Correia,1 Aru Balachandran,2
Jürgen Richt,3 Vincent Beringue,4 Juan-Maria Torres,5 Paul Brown,1 Bob Hills6
and Jean-Philippe Deslys1
1Atomic Energy Commission; Fontenay-aux-Roses, France; 2Canadian Food
Inspection Agency; Ottawa, ON Canada; 3Kansas State University; Manhattan, KS
USA; 4INRA; Jouy-en-Josas, France; 5INIA; Madrid, Spain; 6Health Canada; Ottawa,
ON Canada
†Presenting author; Email: emmanuel.comoy@cea.fr
The constant increase of chronic wasting disease (CWD) incidence in North
America raises a question about their zoonotic potential. A recent publication
showed their transmissibility to new-world monkeys, but no transmission to
old-world monkeys, which are phylogenetically closer to humans, has so far been
reported. Moreover, several studies have failed to transmit CWD to transgenic
mice overexpressing human PrP. Bovine spongiform encephalopathy (BSE) is the
only animal prion disease for which a zoonotic potential has been proven. We
described the transmission of the atypical BSE-L strain of BSE to cynomolgus
monkeys, suggesting a weak cattle-to-primate species barrier. We observed the
same phenomenon with a cattleadapted strain of TME (Transmissible Mink
Encephalopathy). Since cattle experimentally exposed to CWD strains have also
developed spongiform encephalopathies, we inoculated brain tissue from
CWD-infected cattle to three cynomolgus macaques as well as to transgenic mice
overexpressing bovine or human PrP. Since CWD prion strains are highly
lymphotropic, suggesting an adaptation of these agents after peripheral
exposure, a parallel set of four monkeys was inoculated with CWD-infected cervid
brains using the oral route. Nearly four years post-exposure, monkeys exposed to
CWD-related prion strains remain asymptomatic. In contrast, bovinized and
humanized transgenic mice showed signs of infection, suggesting that CWD-related
prion strains may be capable of crossing the cattle-to-primate species barrier.
Comparisons with transmission results and incubation periods obtained after
exposure to other cattle prion strains (c-BSE, BSE-L, BSE-H and cattle-adapted
TME) will also be presented, in order to evaluate the respective risks of each
strain.
Envt.07:
Pathological Prion Protein (PrPTSE) in Skeletal Muscles of Farmed and Free
Ranging White-Tailed Deer Infected with Chronic Wasting Disease
Martin L. Daus,1,† Johanna Breyer,2 Katjs Wagenfuehr,1 Wiebke Wemheuer,2
Achim Thomzig,1 Walter Schulz-Schaeffer2 and Michael Beekes1 1Robert Koch
Institut; P24 TSE; Berlin, Germany; 2Department of Neuropathology, Prion and
Dementia Research Unit, University Medical Center Göttingen; Göttingen, Germany
†Presenting author; Email: dausm@rki.de
Chronic wasting disease (CWD) is a contagious, rapidly spreading
transmissible spongiform encephalopathy (TSE) occurring in cervids in North
America. Despite efficient horizontal transmission of CWD among cervids natural
transmission of the disease to other species has not yet been observed. Here, we
report a direct biochemical demonstration of pathological prion protein PrPTSE
and of PrPTSE-associated seeding activity in skeletal muscles of CWD-infected
cervids. The presence of PrPTSE was detected by Western- and postfixed frozen
tissue blotting, while the seeding activity of PrPTSE was revealed by protein
misfolding cyclic amplification (PMCA). The concentration of PrPTSE in skeletal
muscles of CWD-infected WTD was estimated to be approximately 2000- to
10000-fold lower than in brain tissue. Tissue-blot-analyses revealed that PrPTSE
was located in muscle- associated nerve fascicles but not, in detectable
amounts, in myocytes. 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.
P.10.15
ADAPTATION OF CHRONIC WASTING DISEASE (CWD) INTO HAMSTERS, EVIDENCE OF A
WISCONSIN STRAIN OF CWD
Chad Johnson1, Judd Aiken2,3,4 and Debbie McKenzie4,5 1 Department of
Comparative Biosciences, University of Wisconsin, Madison WI, USA 53706 2
Department of Agriculture, Food and Nutritional Sciences, 3 Alberta Veterinary
Research Institute, 4.Center for Prions and Protein Folding Diseases, 5
Department of Biological Sciences, University of Alberta, Edmonton AB, Canada
T6G 2P5
The identification and characterization of prion strains is increasingly
important for the diagnosis and biological definition of these infectious
pathogens. Although well-established in scrapie and, more recently, in BSE,
comparatively little is known about the possibility of prion strains in chronic
wasting disease (CWD), a disease affecting free ranging and captive cervids,
primarily in North America. We have identified prion protein variants in the
white-tailed deer population and demonstrated that Prnp genotype affects the
susceptibility/disease progression of white-tailed deer to CWD agent. The
existence of cervid prion protein variants raises the likelihood of distinct CWD
strains. Small rodent models are a useful means of identifying prion strains. We
intracerebrally inoculated hamsters with brain homogenates and phosphotungstate
concentrated preparations from CWD positive hunter-harvested (Wisconsin CWD
endemic area) and experimentally infected deer of known Prnp genotypes. These
transmission studies resulted in clinical presentation in primary passage of
concentrated CWD prions. Subclinical infection was established with the other
primary passages based on the detection of PrPCWD in the brains of hamsters and
the successful disease transmission upon second passage. Second and third
passage data, when compared to transmission studies using different CWD inocula
(Raymond et al., 2007) indicate that the CWD agent present in the Wisconsin
white-tailed deer population is different than the strain(s) present in elk,
mule-deer and white-tailed deer from the western United States endemic
region.
