Susceptibility Chronic Wasting Disease (CWD) in wild cervids to Humans 2005 - December 14, 2012
2005
Award Number: DAMD17-03-1-0294
TITLE: Genetic Susceptibility and Biological Characterization of Chronic
Wasting Disease
PRINCIPAL INVESTIGATOR: Debbie I. McKenzie, Ph.D.
CONTRACTING ORGANIZATION: Wisconsin-Madison University Madison, WI
53706-1490 REPORT
DATE: July 2005 TYPE OF REPORT: Annual 20060309 136
PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort Detrick,
Maryland 21702-5012
14. ABSTRACT
The goals of this proposal are to: (i) identify prion protein (Prnp)
variability in the Wisconsin free-ranging white-tailed deer population, (ii)
determine the frequency of these Prnp alleles in CWD-positive and -negative
deer, (iii) characterize the effect of these allelic variations on the
biochemical and biological properties of the CWD agent and iv) to determine the
likelihood of CWD transmission to humans. Deer Prnp alleles have been sequenced
from CWD-positive and -negative deer. Several new alleles have been identified.
Two alleles are underrepresented in the CWD-positive animals suggesting they may
reduce susceptibility to infection. Tissue from genetically defined, CWD
infected deer has been used for determining the protease digestion properties of
the wild-type PrPCWD protein and for successfully orally infecting deer with CWD
agent of known genotypes. Transgenic mice, expressing cervid PrP, have been
successfully infected with CWD agent providing a rodent model for the analysis
of CWD infection.
Introduction:
CWD is the only prion disease occurring in wild, free-ranging animals (deer
and elk). It has been identified in free-ranging cervids in Colorado, Nebraska,
New Mexico, South Dakota, Saskatchewan, Wisconsin and Wyoming. In Wisconsin,
this contagious disease is endemic in a region of the state having an
exceedingly high deer density (-53 deer/square mile). It is not known whether
all deer are equally susceptible to CWD. Since the prion protein gene is the
genetic susceptibility factor for prion diseases, we initiated a study to define
the prion protein gene in Wisconsin white-tailed deer. The identification of
four different deer PrP proteins and their apparent unequal frequency in CWD
infected and uninfected deer suggest there may be differing levels of genetic
susceptibility to the disease. In addition, the existence of different PrP
proteins raises the possibility of the existence of different CWD strains. Our
proposed studies will focus upon characterizing the PrP gene in additional
CWD-infected and uninfected deer, determining whether different CWD strains
exist and the potential of the genetically defined CWD isolates to cause disease
in humans.
SNIP...
We previously estimated that approximately 91% of the CWD-negative deer had
allelic combinations found in CWD-positive deer suggesting that there was not a
complete barrier to transmission. By expanding the number of animals genotyped,
we determined that 96+/-3 % of the white-tailed deer are genetically susceptible
to CWD. Our studies indicate that, although there are two alleles that confer
levels of resistance to CWD, resistance is not complete and the alleles are not
abundant. Thus, significant genetic barriers to disease progression do not exist
in the Wisconsin white-tailed deer population.
SNIP...
Specific Aim 4. To ascertain whether CWD is potentially transmissible to
humans.
Transgenic animals expressing the human PrP gene at high levels is
currently be developed. Only recently has tissue from one of the
experimentally-infected animals become available. This tissue will be used to
infect mice transgenic with the human PrP gene.
Key Research Accomplishments:
1. Our genotyping of deer in the disease eradication zone of south-central
Wisconsin suggests that deer with theG96S genotype have a reduced susceptibility
to CWD.
2. Deer with the Q95H Prnp genotype may also have a reduced susceptibility
to CWD.
3. We determined that 96+/-3 % of the white-tailed deer, in Wisconsin, are
genetically susceptible to CWD.
4. The CWD pseudogene, described in mule deer and in captive white-tailed
deer, is also present in the free-ranging white-tailed deer in Wisconsin.
5. Analysis of a deer with intercurrent disease demonstrates the presence
of PrPCWD in the retropharyngeal lymph nodes, confirming that the orally dosed
animals were successfully infected with CWD.
6. An experimentally infected wt/wt deer was positive for CWD, with high
levels of PrPC deposition in the retropharyngeal lymph nodes and the obex of the
brain.
7. Tg mice have been generated that will support infection with CWD agent.
SNIP...
Conclusions: All aspects of this project are progressing well. Analysis of
two deer that were orally infected with CWD agent demonstrates that the oral
infections were successful. One of the deer, euthanized prior to onset of
clinical disease was positive for CWD in the retropharyngeal lymph nodes, one of
the first tissues to be positive in infection. The second animal, much further
into the incubation period, had high levels of PrPcWD in both the lymph nodes
and the obex of the brain. These animals will provide tissue for subsequent
inoculations as well as for biochemical analyses. We have sequenced a
sufficiently large number of deer, both CWD-positive and -negative, to provide
statistical power to our conclusions. The deer genotyping studies also suggest
that the amino acid changes at codons 95 and 96 may affect susceptibility of
deer to infection with the CWD agent. Subsequent inoculations into deer will
further substantiate this observation. Mice, carrying the cervid Prnp
transgenes, can be successfully infected with the CWD agent. These transgenic
mice will provide an alternative model for testing strain differences in CWD
inocula derived from deer with different Prnp genotypes.
