Research article
Open Access
Goat K222-PrPC polymorphic variant does not provide resistance to atypical
scrapie in transgenic mice
Patricia Aguilar-Calvo1, 6, Juan-Carlos Espinosa1, Olivier Andréoletti2,
Lorenzo González3, Leonor Orge4, Ramón Juste5 and Juan-María Torres1Email author
Veterinary Research201647:96 DOI: 10.1186/s13567-016-0380-7
© The Author(s) 2016
Received: 11 June 2016
Accepted: 1 September 2016
Published: 22 September 2016
Abstract Host prion (PrPC) genotype is a major determinant for the
susceptibility to prion diseases. The Q/K222-PrPC polymorphic variant provides
goats and mice with high resistance against classical scrapie and bovine
spongiform encephalopathy (BSE); yet its effect against atypical scrapie is
unknown. Here, transgenic mice expressing the goat wild-type (wt) or the
K222-PrPC variant were intracerebrally inoculated with several natural cases of
atypical scrapie from sheep and goat and their susceptibility to the prion
disease was determined. Goat wt and K222-PrPC transgenic mice were 100%
susceptible to all the atypical scrapie isolates, showing similar survival times
and almost identical disease phenotypes. The capacity of the K222-PrPC variant
to replicate specifically the atypical scrapie strain as efficiently as the goat
wt PrPC, but not the classical scrapie or cattle-BSE as previously reported,
further suggests the involvement of concrete areas of the host PrPC in the
strain-dependent replication of prions.
snip...
Susceptibility to prions and disease phenotypes are likely modulated by
conformational properties of prion strains and the PrPC and PrPSc amino acid
sequence [13]. Some host PrPC amino acid sequences may have greater “plasticity”
or ability to misfold—as proposed for the unique susceptibility of bank voles to
a wide variety of prion diseases [14] and to “in vitro” conversion experiments
[15]—while others may show the opposite situation, locking PrPC and preventing
its conversion by different prion strains. Nonetheless, the plasticity of the
host PrPC would not explain why certain amino acid substitutions inhibit the
replication of some prion strains but not others. A clear example is the goat
K222 variant which provides high resistance against classical scrapie and bovine
spongiform encephalopathy (BSE) from cattle—being protective even in
heterozygous mice and goats [5, 6, 9]—but it is as efficient as the goat wt PrPC
in replicating sheep and goat-BSE [5] and atypical scrapie when intracerebrally
inoculated. The resistance of the K222 variant to classical scrapie was
associated to the additional positive charge at codon 222 provided by the lysine
amino acid, which could interfere with the PrPC:PrPSc interaction, abolishing or
lowering the conversion rates of PrPC [16]. Similarly, the perturbations in the
PrPC surface charge distribution and structural rearrangements mainly localized
at the β2–α2 loop region (residues 169–179 in goat PrPC numbering) are likely to
underlie the resistance of the human E/K219 variant against CJD [17].
More recently, the existence of critical initial PrPC–PrPSc interaction
sites during the templating of PrPC by different prions was proposed [18]. The
involvement of specific PrPC areas in the strain-dependent replication of prions
could account for the variable role of the K222-PrPC variant in the
susceptibility to scrapie. While for classical scrapie polymorphic variants
along the PrPC have been associated to modulate the susceptibility to the
disease, for atypical scrapie only few have been reported—A/V136, F/L141, R/H154
and Q/R171 [4, 19]— that, interestingly, are all located within β1–α1 and β2–α2
loops. This area could be the critical segment for atypical scrapie interaction
with the host PrPC and therefore any amino acid exchange outside this segment
would not affect the capacity of replication of the atypical scrapie, as
observed in our transmission study in goat wt and K222-PrPC mice. In fact this
area seems to be accessible in the abnormally folded aggregate of the atypical
scrapie agent as suggested by the observation that the C-terminal part of
atypical scrapie PrPSc can be specifically trimmed by PK [20]. In conclusion,
although more information is still needed to decipher the mechanisms of prion
conversion, our study points to the involvement of specific PrPC areas in the
strain-dependent replication of prions. Thus, strategies to fight prion diseases
based on genotype breeding programs should be prion strain targeted.
*** Grant Agreement number: 222887 ***
*** Project acronym: PRIORITY ***
*** Project title: Protecting the food chain from prions: shaping European
priorities through basic and applied research Funding ***
Scheme: Large-scale integrating project Period covered: from Oct. 1, 2009
to Sept. 30, 2014
Name of the scientific representative of the project's co-ordinator1, Title
and Organisation: Jesús R. Requena, Ph.D., Associate Professor, Department of
medicine, University of Santiago de Compostela, Spàin. Tel: 34-881815464 Fax:
34-881815403 E-mail: jesus.requena@usc.es
Project website¡Error! Marcador no definido. address: www.prionpriority.eu
PRIORITY, PROJECT FINAL REPORT
*** 14) Concluding that atypical scrapie can transmit to Humans and that
its strain properties change as it transmits between species ***
snip...
Block D: Prion epidemiology
Studies on atypical scrapie were identified as a key element of this block,
given the potential risk associated to this agent. We studied the permeability
of Human, bovine and porcine species barriers to atypical scrapie agent
transmission. Experiments in transgenic mice expressing bovine, porcine or human
PrPC suggest that this TSE agent has the intrinsic ability to propagate across
these species barriers including the Human one. Upon species barrier passage the
biological properties and phenotype of atypical scrapie seem to be altered.
Further experiments are currently ongoing (in the framework of this project but
also in other projects) in order to: (i) characterize the properties of the
prion that emerged from the propagation of atypical scrapie in tg Hu; (ii) to
confirm that the phenomena we observed are also true for atypical scrapie
isolates other than the ones we have studied.
In parallel, studies in shep have concluded that:
*** Atypical scrapie can be transmitted by both oral and intracerebral
route in sheep with various PRP genotypes
*** Low but consistent amount of infectivity accumulates in peripheral
tissue (mammary gland, lymph nodes, placenta, skeletal muscles, nerves) of sheep
incubating atypical scrapie.
*** The combination of data from all our studies leads us to conclude that:
*** Atypical scrapie passage through species barriers can lead to the
emergence of various prions including classical BSE (following propagation in
porcine PRP transgenic mice).
*** Atypical scrapie can propagate, with a low efficacy, in human PrP
expressing mice. This suggests the existence of a zoonotic potential for this
TSE agent.
snip...