CHRONIC WASTING DISEASE CWD
Transmissibility to humans.
The current state of epidemiological research suggests a rather robust
barrier for the transmission of CWD to humans. Particularly, the surveillance of
human prion diseases in areas with a long history of endemic CWD such as
Colorado and Wyoming did not reveal evidence for zoonotic transmissions of the
disease to cervid hunters or consumers of meat from elk and deer.66. Belay ED,
Maddox RA, Williams ES, Miller MW, Gambetti P, Schonberger LB. Chronic wasting
disease and potential transmission to humans. Emerg Infect Dis 2004; 10:977 -
984; PMID: 15207045 [CrossRef] View all references,1111. Belay ED, Abrams J,
Kenfield J, Weidenbach K, Maddox RA, Lawaczeck E, et al. Monitoring the
potential transmission of chronic wasting disease to humans (Abstract Oral.40,
Prion 2011 Oral Presentations). Prion 2011; 5:17 Supplemental Issue
April/May/June 2011 View all references
However, as discussed by Belay et al.66. Belay ED, Maddox RA, Williams ES,
Miller MW, Gambetti P, Schonberger LB. Chronic wasting disease and potential
transmission to humans. Emerg Infect Dis 2004; 10:977 - 984; PMID: 15207045
[CrossRef] View all references
the intensity of human exposure to CWD prions may increase due to a further
spread and rising prevalence of the disease in cervids. Therefore, and with the
generally long latency periods of human prion diseases in mind, previous
epidemiological findings cannot be readily extrapolated. Until recently,
experimental studies that pursued biochemical approaches or used transgenic mice
to ascertain the susceptibility of humans to CWD infections consistently seemed
to corroborate current epidemiological findings: CWD-infected cervid brain
tissue did not seed the conversion of PrPC into PrPres in PMCA assays using
brain homogenate from macaques or transgenic mice expressing human PrPC as test
substrate,1212. Kurt TD, Telling GC, Zabel MD, Hoover EA. Trans-species
amplification of PrP(CWD) and correlation with rigid loop 170N. Virology 2009;
387:235 - 243; PMID: 19269662; http://dx.doi.org/10.1016/j.virol.2009.02.025
[CrossRef] View all references
and transgenic mice overexpressing human PrPC were resistant to infection
after intracerebral challenge with CWD prions from mule deer.1313. Sandberg MK,
Al-Doujaily H, Sigurdson CJ, Glatzel M, O'Malley C, Powell C, et al. Chronic
wasting disease prions are not transmissible to transgenic mice overexpressing
human prion protein. J Gen Virol 2010; 91:2651 - 2657; PMID: 20610667; http://dx.doi.org/10.1099/vir.0.024380-0
[CrossRef] View all references
However, a study published by Barria et al.1414. Barria MA, Telling GC,
Gambetti P, Mastrianni JA, Soto C. Generation of a new form of human PrPSc in
vitro by interspecies transmission from cervid prions. J Biol Chem 2011;
286:7490 - 7495; PMID: 21209079; http://dx.doi.org/10.1074/jbc.M110.198465
[CrossRef] View all references
in March 2011 found that cervid PrPTSE can seed the conversion of human
PrPC into PrPres by PMCA when the CWD agent has been previously passaged in
vitro or in vivo. Specifically, this was demonstrated for CWD prions from
naturally affected mule deer either passaged by serial PMCA using deer PrPC as
conversion substrate or in transgenic mice expressing cervid PrPC. The authors
of this study pointed out that CWD prions may undergo a gradual process of
change and adaptation via successive passages in the cervid population. They
concluded that the reported findings, if corroborated by infectivity assays, may
imply “that CWD prions have the potential to infect humans and that this ability
progressively increases with CWD spreading.” Cynomolgus macaques used as a
primate model for testing the susceptibility of humans to CWD as close to
reality as possible have not shown clinical signs of a prion disease at nearly 6
years after intracerebral or peroral inoculation of CWD agents from white-tailed
deer, Rocky Mountain elk or mule deer.1515. Race B, Meade-White KD, Miller MW,
Barbian KD, Rubenstein R, LaFauci G, et al. Susceptibilities of nonhuman
primates to chronic wasting disease. Emerg Infect Dis 2009; 15:1366 - 1376;
PMID: 19788803; http://dx.doi.org/10.3201/eid1509.090253
[CrossRef] View all references
In contrast to macaques, squirrel monkeys were susceptible to CWD infection
by the intracerebral route and showed even a low rate of disease transmission
after oral challenge.1515. Race B, Meade-White KD, Miller MW, Barbian KD,
Rubenstein R, LaFauci G, et al. Susceptibilities of nonhuman primates to chronic
wasting disease. Emerg Infect Dis 2009; 15:1366 - 1376; PMID: 19788803; http://dx.doi.org/10.3201/eid1509.090253
[CrossRef] View all references,1616. Marsh RF, Kincaid AE, Bessen RA, Bartz JC.