SNIP...SEE FULL TEXT ;
2006
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 intraspecies 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 and plasma supplies.
2007
Human Transmissible Spongiform Encephalopathies: A Critical scientific
Investment Final Report of the National Prion Research Program US Army Medical
Research and Materiel Command Congressionally Directed Medical Research Programs
Fort Detrick, Maryland 2007
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.
These threats to the food and blood supplies are serious because the
incubation time for prion diseases is so long and there is no reliable
ante-mortem diagnostic test, i.e., a test that can be performed to detect the
disease while the person or animal is alive. Definitive diagnosis can be only
made by examining central nervous system tissue at autopsy. Prions do not elicit
an obvious immune response, so detection by measuring an immune response in the
host has not been possible. Developing a diagnostic test to detect prions in
peripheral tissues is dependent on surmounting two major impediments: (1) PrPSc
has exactly the same amino acid sequence as PrPC and (2) PrPSc represents only
0.001% of the total prion protein in an affected host. SNIP...
NPRP-funded investigators studied interspecies transmission of CWD by
comparative sequence analysis. This research has identified genotypic
differences in prion protein that may affect susceptibility to CWD, as has been
shown for scrapie. Identifying the effects of prion protein structural
differences on infectivity for CWD may have applications to many prion
diseases.
SNIP...
biological material for human use. The goal of prevention is to reduce the
amount of prion contaminated material to which human may be exposed. The
workgroup members suggested that the current surveillance methods need to be
maintained and improved. Some group members expressed concern for the level of
resources needed being too low to continue current levels of surveillance.
Animal identification is the first step in surveillance. Traceback is a method
by which an affected animal can be tracked back to its origin and the potential
source of infection. Traceback is done through the National Animal
Identification System (NAIS). The USDA representative suggested that traceback
was important to reduce the spread of prion disease in livestock. Issues of the
business cost for traceback are also a consideration.
Recommendations from Workgroup 3
* Develop policy on CWD surveillance. CWD occurs naturally in the wild
among deer, elk, and moose. It poses a threat to hunters and others who consume
meat from these animals. Deer meat (venison) is sometimes sent by hunters to
commercial processors to be preserved as sausage and jerky (dried meat). If the
venison is from a deer with CWD, it could contaminate processing machinery and
spread the disease to previously uncontaminated meat products and then to
unsuspecting consumers. Another threat is that deer are frequently raised on
deer farms for hunting purposes and not monitored for CWD. Deer from farms can
be sold and transported across state lines to other commercial farms, posing a
significant risk of spreading CWD even further. A federal surveillance and
monitoring program for CWD in wild and commercial herds is needed.
SNIP...
In terms of vaccines, the workgroup said vaccines were an important
consideration. Studying the immune response during infection is of interest. If
the Government had a vaccine or other alternate intervention to stop CWD
transmission, this would be of great importance. In relation to CWD and hunters,
Government regulators such as State Fish and Wildlife or Game officers need to
better promote the requirement to turn in deer heads to determine the real
prevalence of the disease. If ante mortem tests were available, State Fish and
Wildlife offices could offer them to hunters before they slaughter deer for
consumption. However, the repercussions for testing include the socio-economic
effects of finding increased prevalence of CWD on the hunting industry.
2008
Award Number: DAMD17-03-1-0542 TITLE: Epidemiology of Chronic Wasting
Disease: PrPres Detection, Shedding, and Environmental Contamination PRINCIPAL
INVESTIGATOR: Randolph V. Lewis, Ph.D. Michael W. Miller Terry Kreeger Lisa L.
Wolfe CONTRACTING ORGANIZATION: University of Wyoming Laramie, Wyoming 82070
REPORT DATE: August 2008 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical
Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION
STATEMENT: Approved for Public Release; Distribution Unlimited
14. ABSTRACT Chronic wasting disease (CWD) of deer and elk is unique among
the transmissible spongiform encephalopathies. Our long-term goal is to better
understand the epidemiology of CWD and thus develop strategies for management
and control. The specific goals of these studies are to develop sensitive assays
for PrPres as a marker for infectivity, and use these techniques to monitor the
dynamics and modes of shedding of PrPres from orally infected mule and
white-tailed deer and elk. Finally these techniques will be applied to
investigating the nature of environmental contamination that may be associated
with CWD transmission. Protease resistant prion protein from brains of CWD
affected deer and elk (PrPres) and cellular PrPc were purified and used in a
variety of detection assays. PrPres was detected using antibody-based
techniques, which although substantially more sensitive than any current assay
still need improvement. Deer and elk have been and infected orally to determine
CWD shedding in vivo. We have not identified several protein biomarkers as
indicators of prion infection in urine from deer and elk. As the grant ends we
have established a very large bank of various deer and elk tissues and fluids
starting prior to infection and periodically throughout the infection.
SNIP...