We advance our main conclusions and recommendations, in particular as they
might affect public policy, including a detailed elaboration of the evidence
that led to them. Our main recommendations are:
a. The issue of re-introducing ruminant protein into the food-chain The
opinion of the members of Priority is that sustaining an absolute feed ban for
ruminant protein to ruminants is the essential requirement, especially since the
impact of non-classical forms of scrapie in sheep and goats is not fully
understood and cannot be fully estimated. Therefore, the consortium strongly
recommends prohibiting re-introduction of processed ruminant protein into the
food-chain. Arguments in support of this opinion are:
• the large (and still uncharacterized) diversity of prion agents that
circulate in animal populations;
• the uncertainties related to prion epidemiology in animal
populations;
• the unknown efficacy of industrial processes applied to reduce
microbiological risk during processed animal protein (PAP) production on most
prion agents; • the intrinsic capacity of prions to cross interspecies
transmission barriers; • the lack of sensitive methodology for identifying cross
contamination in food.
• the evolution of natural food chains in nature (i.e. who eats whom or
what) has generated an efficient barrier preventing, to some extent, novel prion
epidemies and that this naturally evolved ecology should be respected.
The consortium is also hesitant to introduce processed ruminant proteins
into fish food considering the paucity of data on prion infections in fishes and
sea animals including those of mammalian origin, and the risk of establishing an
environmental contamination of the oceans that cannot be controlled.
b. Atypical prion agents and surveillance
Atypical prion agents (see below) will probably continue to represent the
dominant form of prion diseases in the near future, particularly in Europe.
*** Atypical L-type BSE has clear zoonotic potential, as demonstrated in
experimental models.
*** Similarly, there are now some data that seem to indicate that the
atypical scrapie agent can cross various species barriers.
*** Moreover, the current EU policy for eradicating scrapie (genetic
selection in affected flocks) is ineffective for preventing atypical scrapie.
*** The recent identification of cell-to-cell propagation and the
protein-encoded strain properties of human neurodegenerative diseases such as
Alzheimer's disease and Parkinson's disease, suggest that they bear the
potential to be transmissible even if not with the same efficiency as CJD. More
epidemiological data from large cohorts are necessary to reach any conclusion on
the impact of their transmissibility on public health. Re-evaluations of safety
precautions may become necessary depending on the outcome of these studies. In
that context it would appear valuable
• to develop knowledge related to the pathogenesis and inter-individual
transmission of atypical prion agents in ruminants (both intra- and
inter-species)
• to improve the sensitivity of detection assays that are applied in the
field towards this type of agent
• to maintain a robust surveillance of both animal and human populations
c. The need for extended research on prions
Intensified searching for a molecular determinants of the species barrier
is recommended, since this barrier is a key for many important policy areas -
risk assessment, proportional policies, the need for screening of human products
and food. In this respect, prion strain structural language also remains an
important issue for public health for the foreseeable future. Understanding the
structural basis for strains and the basis for adaptation of a strain to a new
host will require continued fundamental research. Prions maintain a complex
two-way relationship with the host cell and fundamental research is needed on
mechanisms for their transmission, replication and cause of nervous system
dysfunction and death.
Early detection of prion infection, ideally at preclinical stage, also
remains crucial for development of effective treatment strategies in humans
affected by the disease.
Position of the Priority consortium
Nearly 30 years ago, the appearance in the UK of Bovine Spongiform
Encephalopathy (BSE) quickly brought the previously obscure “prion diseases” to
the spotlight. The ensuing health and food crises that spread throughout Europe
had devastating consequences. In the UK alone, there were more than 36,000 farms
directly affected by BSE and the transmission of BSE prions to humans via the
food chain has caused over 200 people in Europe to die from variant
Creutzfeldt-Jakob disease (vCJD) (http://www.cjd.ed.ac.uk
Origins of prion epidemies
Classical BSE now appears to be under control, with 18 EU Member States
having achieved the World Organisation for Animal Health (Office International
Epizooties) „negligible risk‟ status (May 2014; http://www.oie.int/en/animal-health-in-the-world/official-disease-status/bse/list-of-bse-risk-status/),
and the remaining MS assessed as „controlled‟ risk. Of note, research, including
EU-funded research, has played a key role in this success: while the origin of
the infection was never defined, the principle driver of the epidemic was
identified as prions in Meat and Bone Meal (MBM). Tests based on prion
protein-specific antibodies were developed, allowing detection of infected
animals, and a better understanding of disease pathogenesis and the distribution
of infectivity in edible tissues; experimental investigation of transmission
barriers between different species allowed a rational estimation of risks, etc.
All of this led to the implementation of rational and effective policies, such
as the MBM ban to protect the animal feed chain, and the Specified Risk Material
(SRM) regulations to protect the human food chain.
In spite of this progress, prions are still a threat. Epidemiological
re-assessment indicates that the ∼10 year incubation period separating the peaks
of the BSE and the vCJD epidemics is probably too short. In addition, results
from a large number of human tonsil and appendix analyses in the UK suggest that
there may be a high number of asymptomatic individuals who are positive for the
disease-associated conformer prion protein PrPSc. While vCJD is the only form of
human prion disease that has been consistently demonstrated to have
lymphoreticular involvement, there has been no systematic investigation of
lymphoid tissue in cases with other prion diseases.
The human prion problem
The clinical cases of vCJD identified to date have all shared a common PrP
genotype (M129M), although one pre-clinical case was confirmed as an M129V
heterozygote, and it has been mooted that perhaps only the M129M proportion of
the population is susceptible. However, in the UK appendix study, PrP
accumulation was described in samples representing every codon 129 genotype,
raising the possibility that genotype does not confer resistance but instead
modulates incubation period. Apart from the two UK studies, the lymphoid tissues
of non-CJD patients have not been examined for the presence of PrPSc, so, these
cases may not solely represent pre-clinical vCJD, but also other forms of prion
disease.
Recent experiments in highly susceptible mouse models indicate the presence
of infectivity in blood or blood components at late disease stages in sporadic
CJD. The significance of this experimental finding for humans has to be explored
in more detail and, at the present time, there is no evidence for the
transmission of prions via blood in sporadic CJD. However a likely scenario is
that all those with signs of infection or abnormal PrP accumulation in
peripheral tissue could have infective blood, posing the risk for transmission
via blood products, which has been clearly demonstrated in experimental models,
and confirmed in several cases of vCJD in man. Altogether, these data clearly
demonstrate the potential risk of a second wave of vCJD, particularly when the
number people identified with lymphoid accumulation of PrPSc (16/32,411) gives a
prevalence estimate in the UK of 493 per million, much higher than the number of
clinical cases seen to date.