Interspecies transmission of chronic wasting disease prions to squirrel monkeys
(Saimiri sciureus). J Virol 2005; 79:13794 - 13796; PMID: 16227298; http://dx.doi.org/10.1128/JVI.79.21.13794-6.2005
[CrossRef] View all references
Since humans are phylogenetically closer related to macaques than to
squirrel monkeys, macaques are regarded as the more relevant primate model for
assessing the zoonotic transmissibility of CWD.1515. Race B, Meade-White KD,
Miller MW, Barbian KD, Rubenstein R, LaFauci G, et al. Susceptibilities of
nonhuman primates to chronic wasting disease. Emerg Infect Dis 2009; 15:1366 -
1376; PMID: 19788803; http://dx.doi.org/10.3201/eid1509.090253
[CrossRef] View all references
Ongoing transmission studies in macaques. In addition to the primate study
by Race et al.1515. Race B, Meade-White KD, Miller MW, Barbian KD, Rubenstein R,
LaFauci G, et al. Susceptibilities of nonhuman primates to chronic wasting
disease. Emerg Infect Dis 2009; 15:1366 - 1376; PMID: 19788803; http://dx.doi.org/10.3201/eid1509.090253
[CrossRef] View all references
two further studies in which macaques were challenged with tissue
homogenates from CWD-affected cervids by intracerebral inoculation or via the
oral route have been reported to be in progress.1717. Comoy E, Durand V, Correia
E, Balachandran A, Richt JA, Beringue V, et al. Zoonotic potential of CWD:
Experimental transmissions to non-human primates (Abstract Envt.06, Prion 2011
Poster Presentations). Prion 2011; 5:101 View all references,1818. Motzkus D,
Schulz-Schaeffer WJ, Beekes M, Schätzl HM, Jirik FR, Schmädicke AC, et al.
Transmission of CWD to non-human primates: Interim results of a comprehensive
study on the transmissibility to humans (Abstract Envt. 22, Prion 2011 Poster
Presentations). Prion 2011; 5:107 Supplemental Issue April/May/June 2011 View
all references
The purpose, research effort, financial investment and ethical aspects of
these studies demand an utmost experimental scrutiny, careful data analysis and
thorough exploitation of results. This has two immediate implications: (1) Since
the incubation period of CWD may be very long in case of primary (i.e.,
inter-species) transmission to macaques a sustained monitoring of the animals
appears mandatory for many years despite negative interim findings. (2)
Increasing evidence suggests the existence of different CWD agents (see below),
and theoretically, CWD prions may also change over time thereby possibly
altering their potential host range. Thus, CWD isolates used in individual or
pooled inocula for the challenge of macaques should be typed as precisely as
possible in terms of their strain characteristics and molecular identity. Other
field isolates could then be checked for their similarity or dissimilarity to
the macaque-tested CWD agents in order to ascertain whether or not they are
covered by the ongoing primate risk assessments. Evidence for Distinct CWD
Strains Jump to section Transmissible Spongiform... Exposure of Humans to CWD
Prions CWD Risk Assessments Evidence for Distinct CWD Strains Outlook Disclosure
of Potential Conflicts of Interest Funding Figures and Tables Biochemical
indications for isolate-dependent structural differences of PrPTSE. In 2002 it
was reported that glycoform patterns of PrPTSE showed differences among
individual CWD-affected cervids.1919. Race RE, Raines A, Baron TG, Miller MW,
Jenny A, Williams ES. Comparison of abnormal prion protein glycoform patterns
from transmissible spongiform encephalopathy agent-infected deer, elk, sheep and
cattle. J Virol 2002; 76:12365 - 12368; PMID: 12414979; http://dx.doi.org/10.1128/JVI.76.23.12365-8.2002
[CrossRef] View all references
In a variety of studies the glycosylation of PrPTSE had been previously
established as a biochemical feature that may differ between distinct TSE
agents.2020. Parchi P, Capellari S, Chen SG, Petersen RB, Gambetti P, Kopp N, et
al. Typing prion isoforms. Nature 1997; 386:232 - 234; PMID: 9069279; http://dx.doi.org/10.1038/386232a0
[CrossRef] View all references,2121. Aguzzi A, Heikenwalder M, Polymenidou M.
Insights into prion strains and neurotoxicity. Nat Rev Mol Cell Biol 2007; 8:552
- 561; PMID: 17585315; http://dx.doi.org/10.1038/nrm2204
[CrossRef] View all references
Accordingly, the finding by Race et al. possibly indicated CWD infections
with different or multiple strains of agent, although, alternatively, it could
also be explained by random selection from a heterogeneous population of
CWD-affected ruminants.1919. Race RE, Raines A, Baron TG, Miller MW, Jenny A,
Williams ES. Comparison of abnormal prion protein glycoform patterns from
transmissible spongiform encephalopathy agent-infected deer, elk, sheep and
cattle. J Virol 2002; 76:12365 - 12368; PMID: 12414979; http://dx.doi.org/10.1128/JVI.76.23.12365-8.2002
[CrossRef] View all references
Using a conformation-dependent immunoassay (CDI), Safar et al. found
evidence for different conformations of PrPTSE in elk CWD as compared with
white-tailed and mule deer CWD.2222. Safar JG, Scott M, Monaghan J, Deering C,
Didorenko S, Vergara J, et al. Measuring prions causing bovine spongiform
encephalopathy or chronic wasting disease by immunoassays and transgenic mice.
Nat Biotechnol 2002; 20:1147 - 1150; PMID: 12389035; http://dx.doi.org/10.1038/nbt748
[CrossRef] View all references
However, the amino acid sequences of elk and deer PrPC differ at residues
226 (glutamic acid in elk and glutamine in deer), and it remained to be
established whether the structural differences detected by CDI were related to
biologically distinct CWD strains. Isolation of CWD-associated agents causing
distinct phenotypes in laboratory rodents. Classically, prion strains are
differentiated based on their incubation periods in inbred mice with distinct
PrP genotypes and by lesion profiles of the vacuolation in selected brain areas
of reporter animals.2323. Bruce ME, Fraser H. Scrapie strain variation and its
implications. Curr Top Microbiol Immunol 1991; 172:125 - 138; PMID: 1810707
[CrossRef] View all references
When Raymond et al. serially passaged a CWD inoculum from mule deer either
in Syrian hamsters or first into transgenic mice expressing hamster PrPC, and
then further on in hamsters, they obtained two distinct isolates termed
SghaCWDmd-f and SghaCWDmd-s, respectively.2424. Raymond GJ, Raymond LD,
Meade-White KD, Hughson AG, Favara C, Gardner D, et al. Transmission and
adaptation of chronic wasting disease to hamsters and transgenic mice: evidence
for strains. J Virol 2007; 81:4305 - 4314; PMID: 17287284; http://dx.doi.org/10.1128/JVI.02474-06
[CrossRef] View all references
The first isolate showed an about 5-fold shorter incubation period in
Syrian hamsters than the latter, and the cerebral patterns of PrPTSE deposition
and gliosis in clinically affected hamsters were also different. Based on their
findings the authors concluded that the “cervid-derived inocula may have
contained or diverged into at least two distinct transmissible spongiform
encephalopathy strains.” Angers et al. transmitted CWD inocula from elk and deer
to transgenic mice expressing cervid PrP and found that these mice were affected
by one of two strains, referred to as CWD1 and CWD2, that caused different
incubation times and lesion profiles.2525. Angers RC, Kang HE, Napier D,
Browning S, Seward T, Mathiason C, et al. Prion strain mutation determined by
prion protein conformational compatibility and primary structure. Science 2010;
328:1154 - 1158; PMID: 20466881; http://dx.doi.org/10.1126/science.1187107
[CrossRef] View all references
The results of this study “appear to reflect strain constitutions in the
natural host, rather than adaptation and divergence of progenitor strains in
recipient mice,” according to the authors. Interestingly, CWD1 and CWD2 did not
show recognizably different biochemical properties of their PrPTSE. The
electrophoretic migration and glycosylation patterns as well as the stability
characteristics after treatment with guanidine hydrochloride were
indistinguishable for CWD1- and CWD2-associated PrPTSE. Consistent with these
findings it has been previously reported that biologically distinct prion
strains cannot always be differentiated by biochemical PrPTSE-typing or
characterization of the conformational stability of PrPTSE.2626. Thomzig A,
Spassov S, Friedrich M, Naumann D, Beekes M. Discriminating scrapie and bovine
spongiform encephalopathy isolates by infrared spectroscopy of pathological
prion protein. J Biol Chem 2004; 279:33847 - 33854; PMID: 15155741; http://dx.doi.org/10.1074/jbc.M403730200
[CrossRef] View all references,2727. Peretz D, Scott MR, Groth D, Williamson RA,
Burton DR, Cohen FE, et al. Strain-specified relative conformational stability
of the scrapie prion protein. Protein Sci 2001; 10:854 - 863; PMID: 11274476; http://dx.doi.org/10.1110/ps.39201
[CrossRef] View all references
UPDATED DATA ON 2ND CWD STRAIN Wednesday, September 08, 2010 CWD PRION
CONGRESS SEPTEMBER 8-11 2010
OR-12: Chronic wasting disease transmission and pathogenesis in cervid and
non-cervid Species
Edward A. Hoover, Candace K. Mathiason, Nicholas J. Haley, Timothy D. Kurt,
Davis M. Seelig, Nathaniel D. Denkers, Amy V. Nalls, Mark D. Zabel, and Glenn C.