The animal prion problem
An increasing number of reports on cases of “atypical” BSE in cattle
throughout the EU and beyond may lead to a new epidemic, particularly since we
still do not understand all factors determining the species barrier. Ovine
scrapie is another concern, because it could mask ovine BSE, presumably
transmissible to humans. Scrapie is endemic and not likely to be eradicated
soon, although current control measures are effective at greatly reducing
disease incidence. Atypical forms, which may be spontaneous, are not affected by
these control measures and these forms of disease will persist in the global
animal population. The low prevalence of these disease forms makes effective
surveillance very challenging. However, there is a clear risk attendant on
ignoring these cases without an understanding of their possible zoonotic
potential, particularly when most forms of human disease have no established
aetiology. In summary, atypical cases of BSE and scrapie presently clearly
outnumber classical cases in cattle and sheep in all member states.
We will highlight the state-of-the-art knowledge and point out scientific
challenges and the major questions for research. Strategic objectives and
priorities in Europe in the future for research that aims to control, eliminate
or eradicate the threat posed by prions to our food and health are also
indicated.
The Priority project has focused on 4 themes, namely the structure,
function, conversion and toxicity of prions; detection of prions; mechanisms of
prion transmission and spreading and epidemiology of prion diseases. This paper
summarizes the opinions/positions reached within these themes at the end of the
project.
Assessment of the PrPc amino-terminal domain in prion species barriers
Kristen A. Davenporta, Davin M. Hendersona, Candace K. Mathiasona and
Edward A. Hoovera# + Author Affiliations
Prion Research Center, Department of Microbiology, Immunology and
Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado
State University, Fort Collins, CO 80523a ABSTRACT Chronic wasting disease (CWD)
in cervids and bovine spongiform encephalopathy (BSE) in cattle are prion
diseases that are caused by the same protein-misfolding mechanism, but appear to
pose different risks to humans. We are interested in understanding the
differences between the species barriers of CWD and BSE. We used real-time,
quaking-induced conversion (RT-QuIC) to model the central molecular event in
prion disease, the templated misfolding of the normal prion protein, PrPc, to a
pathogenic, amyloid isoform, PrPSc. We examined the role of the PrPc
amino-terminal domain (NTD, aa23-90) in cross-species conversion by comparing
the conversion efficiency of various prion seeds in either full-length
(aa23-231) or truncated (aa90-231) PrPc. We demonstrate that the presence of
white-tailed deer and bovine NTDs hindered seeded conversion of PrPc, but human
and bank vole NTDs did the opposite. Additionally, full-length human and bank
vole PrPc were more likely to be converted to amyloid by CWD prions than were
their truncated forms. A chimera with replacement of the human NTD by the bovine
NTD resembled human PrPc. The requirement for an NTD, but not for the specific
human sequence, suggests that the NTD interacts with other regions of the human
PrPc to increase promiscuity. These data contribute to the evidence that, in
addition to primary sequence, prion species barriers are controlled by
interactions of the substrate NTD with the rest of the substrate PrPc molecule.
Importance We demonstrate that the amino-terminal domain of the normal
prion protein, PrPc, hinders seeded conversion of bovine and white-tailed deer
PrPc to the prion form, but it facilitates conversion of the human and bank vole
PrPc to the prion form. Additionally, we demonstrate that the amino-terminal
domain of human and bank vole PrPc requires interaction with the rest of the
molecule to facilitate conversion by CWD prions. These data suggest that
interactions of the amino-terminal domain with the rest of the PrPc molecule
play an important role in the susceptibility of humans to CWD prions.
snip...
We found that human rPrPc can be readily converted to an amyloid state by
CWD prions, and that the NTD facilitates this conversion. As there is little
evidence for the susceptibility of humans to CWD, the biologic significance of
our observation remains to be determined. However, the role of the NTD in this
in vitro phenomenon may be important to the in vivo mechanism as well. RT-QuIC,
transgenic mouse bioassay, and PMCA measure different outcomes. This manuscript
compares the efficiency of initial amyloid formation, while bioassay and PMCA
reflect total accumulation of protease-resistant PrPSc, which may explain the
difference in the apparent susceptibility of full-length human rPrPc in these
models. The molecular underpinnings for species barriers and trans-species prion
conversion remain a complex, yet important problem in prion biology. We propose
that an interaction between the amino terminal
FOOTNOTES
↵#Address correspondence to Edward A. Hoover, edward.hoover@colostate.edu
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
Tuesday, September 27, 2016
Classical Scrapie Diagnosis in ARR/ARR Sheep in Brazil
Acta Scientiae Veterinariae, 2015. 43(Suppl 1): 69.
Wednesday, September 28, 2016
Norway sides with OIE, decides to expose millions of consumers to the
ATYPICAL BSE SRM TSE Prion aka mad cow type disease
Friday, September 23, 2016
North Iceland reporting more cases of Scrapie (Rida)
Monday, September 19, 2016
Identification of the first case of atypical scrapie in Japan
Monday, September 19, 2016
Evidence of scrapie transmission to sheep via goat milk
Tuesday, September 06, 2016
A comparison of classical and H-type bovine spongiform encephalopathy
associated with E211K prion protein polymorphism in wild type and EK211 cattle
following intracranial inoculation
‘’We demonstrate that the presence of white-tailed deer and bovine NTDs
hindered seeded conversion of PrPc, but human and bank vole NTDs did the
opposite. Additionally, full-length human and bank vole PrPc were more likely to
be converted to amyloid by CWD prions than were their truncated forms. ‘’
***Moreover, sporadic disease has never been observed in breeding colonies
or primate research laboratories, most notably among hundreds of animals over
several decades of study at the National Institutes of Health25, and in nearly
twenty older animals continuously housed in our own facility.***
Monday, May 02, 2016
*** Zoonotic Potential of CWD Prions: An Update Prion 2016 Tokyo ***
SCRAPIE AND CWD ZOONOSIS
PRION 2016 CONFERENCE TOKYO
Saturday, April 23, 2016
*** SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016
***
Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X
Saturday, September 24, 2016
Assessment of the PrPc amino-terminal domain in prion species barriers
*** Evidence That Transmissible Mink Encephalopathy Results from Feeding
Infected Cattle ***
Over the next 8-10 weeks, approximately 40% of all the adult mink on the
farm died from TME.
snip...