Telling
Prion Research Program, Department of Microbiology, Immunology, and
Pathology; Colorado State University; Fort Collins, CO USA
Since its recognition as a TSE in the late 1970s, chronic wasting disease
(CWD) of cervids has been distinguished by its facile spread and is now
recognized in 18 states, 2 Canadian provinces, and South Korea. The efficient
horizontal spread of CWD reflects a prion/host relationship that facilitates
efficient mucosal uptake, peripheral lymphoid amplification, and dissemination
by exploiting excretory tissues and their products, helping to establish
indirect/environmental and well as direct (e.g., salivary) transmission. Recent
studies from our group also support the likelihood of early life mother to
offspring and aerosol CWD prion transmission. Studies of cervid CWD exposure by
natural routes indicate that incubation period for detection of overt infection,
while still uncertain, may be much longer than originally thought.
Several non-cervid species can be infected by CWD experimentally (e.g.,
ferrets, voles, cats) with consequent species-specific disease phenotypes. The
species-adapted prions so generated can be transmitted by mucosal, i.e., more
natural, routes. Whether non-cervid species sympatric with deer/elk can be
infected in nature, however, remains unknown. In vitro CWD prion amplification
studies, in particular sPMCA, can foreshadow in vivo susceptibility and suggest
the importance of the PrPC rigid loop region in species barrier permissiveness.
Trans-species CWD amplification appears to broaden the host range/strain
characteristics of the resultant prions. The origins of CWD remain unknown,
however, the existence of multiple CWD prion strains/ quasi-species, the
mechanisms of prion shedding/dissemination, and the relationship between sheep
scrapie and CWD merit further investigation.
Monday, May 23, 2011
CDC Assesses Potential Human Exposure to Prion Diseases Travel Warning
Public release date: 23-May-2011
Contact: Francesca Costanzo adajmedia@elsevier.com 215-239-3249 Elsevier
Health Sciences
CDC assesses potential human exposure to prion diseases Study results
reported in the Journal of the American Dietetic Association Philadelphia, PA,
May 23, 2011 – Researchers from the Centers for Disease Control and Prevention
(CDC) have examined the potential for human exposure to prion diseases, looking
at hunting, venison consumption, and travel to areas in which prion diseases
have been reported in animals. Three prion diseases in particular – bovine
spongiform encephalopathy (BSE or “Mad Cow Disease”), variant Creutzfeldt-Jakob
disease (vCJD), and chronic wasting disease (CWD) – were specified in the
investigation. The results of this investigation are published in the June issue
of the Journal of the American Dietetic Association.
“While prion diseases are rare, they are generally fatal for anyone who
becomes infected. More than anything else, the results of this study support the
need for continued surveillance of prion diseases,” commented lead investigator
Joseph Y. Abrams, MPH, National Center for Emerging and Zoonotic Infectious
Diseases, CDC, Atlanta.”But it’s also important that people know the facts about
these diseases, especially since this study shows that a good number of people
have participated in activities that may expose them to infection-causing
agents.”
Although rare, human prion diseases such as CJD may be related to BSE.
Prion (proteinaceous infectious particles) diseases are a group of rare brain
diseases that affect humans and animals. When a person gets a prion disease,
brain function is impaired. This causes memory and personality changes,
dementia, and problems with movement. All of these worsen over time. These
diseases are invariably fatal. Since these diseases may take years to manifest,
knowing the extent of human exposure to possible prion diseases could become
important in the event of an outbreak.