The rancher was a ''dead stock'' feeder using mostly (>95%) downer or
dead dairy cattle...
In Confidence - Perceptions of unconventional slow virus diseases of
animals in the USA - APRIL-MAY 1989 - G A H Wells
3. Prof. A. Robertson gave a brief account of BSE. The US approach was to
accord it a very low profile indeed. Dr. A Thiermann showed the picture in the
''Independent'' with cattle being incinerated and thought this was a fanatical
incident to be avoided in the US at all costs. ...
”The occurrence of CWD must be viewed against the contest of the locations
in which it occurred. It was an incidental and unwelcome complication of the
respective wildlife research programmes. Despite it’s subsequent recognition as
a new disease of cervids, therefore justifying direct investigation, no specific
research funding was forthcoming. The USDA veiwed it as a wildlife problem and
consequently not their province!” ...page 26.
Scrapie-like disorder in a Nyala (Tragelaphus angasi)
IN CONFIDENCE
Spongiform encephalopathy has so far only been recorded in the sheep and
goat, man, mink, and several deer including the mule deer, black tailed deer and
the elk (most, if not all, of the deer incidents occurred in wild life parts in
Wyoming and Colorado). Clinical cases in deer all occurred from 3 1/2 to 5 years
old and usually 60-80% losses occurred over a 4 year period...
The clinical and neuropathological findings in F22 are consistent with the
spongiform encephalopathies of animals and man. The agents causing spongiform
encephalopathy in various species cannot be unequivocally distinguished and some
isolates of human agent cause neurologic disease in goats indistinguishable from
scrapie. The spongiform encephalopathies are invariably fatal once clinical
signs of disease are evident and as very high fatality rates (79% of 67 animals)
are recorded in Mule deer it is important that an awareness of the disease is
maintained at Marwell.
Thursday, August 04, 2016
MEETING ON THE FEASIBILITY OF CARRYING OUT EPIDEMIOLOGICAL STUDIES ON
CREUTZFELDT JAKOB DISEASE 1978 THE SCRAPIE FILES IN CONFIDENCE CONFIDENTIAL SCJD
snip...
1979
SILENCE ON CJD AND SCRAPIE
1980
SILENCE ON CJD AND SCRAPIE
*** 1981 NOVEMBER
snip...see full text ;
Thursday, August 04, 2016
MEETING ON THE FEASIBILITY OF CARRYING OUT EPIDEMIOLOGICAL STUDIES ON
CREUTZFELDT JAKOB DISEASE 1978 THE SCRAPIE FILES IN CONFIDENCE CONFIDENTIAL SCJD
Scrapie Field Trial Experiments Mission, Texas, The Moore Air Force Base
Scrapie Experiment 1964
How Did CWD Get Way Down In Medina County, Texas?
Confucius ponders...
Could the Scrapie experiments back around 1964 at Moore Air Force near
Mission, Texas, could this area have been ground zero for CWD TSE Prion (besides
the CWD cases that have waltzed across the Texas, New Mexico border near WSMR
Trans Pecos region since around 2001)?
Epidemiology of Scrapie in the United States 1977
snip...
Scrapie Field Trial Experiments Mission, Texas
A Scrapie Field Trial was developed at Mission, Texas, to provide
additional information for the eradication program on the epidemiology of
natural scrapie. The Mission Field Trial Station is located on 450 acres of
pastureland, part of the former Moore Air Force Base, near Mission, Texas. It
was designed to bring previously exposed, and later also unexposed, sheep or
goats to the Station and maintain and breed them under close observation for
extended periods to determine which animals would develop scrapie and define
more closely the natural spread and other epidemiological aspects of the
disease.
The 547 previously exposed sheep brought to the Mission Station beginning
in 1964 were of the Cheviot, Hampshire, Montadale, or Suffolk breeds. They were
purchased as field outbreaks occurred, and represented 21 bloodlines in which
scrapie had been diagnosed. Upon arrival at the Station, the sheep were
maintained on pasture, with supplemental feeding as necessary. The station was
divided into 2 areas: (1) a series of pastures and-pens occupied by male animals
only, and (2) a series of pastures and pens occupied by females and young
progeny of both sexes. ...
snip...see full text ;
P.97: Scrapie transmits to white-tailed deer by the oral route and has a
molecular profile similar to chronic wasting disease and distinct from the
scrapie inoculum
Justin Greenlee1, S Jo Moore1, Jodi Smith1, M Heather West Greenlee2, and
Robert Kunkle1
1National Animal Disease Center; Ames, IA USA;
2Iowa State University; Ames, IA USA
The purpose of this work was to determine susceptibility of white-tailed
deer (WTD) to the agent of sheep scrapie and to compare the resultant PrPSc to
that of the original inoculum and chronic wasting disease (CWD). We inoculated
WTD by a natural route of exposure (concurrent oral and intranasal (IN); n D 5)
with a US scrapie isolate. All scrapie-inoculated deer had evidence of PrPSc
accumulation. PrPSc was detected in lymphoid tissues at preclinical time points,
and deer necropsied after 28 months post-inoculation had clinical signs,
spongiform encephalopathy, and widespread distribution of PrPSc in neural and
lymphoid tissues. Western blotting (WB) revealed PrPSc with 2 distinct molecular
profiles. WB on cerebral cortex had a profile similar to the original scrapie
inoculum, whereas WB of brainstem, cerebellum, or lymph nodes revealed PrPSc
with a higher profile resembling CWD. Homogenates with the 2 distinct profiles
from WTD with clinical scrapie were further passaged to mice expressing cervid
prion protein and intranasally to sheep and WTD. In cervidized mice, the 2
inocula have distinct incubation times. Sheep inoculated intranasally with WTD
derived scrapie developed disease, but only after inoculation with the inoculum
that had a scrapie-like profile. The WTD study is ongoing, but deer in both
inoculation groups are positive for PrPSc by rectal mucosal biopsy. In summary,
this work demonstrates that WTD are susceptible to the agent of scrapie, 2
distinct molecular profiles of PrPSc are present in the tissues of affected
deer, and inoculum of either profile readily passes to deer.
Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Title: Scrapie transmits to white-tailed deer by the oral route and has a
molecular profile similar to chronic wasting disease
Authors
item Greenlee, Justin item Moore, S - item Smith, Jodi - item Kunkle,
Robert item West Greenlee, M -
Submitted to: American College of Veterinary Pathologists Meeting
Publication Type: Abstract Only Publication Acceptance Date: August 12, 2015
Publication Date: N/A Technical Abstract: The purpose of this work was to
determine susceptibility of white-tailed deer (WTD) to the agent of sheep
scrapie and to compare the resultant PrPSc to that of the original inoculum and
chronic wasting disease (CWD). We inoculated WTD by a natural route of exposure
(concurrent oral and intranasal (IN); n=5) with a US scrapie isolate. All
scrapie-inoculated deer had evidence of PrPSc accumulation. PrPSc was detected
in lymphoid tissues at preclinical time points, and deer necropsied after 28
months post-inoculation had clinical signs, spongiform encephalopathy, and
widespread distribution of PrPSc in neural and lymphoid tissues. Western
blotting (WB) revealed PrPSc with 2 distinct molecular profiles. WB on cerebral
cortex had a profile similar to the original scrapie inoculum, whereas WB of
brainstem, cerebellum, or lymph nodes revealed PrPSc with a higher profile
resembling CWD. Homogenates with the 2 distinct profiles from WTD with clinical
scrapie were further passaged to mice expressing cervid prion protein and
intranasally to sheep and WTD. In cervidized mice, the two inocula have distinct
incubation times. Sheep inoculated intranasally with WTD derived scrapie
developed disease, but only after inoculation with the inoculum that had a
scrapie-like profile. The WTD study is ongoing, but deer in both inoculation
groups are positive for PrPSc by rectal mucosal biopsy. In summary, this work
demonstrates that WTD are susceptible to the agent of scrapie, two distinct
molecular profiles of PrPSc are present in the tissues of affected deer, and
inoculum of either profile readily passes to deer.
White-tailed Deer are Susceptible to Scrapie by Natural Route of Infection
Jodi D. Smith, Justin J. Greenlee, and Robert A. Kunkle; Virus and Prion
Research Unit, National Animal Disease Center, USDA-ARS
Interspecies transmission studies afford the opportunity to better
understand the potential host range and origins of prion diseases. Previous
experiments demonstrated that white-tailed deer are susceptible to sheep-derived
scrapie by intracranial inoculation. The purpose of this study was to determine
susceptibility of white-tailed deer to scrapie after a natural route of
exposure. Deer (n=5) were inoculated by concurrent oral (30 ml) and intranasal
(1 ml) instillation of a 10% (wt/vol) brain homogenate derived from a sheep
clinically affected with scrapie. Non-inoculated deer were maintained as
negative controls. All deer were observed daily for clinical signs. Deer were
euthanized and necropsied when neurologic disease was evident, and tissues were
examined for abnormal prion protein (PrPSc) by immunohistochemistry (IHC) and
western blot (WB). One animal was euthanized 15 months post-inoculation (MPI)
due to an injury. At that time, examination of obex and lymphoid tissues by IHC
was positive, but WB of obex and colliculus were negative. Remaining deer
developed clinical signs of wasting and mental depression and were necropsied
from 28 to 33 MPI. Tissues from these deer were positive for scrapie by IHC and
WB. Tissues with PrPSc immunoreactivity included brain, tonsil, retropharyngeal
and mesenteric lymph nodes, hemal node, Peyer’s patches, and spleen. This work
demonstrates for the first time that white-tailed deer are susceptible to sheep
scrapie by potential natural routes of inoculation. In-depth analysis of tissues
will be done to determine similarities between scrapie in deer after
intracranial and oral/intranasal inoculation and chronic wasting disease
resulting from similar routes of inoculation.
see full text ;
PO-039: A comparison of scrapie and chronic wasting disease in white-tailed
deer
Justin Greenlee, Jodi Smith, Eric Nicholson US Dept. Agriculture;
Agricultural Research Service, National Animal Disease Center; Ames, IA USA
White-tailed deer are susceptible to the agent of sheep scrapie by
intracerebral inoculation
snip...
It is unlikely that CWD will be eradicated from free-ranging cervids, and
the disease is likely to continue to spread geographically [10]. However, the
potential that white-tailed deer may be susceptible to sheep scrapie by a
natural route presents an additional confounding factor to halting the spread of
CWD. This leads to the additional speculations that
1) infected deer could serve as a reservoir to infect sheep with scrapie
offering challenges to scrapie eradication efforts and
2) CWD spread need not remain geographically confined to current endemic
areas, but could occur anywhere that sheep with scrapie and susceptible cervids
cohabitate.
This work demonstrates for the first time that white-tailed deer are
susceptible to sheep scrapie by intracerebral inoculation with a high attack
rate and that the disease that results has similarities to CWD. These
experiments will be repeated with a more natural route of inoculation to
determine the likelihood of the potential transmission of sheep scrapie to
white-tailed deer. If scrapie were to occur in white-tailed deer, results of
this study indicate that it would be detected as a TSE, but may be difficult to
differentiate from CWD without in-depth biochemical analysis.
2012
PO-039: A comparison of scrapie and chronic wasting disease in white-tailed
deer
Justin Greenlee, Jodi Smith, Eric Nicholson US Dept. Agriculture;
Agricultural Research Service, National Animal Disease Center; Ames, IA USA
snip...
The results of this study suggest that there are many similarities in the
manifestation of CWD and scrapie in WTD after IC inoculation including early and
widespread presence of PrPSc in lymphoid tissues, clinical signs of depression
and weight loss progressing to wasting, and an incubation time of 21-23 months.
Moreover, western blots (WB) done on brain material from the obex region have a
molecular profile similar to CWD and distinct from tissues of the cerebrum or
the scrapie inoculum. However, results of microscopic and IHC examination
indicate that there are differences between the lesions expected in CWD and
those that occur in deer with scrapie: amyloid plaques were not noted in any
sections of brain examined from these deer and the pattern of immunoreactivity
by IHC was diffuse rather than plaque-like.
*** After a natural route of exposure, 100% of WTD were susceptible to
scrapie.
Deer developed clinical signs of wasting and mental depression and were
necropsied from 28 to 33 months PI. Tissues from these deer were positive for
PrPSc by IHC and WB. Similar to IC inoculated deer, samples from these deer
exhibited two different molecular profiles: samples from obex resembled CWD
whereas those from cerebrum were similar to the original scrapie inoculum. On
further examination by WB using a panel of antibodies, the tissues from deer
with scrapie exhibit properties differing from tissues either from sheep with
scrapie or WTD with CWD. Samples from WTD with CWD or sheep with scrapie are
strongly immunoreactive when probed with mAb P4, however, samples from WTD with
scrapie are only weakly immunoreactive. In contrast, when probed with mAb’s 6H4
or SAF 84, samples from sheep with scrapie and WTD with CWD are weakly
immunoreactive and samples from WTD with scrapie are strongly positive. This
work demonstrates that WTD are highly susceptible to sheep scrapie, but on first
passage, scrapie in WTD is differentiable from CWD.