CDC investigators evaluated the results of the 2006-2007 population survey
conducted by the Foodborne Diseases Active Surveillance Network (FoodNet). This
survey collects information on food consumption practices, health outcomes, and
demographic characteristics of residents of the participating Emerging
Infections Program sites. The survey was conducted in Connecticut, Georgia,
Maryland, Minnesota, New Mexico, Oregon, and Tennessee, as well as five counties
in the San Francisco Bay area, seven counties in the Greater Denver area, and 34
counties in western and northeastern New York.
Survey participants were asked about behaviors that could be associated
with exposure to the agents causing BSE and CWD, including travel to the nine
countries considered to be BSE-endemic (United Kingdom, Republic of Ireland,
France, Portugal, Switzerland, Italy, the Netherlands, Germany, Spain) and the
cumulative length of stay in each of those countries. Respondents were asked if
they ever had hunted for deer or elk, and if that hunting had taken place in
areas considered to be CWD-endemic (northeastern Colorado, southeastern Wyoming
or southwestern Nebraska). They were also asked if they had ever consumed
venison, the frequency of consumption, and whether the meat came from the
wild.
The proportion of survey respondents who reported travel to at least one of
the nine BSE endemic countries since 1980 was 29.5%. Travel to the United
Kingdom was reported by 19.4% of respondents, higher than to any other
BSE-endemic country. Among those who traveled, the median duration of travel to
the United Kingdom (14 days) was longer than that of any other BSE-endemic
country. Travelers to the UK were more likely to have spent at least 30 days in
the country (24.9%) compared to travelers to any other BSE endemic country. The
prevalence and extent of travel to the UK indicate that health concerns in the
UK may also become issues for US residents.
The proportion of survey respondents reporting having hunted for deer or
elk was 18.5% and 1.2% reported having hunted for deer or elk in CWD-endemic
areas. Venison consumption was reported by 67.4% of FoodNet respondents, and
88.6% of those reporting venison consumption had obtained all of their meat from
the wild. These findings reinforce the importance of CWD surveillance and
control programs for wild deer and elk to reduce human exposure to the CWD
agent. Hunters in CWD-endemic areas are advised to take simple precautions such
as: avoiding consuming meat from sickly deer or elk, avoiding consuming brain or
spinal cord tissues, minimizing the handling of brain and spinal cord tissues,
and wearing gloves when field-dressing carcasses.
According to Abrams, “The 2006-2007 FoodNet population survey provides
useful information should foodborne prion infection become an increasing public
health concern in the future. The data presented describe the prevalence of
important behaviors and their associations with demographic characteristics.
Surveillance of BSE, CWD, and human prion diseases are critical aspects of
addressing the burden of these diseases in animal populations and how that may
relate to human health.”
###
The article is “Travel history, hunting, and venison consumption related to
prion disease exposure, 2006-2007 FoodNet population survey” by Joseph Y.
Abrams, MPH; Ryan A. Maddox, MPH; Alexis R Harvey, MPH; Lawrence B. Schonberger,
MD; and Ermias D. Belay, MD. It appears in the Journal of the American Dietetic
Association, Volume 111, Issue 6 (June 2011) published by Elsevier.
In an accompanying podcast CDC’s Joseph Y. Abrams discusses travel,
hunting, and eating venison in relation to prion diseases. It is available at http://adajournal.org/content/podcast.
Thursday, May 26, 2011
Travel History, Hunting, and Venison Consumption Related to Prion Disease
Exposure, 2006-2007 FoodNet Population Survey
Journal of the American Dietetic Association Volume 111, Issue 6 , Pages
858-863, June 2011.
Travel History, Hunting, and Venison Consumption Related to Prion Disease
Exposure, 2006-2007 FoodNet Population Survey
Joseph Y. Abrams, MPH, Ryan A. Maddox, MPH , Alexis R. Harvey, MPH ,
Lawrence B. Schonberger, MD , Ermias D. Belay, MD
Accepted 15 November 2010. Abstract Full Text PDF References .
Abstract
The transmission of bovine spongiform encephalopathy (BSE) to human beings
and the spread of chronic wasting disease (CWD) among cervids have prompted
concerns about zoonotic transmission of prion diseases. Travel to the United
Kingdom and other European countries, hunting for deer or elk, and venison
consumption could result in the exposure of US residents to the agents that
cause BSE and CWD. The Foodborne Diseases Active Surveillance Network 2006-2007
population survey was used to assess the prevalence of these behaviors among
residents of 10 catchment areas across the United States. Of 17,372 survey
respondents, 19.4% reported travel to the United Kingdom since 1980, and 29.5%
reported travel to any of the nine European countries considered to be
BSE-endemic since 1980. The proportion of respondents who had ever hunted deer
or elk was 18.5%, and 1.2% had hunted deer or elk in a CWD–endemic area. More
than two thirds (67.4%) reported having ever eaten deer or elk meat. Respondents
who traveled spent more time in the United Kingdom (median 14 days) than in any
other BSE-endemic country. Of the 11,635 respondents who had consumed venison,
59.8% ate venison at most one to two times during their year of highest
consumption, and 88.6% had obtained all of their meat from the wild. The survey
results were useful in determining the prevalence and frequency of behaviors
that could be important factors for foodborne prion transmission.