2011
*** After a natural route of exposure, 100% of white-tailed deer were
susceptible to scrapie.
White-tailed Deer are Susceptible to Scrapie by Natural Route of Infection
Jodi D. Smith, Justin J. Greenlee, and Robert A. Kunkle; Virus and Prion
Research Unit, National Animal Disease Center, USDA-ARS
Interspecies transmission studies afford the opportunity to better
understand the potential host range and origins of prion diseases. Previous
experiments demonstrated that white-tailed deer are susceptible to sheep-derived
scrapie by intracranial inoculation. The purpose of this study was to determine
susceptibility of white-tailed deer to scrapie after a natural route of
exposure. Deer (n=5) were inoculated by concurrent oral (30 ml) and intranasal
(1 ml) instillation of a 10% (wt/vol) brain homogenate derived from a sheep
clinically affected with scrapie. Non-inoculated deer were maintained as
negative controls. All deer were observed daily for clinical signs. Deer were
euthanized and necropsied when neurologic disease was evident, and tissues were
examined for abnormal prion protein (PrPSc) by immunohistochemistry (IHC) and
western blot (WB). One animal was euthanized 15 months post-inoculation (MPI)
due to an injury. At that time, examination of obex and lymphoid tissues by IHC
was positive, but WB of obex and colliculus were negative. Remaining deer
developed clinical signs of wasting and mental depression and were necropsied
from 28 to 33 MPI. Tissues from these deer were positive for scrapie by IHC and
WB. Tissues with PrPSc immunoreactivity included brain, tonsil, retropharyngeal
and mesenteric lymph nodes, hemal node, Peyer’s patches, and spleen. This work
demonstrates for the first time that white-tailed deer are susceptible to sheep
scrapie by potential natural routes of inoculation. In-depth analysis of tissues
will be done to determine similarities between scrapie in deer after
intracranial and oral/intranasal inoculation and chronic wasting disease
resulting from similar routes of inoculation.
see full text ;
Friday, April 22, 2016
*** Texas Scrapie Confirmed in a Hartley County Sheep where CWD was
detected in a Mule Deer
Friday, February 26, 2016
TEXAS Hartley County Mule Deer Tests Positive for Chronic Wasting Disease
CWD TSE Prion
Tuesday, June 07, 2016
Comparison of two US sheep scrapie isolates supports identification as
separate strains
Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
‘’We demonstrate that the presence of white-tailed deer and bovine NTDs
hindered seeded conversion of PrPc, but human and bank vole NTDs did the
opposite. Additionally, full-length human and bank vole PrPc were more likely to
be converted to amyloid by CWD prions than were their truncated forms. ‘’
***Moreover, sporadic disease has never been observed in breeding colonies
or primate research laboratories, most notably among hundreds of animals over
several decades of study at the National Institutes of Health25, and in nearly
twenty older animals continuously housed in our own facility.***
Transmission of scrapie prions to primate after an extended silent
incubation period
Emmanuel E. Comoy , Jacqueline Mikol , Sophie Luccantoni-Freire , Evelyne
Correia , Nathalie Lescoutra-Etchegaray , Valérie Durand , Capucine Dehen ,
Olivier Andreoletti , Cristina Casalone , Juergen A. Richt , Justin J. Greenlee
, Thierry Baron , Sylvie L. Benestad , Paul Brown & Jean-Philippe Deslys
Abstract
Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion
disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD)
in humans and having guided protective measures for animal and human health
against animal prion diseases. Recently, partial transmissions to humanized mice
showed that the zoonotic potential of scrapie might be similar to c-BSE. We here
report the direct transmission of a natural classical scrapie isolate to
cynomolgus macaque, a highly relevant model for human prion diseases, after a
10-year silent incubation period, with features similar to those reported for
human cases of sporadic CJD. Scrapie is thus actually transmissible to primates
with incubation periods compatible with their life expectancy, although fourfold
longer than BSE. Long-term experimental transmission studies are necessary to
better assess the zoonotic potential of other prion diseases with high
prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98
scrapie.
snip...
In addition to previous studies on scrapie transmission to primate1,8,9 and
the recently published study on transgenic humanized mice13, our results
constitute new evidence for recommending that the potential risk of scrapie for
human health should not be dismissed. Indeed, human PrP transgenic mice and
primates are the most relevant models for investigating the human transmission
barrier. To what extent such models are informative for measuring the zoonotic
potential of an animal TSE under field exposure conditions is unknown. During
the past decades, many protective measures have been successfully implemented to
protect cattle from the spread of c-BSE, and some of these measures have been
extended to sheep and goats to protect from scrapie according to the principle
of precaution. Since cases of c-BSE have greatly reduced in number, those
protective measures are currently being challenged and relaxed in the absence of
other known zoonotic animal prion disease. We recommend that risk managers
should be aware of the long term potential risk to human health of at least
certain scrapie isolates, notably for lymphotropic strains like the classical
scrapie strain used in the current study. Relatively high amounts of infectivity
in peripheral lymphoid organs in animals infected with these strains could lead
to contamination of food products produced for human consumption. Efforts should
also be maintained to further assess the zoonotic potential of other animal
prion strains in long-term studies, notably lymphotropic strains with high
prevalence like CWD, which is spreading across North America, and atypical/Nor98
scrapie (Nor98)50 that was first detected in the past two decades and now
represents approximately half of all reported cases of prion diseases in small
ruminants worldwide, including territories previously considered as scrapie
free. Even if the prevailing view is that sporadic CJD is due to the spontaneous
formation of CJD prions, it remains possible that its apparent sporadic nature
may, at least in part, result from our limited capacity to identify an
environmental origin.