CDC
Saturday, February 18, 2012
Occurrence, Transmission, and Zoonotic Potential of Chronic Wasting Disease
CDC Volume 18, Number 3—March 2012
SNIP…
Interspecies transmission of CWD to noncervids has not been observed under
natural conditions. CWD infection of carcass scavengers such as raccoons,
opossums, and coyotes was not observed in a recent study in Wisconsin (22). In
addition, natural transmission of CWD to cattle has not been observed in
experimentally controlled natural exposure studies or targeted surveillance (2).
However, CWD has been experimentally transmitted to cattle, sheep, goats, mink,
ferrets, voles, and mice by intracerebral inoculation (2,29,33).
CWD is likely transmitted among mule, white-tailed deer, and elk without a
major species barrier (1), and other members of the cervid family, including
reindeer, caribou, and other species of deer worldwide, may be vulnerable to CWD
infection. Black-tailed deer (a subspecies of mule deer) and European red deer
(Cervus elaphus) are susceptible to CWD by natural routes of infection (1,34).
Fallow deer (Dama dama) are susceptible to CWD by intracerebral inoculation
(35). Continued study of CWD susceptibility in other cervids is of considerable
interest.
Reasons for Caution There are several reasons for caution with respect to
zoonotic and interspecies CWD transmission. First, there is strong evidence that
distinct CWD strains exist (36). Prion strains are distinguished by varied
incubation periods, clinical symptoms, PrPSc conformations, and CNS PrPSc
depositions (3,32). Strains have been identified in other natural prion
diseases, including scrapie, BSE, and CJD (3). Intraspecies and interspecies
transmission of prions from CWD-positive deer and elk isolates resulted in
identification of >2 strains of CWD in rodent models (36), indicating that
CWD strains likely exist in cervids. However, nothing is currently known about
natural distribution and prevalence of CWD strains. Currently, host range and
pathogenicity vary with prion strain (28,37). Therefore, zoonotic potential of
CWD may also vary with CWD strain. In addition, diversity in host (cervid) and
target (e.g., human) genotypes further complicates definitive findings of
zoonotic and interspecies transmission potentials of CWD.
Intraspecies and interspecies passage of the CWD agent may also increase
the risk for zoonotic CWD transmission. The CWD prion agent is undergoing serial
passage naturally as the disease continues to emerge. In vitro and in vivo
intraspecies transmission of the CWD agent yields PrPSc with an increased
capacity to convert human PrPc to PrPSc (30). Interspecies prion transmission
can alter CWD host range (38) and yield multiple novel prion strains (3,28). The
potential for interspecies CWD transmission (by cohabitating mammals) will only
increase as the disease spreads and CWD prions continue to be shed into the
environment. This environmental passage itself may alter CWD prions or exert
selective pressures on CWD strain mixtures by interactions with soil, which are
known to vary with prion strain (25), or exposure to environmental or gut
degradation.
Given that prion disease in humans can be difficult to diagnose and the
asymptomatic incubation period can last decades, continued research,
epidemiologic surveillance, and caution in handling risky material remain
prudent as CWD continues to spread and the opportunity for interspecies
transmission increases. Otherwise, similar to what occurred in the United
Kingdom after detection of variant CJD and its subsequent link to BSE, years of
prevention could be lost if zoonotic transmission of CWD is subsequently
identified, CWD will likely continue to emerge in North America. …
SNIP…
Generation of a new form of human PrPSc in vitro by inter-species
transmission from cervids prions
Our results have far-reaching implications for human health, since they
indicate that cervid PrPSc can trigger the conversion of human PrPC into PrPSc,
suggesting that CWD might be infectious to humans. Interestingly our findings
suggest that unstable strains from CWD affected animals might not be a problem
for humans, but upon strain stabilization by successive passages in the wild,
this disease might become progressively more transmissible to man.
Our results also have profound implications for understanding the
mechanisms of the prion species barrier and indicate that the transmission
barrier is a dynamic process that depends on the strain and moreover the degree
of adaptation of the strain. If our findings are corroborated by infectivity
assays, they will imply that CWD prions have the potential to infect humans and
that this ability progressively increases with CWD spreading.
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 ??? ***
*** 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.
*** 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.
*** 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.
Tuesday, November 04, 2014
*** Six-year follow-up of a point-source exposure to CWD contaminated
venison in an Upstate New York community: risk behaviours and health outcomes
2005–2011
www.landesbioscience.com
PO-081: Chronic wasting disease in the cat— Similarities to feline
spongiform encephalopathy (FSE)
FELINE SPONGIFORM ENCEPHALOPATHY FSE
Thursday, July 03, 2014
*** How Chronic Wasting Disease is affecting deer population and what’s the
risk to humans and pets?