***Moreover, sporadic disease has never been observed in breeding colonies
or primate research laboratories, most notably among hundreds of animals over
several decades of study at the National Institutes of Health25, and in nearly
twenty older animals continuously housed in our own facility.***
2015
O.05: Transmission of prions to primates after extended silent incubation
periods: Implications for BSE and scrapie risk assessment in human populations
Emmanuel Comoy, Jacqueline Mikol, Valerie Durand, Sophie Luccantoni,
Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys
Atomic Energy Commission; Fontenay-aux-Roses, France
Prion diseases (PD) are the unique neurodegenerative proteinopathies
reputed to be transmissible under field conditions since decades. The
transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that
an animal PD might be zoonotic under appropriate conditions. Contrarily, in the
absence of obvious (epidemiological or experimental) elements supporting a
transmission or genetic predispositions, PD, like the other proteinopathies, are
reputed to occur spontaneously (atpical animal prion strains, sporadic CJD
summing 80% of human prion cases). Non-human primate models provided the first
evidences supporting the transmissibiity of human prion strains and the zoonotic
potential of BSE. Among them, cynomolgus macaques brought major information for
BSE risk assessment for human health (Chen, 2014), according to their
phylogenetic proximity to humans and extended lifetime. We used this model to
assess the zoonotic potential of other animal PD from bovine, ovine and cervid
origins even after very long silent incubation periods.
*** We recently observed the direct transmission of a natural classical
scrapie isolate to macaque after a 10-year silent incubation period,
***with features similar to some reported for human cases of sporadic CJD,
albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked
in humanized mice (Cassard, 2014),
***is the third potentially zoonotic PD (with BSE and L-type BSE),
***thus questioning the origin of human sporadic cases. We will present an
updated panorama of our different transmission studies and discuss the
implications of such extended incubation periods on risk assessment of animal PD
for human health.
===============
***thus questioning the origin of human sporadic cases***
===============
***our findings suggest that possible transmission risk of H-type BSE to
sheep and human. Bioassay will be required to determine whether the PMCA
products are infectious to these animals.
==============
CWD TSE PRION HUMAN ZOONOSIS POTENTIAL, has it already happened, and being
masked as sporadic CJD? and what about iatrogenic, or the pass if forward,
friendly fire mode of transmission of cwd to humans, same thing, sporadic cjd
?
*** WDA 2016 NEW YORK ***
We found that CWD adapts to a new host more readily than BSE and that human
PrP was unexpectedly prone to misfolding by CWD prions. In addition, we
investigated the role of specific regions of the bovine, deer and human PrP
protein in resistance to conversion by prions from another species. We have
concluded that the human protein has a region that confers unusual
susceptibility to conversion by CWD prions.
Student Presentations Session 2
The species barriers and public health threat of CWD and BSE prions
Ms. Kristen Davenport1, Dr. Davin Henderson1, Dr. Candace Mathiason1, Dr.
Edward Hoover1 1Colorado State University
Chronic wasting disease (CWD) is spreading rapidly through cervid
populations in the USA. Bovine spongiform encephalopathy (BSE, mad cow disease)
arose in the 1980s because cattle were fed recycled animal protein. These and
other prion diseases are caused by abnormal folding of the normal prion protein
(PrP) into a disease causing form (PrPd), which is pathogenic to nervous system
cells and can cause subsequent PrP to misfold. CWD spreads among cervids very
efficiently, but it has not yet infected humans. On the other hand, BSE was
spread only when cattle consumed infected bovine or ovine tissue, but did infect
humans and other species. The objective of this research is to understand the
role of PrP structure in cross-species infection by CWD and BSE. To study the
propensity of each species’ PrP to be induced to misfold by the presence of PrPd
from verious species, we have used an in vitro system that permits detection of
PrPd in real-time. We measured the conversion efficiency of various combinations
of PrPd seeds and PrP substrate combinations. We observed the cross-species
behavior of CWD and BSE, in addition to feline-adapted CWD and BSE. We found
that CWD adapts to a new host more readily than BSE and that human PrP was
unexpectedly prone to misfolding by CWD prions. In addition, we investigated the
role of specific regions of the bovine, deer and human PrP protein in resistance
to conversion by prions from another species. We have concluded that the human
protein has a region that confers unusual susceptibility to conversion by CWD
prions. CWD is unique among prion diseases in its rapid spread in natural
populations. BSE prions are essentially unaltered upon passage to a new species,
while CWD adapts to the new species. This adaptation has consequences for
surveillance of humans exposed to CWD.
Wildlife Disease Risk Communication Research Contributes to Wildlife Trust
Administration Exploring perceptions about chronic wasting disease risks among
wildlife and agriculture professionals and stakeholders
Ms. Alyssa Wetterau1, Dr. Krysten Schuler1, Dr. Elizabeth Bunting1, Dr.
Hussni Mohammed1 1Cornell University
Chronic wasting disease (CWD) is a fatal disease of North American
Cervidae. New York State (NYS, USA) successfully managed an outbreak of CWD in
2005 in both captive and wild white-tailed deer (Odocoileus virginianus) with no
reoccurrence of the disease as of 2015. To attain maximum compliance and
efficacy of management actions for prevention of CWD entry, understanding the
varied risk perceptions will allow for targeted, proactive communication efforts
to address divergences between expert-derived risk assessments and stakeholder
risk perceptions. We examined perceived risks associated with CWD introduction
and exposure among agricultural and wildlife agency professionals within and
outside of NYS, as well as stakeholder groups (e.g., hunters and captive cervid
owners). We measured perceived risk using a risk assessment questionnaire online
via Qualtrics survey software and evaluated similarities within, as well as
differences in, perception among participant groups. New York State biologists
employed by the Department of Environmental Conservation and independent non-NYS
wildlife and agricultural professionals thought CWD risks associated with
captive cervids were high; captive cervid owners thought risks for wild and
captive cervids were low. Agriculture and wildlife professional groups agreed on
general risk perceptions. We ranked 15 individual risk hazards into high and low
medium categories based on all responses. Differences between groups were most
evident in hypothetical disease pathways. Any pathway involving inter-state
import of live cervids received high ranking for all groups except captive
cervid owners. Comparatively low risk perceptions by captive cervid operators
may stem from misinformation, lack of understanding of testing programs, and
indemnity payments for animal depopulation. Communication and education directed
at areas of disagreement may facilitate effective disease prevention and
management.
* No evaluation of determination of CWD risk is required for alternative
livestock or captive wildlife shipped directly to slaughter or to a biosecure
facility approved by the Division and the Dept. of Agriculture.
*** We found that CWD adapts to a new host more readily than BSE and that
human PrP was unexpectedly prone to misfolding by CWD prions. In addition, we
investigated the role of specific regions of the bovine, deer and human PrP
protein in resistance to conversion by prions from another species. We have
concluded that the human protein has a region that confers unusual
susceptibility to conversion by CWD prions. CWD is unique among prion diseases
in its rapid spread in natural populations. BSE prions are essentially unaltered
upon passage to a new species, while CWD adapts to the new species. This
adaptation has consequences for surveillance of humans exposed to CWD. ***
PRION 2016 TOKYO
Zoonotic Potential of CWD Prions: An Update
Ignazio Cali1, Liuting Qing1, Jue Yuan1, Shenghai Huang2, Diane Kofskey1,3,
Nicholas Maurer1, Debbie McKenzie4, Jiri Safar1,3,5, Wenquan Zou1,3,5,6,
Pierluigi Gambetti1, Qingzhong Kong1,5,6
1Department of Pathology, 3National Prion Disease Pathology Surveillance
Center, 5Department of Neurology, 6National Center for Regenerative Medicine,
Case Western Reserve University, Cleveland, OH 44106, USA.
4Department of Biological Sciences and Center for Prions and Protein
Folding Diseases, University of Alberta, Edmonton, Alberta, Canada,
2Encore Health Resources, 1331 Lamar St, Houston, TX 77010
Chronic wasting disease (CWD) is a widespread and highly transmissible
prion disease in free-ranging and captive cervid species in North America. The
zoonotic potential of CWD prions is a serious public health concern, but the
susceptibility of human CNS and peripheral organs to CWD prions remains largely
unresolved. We reported earlier that peripheral and CNS infections were detected
in transgenic mice expressing human PrP129M or PrP129V. Here we will present an
update on this project, including evidence for strain dependence and influence
of cervid PrP polymorphisms on CWD zoonosis as well as the characteristics of
experimental human CWD prions.
PRION 2016 TOKYO
In Conjunction with Asia Pacific Prion Symposium 2016
PRION 2016 Tokyo
Prion 2016
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
*** In complement to the recent demonstration that humanized mice are
susceptible to scrapie, we report here the first observation of direct
transmission of a natural classical scrapie isolate to a macaque after a 10-year
incubation period. Neuropathologic examination revealed all of the features of a
prion disease: spongiform change, neuronal loss, and accumulation of PrPres
throughout the CNS.
*** This observation strengthens the questioning of the harmlessness of
scrapie to humans, at a time when protective measures for human and animal
health are being dismantled and reduced as c-BSE is considered controlled and
being eradicated.
*** Our results underscore the importance of precautionary and protective
measures and the necessity for long-term experimental transmission studies to
assess the zoonotic potential of other animal prion strains.
Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X online
Taylor & Francis
Prion 2016 Animal Prion Disease Workshop Abstracts
WS-01: Prion diseases in animals and zoonotic potential
Juan Maria Torres a, Olivier Andreoletti b, J uan-Carlos Espinosa a.
Vincent Beringue c. Patricia Aguilar a,
Natalia Fernandez-Borges a. and Alba Marin-Moreno a
"Centro de Investigacion en Sanidad Animal ( CISA-INIA ). Valdeolmos,
Madrid. Spain; b UMR INRA -ENVT 1225 Interactions Holes Agents Pathogenes. ENVT.
Toulouse. France: "UR892. Virologie lmmunologie MolécuIaires, Jouy-en-Josas.
France
Dietary exposure to bovine spongiform encephalopathy (BSE) contaminated
bovine tissues is considered as the origin of variant Creutzfeldt Jakob (vCJD)
disease in human. To date, BSE agent is the only recognized zoonotic prion.
Despite the variety of Transmissible Spongiform Encephalopathy (TSE) agents that
have been circulating for centuries in farmed ruminants there is no apparent
epidemiological link between exposure to ruminant products and the occurrence of
other form of TSE in human like sporadic Creutzfeldt Jakob Disease (sCJD).
However, the zoonotic potential of the diversity of circulating TSE agents has
never been systematically assessed. The major issue in experimental assessment
of TSEs zoonotic potential lies in the modeling of the ‘species barrier‘, the
biological phenomenon that limits TSE agents’ propagation from a species to
another. In the last decade, mice genetically engineered to express normal forms
of the human prion protein has proved essential in studying human prions
pathogenesis and modeling the capacity of TSEs to cross the human species
barrier.
To assess the zoonotic potential of prions circulating in farmed ruminants,
we study their transmission ability in transgenic mice expressing human PrPC
(HuPrP-Tg). Two lines of mice expressing different forms of the human PrPC
(129Met or 129Val) are used to determine the role of the Met129Val dimorphism in
susceptibility/resistance to the different agents.
These transmission experiments confirm the ability of BSE prions to
propagate in 129M- HuPrP-Tg mice and demonstrate that Met129 homozygotes may be
susceptible to BSE in sheep or goat to a greater degree than the BSE agent in
cattle and that these agents can convey molecular properties and
neuropathological indistinguishable from vCJD. However homozygous 129V mice are
resistant to all tested BSE derived prions independently of the originating
species suggesting a higher transmission barrier for 129V-PrP variant.
Transmission data also revealed that several scrapie prions propagate in
HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the
efficiency of transmission at primary passage was low, subsequent passages
resulted in a highly virulent prion disease in both Met129 and Val129 mice.
Transmission of the different scrapie isolates in these mice leads to the
emergence of prion strain phenotypes that showed similar characteristics to
those displayed by MM1 or VV2 sCJD prion. These results demonstrate that scrapie
prions have a zoonotic potential and raise new questions about the possible link
between animal and human prions.
Saturday, September 24, 2016
Assessment of the PrPc amino-terminal domain in prion species barriers
Tuesday, July 12, 2016
*** Chronic Wasting Disease CWD, Scrapie, Bovine Spongiform Encephalopathy
BSE, TSE, Prion Zoonosis Science History see history of NIH may destroy human
brain collection
Saturday, December 12, 2015
CREUTZFELDT JAKOB DISEASE CJD TSE PRION REPORT DECEMBER 14, 2015
Monday, August 22, 2016
CREUTZFELDT JAKOB DISEASE USA 2015 SPORADIC CJD TOTAL FIGURES REACHES
HIGHEST ANNUAL COUNT TO DATE AT 239 CONFIRMED CASES
Saturday, July 16, 2016
Importation of Sheep, Goats, and Certain Other Ruminants [Docket No.
APHIS-2009-0095]RIN 0579-AD10
WITH great disgust and concern, I report to you that the OIE, USDA, APHIS,
are working to further legalize the trading of Transmissible Spongiform
Encephalopathy TSE Pion disease around the globe.
THIS is absolutely insane. it’s USDA INC.
Terry S. Singeltary Sr.