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
MAY 2002 431 NEWS
TSE threat to US increases
The US Department of Agriculture last month confirmed that two sheep taken
from a farm in Vermont were infected with a form of transmissible spongiform
encephalopathy (TSE). Further tests are being carried out to determine whether
the disease is bovine spongiform encephalopathy (BSE) or scrapie. The sheep were
imported from the Netherlands (Nature Med. 6, 1301; 2000). Analysis will take at
least two years, and if the prion is that which causes BSE, this would be the
first case of disease in the US.
Aguzzi warns of CWD danger
The TSE family of diseases also includes chronic wasting disease (CWD) in
deer, a condition that has spread in the US in recent years (Nature 416, 569;
2002). Speaking at the Days of Molecular Medicine conference in La Jolla in
March, prion expert Adriano Aguzzi issued a strong warning against
underestimating this form of TSE.
"For more than a decade, the US has by-and-large considered mad cows to be
an exquisitely European problem. The perceived need to protect US citizens from
this alien threat has even prompted the deferral of blood donors from Europe,"
he said. "Yet the threat-from-within posed by CWD needs careful consideration,
since the evidence that CWD is less dangerous to humans than BSE is
less-than-complete. Aguzzi went on to point out that CWD is arguably the most
mysterious of all prion diseases.
"Its horizontal spread among the wild population is exceedingly efficient,
and appears to have reached a prevalence unprecedented even by BSE in the UK at
its peak. The pathogenesis of CWD, therefore, deserves a vigorous research
effort. Europeans also need to think about this problem, and it would be timely
and appropriate to increase CWD surveillance in Europe too." Aguzzi has secured
funding from the National Institutes of Health to investigate CWD, and the
effort will be lead by Christina Sigurdson in his department at the University
of Zurich. KAREN BIRMINGHAM, LONDON
Tachygrams show heart rate variability in BSE animals
snip...
about those mad sheep of mad river valley, the ones from Belgium. please
see ;
Friday, February 20, 2015
APHIS Freedom of Information Act (FOIA) Appeal Mouse Bio-Assays
2007-00030-A Sheep Imported From Belgium and the Presence of TSE Prion Disease
Kevin Shea to Singeltary 2015
Saturday, February 28, 2015
BSE CANADA UPDATE Transcript
February 27, 2015
Monday, February 23, 2015
20th BSE Case Raises New Concerns about Canada's Feeding Practices and
Voluntary Testing Program; Highlights Importance of COOL
Monday, October 10, 2011
EFSA Journal 2011 The European Response to BSE: A Success Story
snip...
EFSA and the European Centre for Disease Prevention and Control (ECDC)
recently delivered a scientific opinion on any possible epidemiological or
molecular association between TSEs in animals and humans (EFSA Panel on
Biological Hazards (BIOHAZ) and ECDC, 2011). This opinion confirmed Classical
BSE prions as the only TSE agents demonstrated to be zoonotic so far
*** but the possibility that a small proportion of human cases so far
classified as "sporadic" CJD are of zoonotic origin could not be excluded.
*** Moreover, transmission experiments to non-human primates suggest that
some TSE agents in addition to Classical BSE prions in cattle (namely L-type
Atypical BSE, Classical BSE in sheep, transmissible mink encephalopathy (TME)
and chronic wasting disease (CWD) agents) might have zoonotic potential.
snip...
Thursday, August 12, 2010
Seven main threats for the future linked to prions
First threat
The TSE road map defining the evolution of European policy for protection
against prion diseases is based on a certain numbers of hypotheses some of which
may turn out to be erroneous. In particular, a form of BSE (called atypical
Bovine Spongiform Encephalopathy), recently identified by systematic testing in
aged cattle without clinical signs, may be the origin of classical BSE and thus
potentially constitute a reservoir, which may be impossible to eradicate if a
sporadic origin is confirmed.
*** Also, a link is suspected between atypical BSE and some apparently
sporadic cases of Creutzfeldt-Jakob disease in humans.
*** These atypical BSE cases constitute an unforeseen first threat that
could sharply modify the European approach to prion diseases.
Second threat
snip...
Wednesday, March 04, 2015
National Scrapie Eradication Report - January 2015 USDA Animal and Plant
Health Inspection Service sent this bulletin at 03/03/2015 03:00 PM EST
Monday, March 02, 2015
Rapid and Sensitive RT-QuIC Detection of Human Creutzfeldt-Jakob Disease
Using Cerebrospinal Fluid
TSS
posted by Terry S. Singeltary Sr. at
5:42 PM
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