KEY RESEARCH ACCOMPLISHMENTS
• CWD infections established and confirmed in mule deer and white-tailed
deer.
• PrPCWD demonstrated in tonsil and rectal mucosa biopsies from infected
mule deer and white-tailed deer.
• Clinical CWD demonstrated in experimentally infected mule deer and
white-tailed deer.
• Archived materials shared with other laboratories to advance overall
progress on developing sensitive assays for prion detection in blood.
REPORTABLE OUTCOMES
• Demonstrating PrPCWD in plasma of mule deer (Chang et al. 2007) has
applications to both antemortem CWD diagnosis and to other prion diseases that
may improve the efficacy and efficiency of ongoing surveillance and health
management programs worldwide.
SNIP...SEE FULL TEXT ;
Rapid and Early Detection of Prions
Principal Investigator Brandt Cassidy, Ph.D.
Co-Principal Investigator Ken Clinkenbeard, Ph.D.
DNA Solutions, Inc., a small business based in Oklahoma City, Oklahoma,
received a Phase II SBIR award in December 2007 to continue development of a
system for live detection of CWD in collaboration with Oklahoma State
University. This infectious disease affects several species of deer, moose, and
elk and is closely related to bovine spongiform encephalopathy (mad cow
disease), Creutzfeldt-Jakob’s disease, and Alzheimer’s disease. The
investigators will create a cell culture model system by selecting for cells
that display rapid and sustained prion propagation after exposure to
CWD-positive brain homogenate. After optimizing culturing conditions and an
Elispot detection method, the project should result in a test sensitive enough
to detect CWD from easily obtainable antemortem samples, such as blood, saliva,
urine, feces, or biopsy samples.
2009
P35
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.
Saunders SE, Bartelt-Hunt SL, Bartz JC. Occurrence, transmission, and
zoonotic potential of chronic wasting disease. Emerg Infect Dis. 2012 Mar .
or
In vitro prion replication assays report a relatively low efficiency of CWD
PrPSc-directed conversion of human PrPc to PrPSc (30), and transgenic mice
overexpressing human PrPc are resistant to CWD infection (31); these findings
indicate low zoonotic potential. However, squirrel monkeys are susceptible to
CWD by intracerebral and oral inoculation (32). Cynomolgus macaques, which are
evolutionarily closer to humans than squirrel monkeys, are resistant to CWD
infection (32). Regardless, the finding that a primate is orally susceptible to
CWD is of concern.
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,
Ref 32: free full text at:
comparison of human, macaque, squirrel monkey, mule deer and elk at:
Race B, Meade-White KD, Miller MW, Barbian KD, Rubenstein R, LaFauci G,
Susceptibilities of nonhuman primates to chronic wasting disease.
Emerg Infect Dis. 2009;15:1366–76.
Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy,
or prion disease, that affects deer, elk, and moose. Human susceptibility to CWD
remains unproven despite likely exposure to CWD-infected cervids. We used 2
nonhuman primate species, cynomolgus macaques and squirrel monkeys, as human
models for CWD susceptibility. CWD was inoculated into these 2 species by
intracerebral and oral routes. After intracerebral inoculation of squirrel
monkeys, 7 of 8 CWD isolates induced a clinical wasting syndrome within 33-53
months. The monkeys' brains showed spongiform encephalopathy and
protease-resistant prion protein (PrPres) diagnostic of prion disease. After
oral exposure, 2 squirrel monkeys had PrPres in brain, spleen, and lymph nodes
at 69 months postinfection. In contrast, cynomolgus macaques have not shown
evidence of clinical disease as of 70 months postinfection. Thus, these 2
species differed in susceptibility to CWD. Because humans are evolutionarily
closer to macaques than to squirrel monkeys, they may also be resistant to
CWD.
Genetic Susceptibility to CWD in Free-Ranging White-Tailed Deer: Complement Component C1q and Prnp Polymorphisms
Julie A. Blanchong1*, Dennis M. Heisey2, Kim T. Scribner3, Scot V.
Libants4, Chad Johnson5, Judd M. Aiken6, Julia A. Langenberg7, and Michael D.
Samuel8 1Department of Wildlife Ecology, University of Wisconsin-Madison,
Madison, WI 53706 2USGS National Wildlife Health Center, Madison, WI 53711
3Department of Fisheries and Wildlife and Department of Zoology, Michigan State
University, East Lansing, MI 48824 4Department of Fisheries and Wildlife,
Michigan State University, East Lansing, MI 48824 5Department of Animal Health
and Biomedical Sciences, University of Wisconsin, 1655 Linden Drive, Madison,
WI, 53706 6Department of Animal Health and Biomedical Sciences, University of
Wisconsin, 1655 Linden Drive, Madison, WI, 53706 7Wisconsin Department of
Natural Resources, Madison, WI 53716 8Wisconsin Cooperative Wildlife Research
Unit, University of Wisconsin-Madison, Madison, WI 53706 *Corresponding author
e-mail: julieb@iastate.edu
The genetic basis of susceptibility to chronic wasting disease (CWD) in
wild cervids is of great interest. Traditional association studies of disease
susceptibility in free-ranging populations face considerable challenges
including: the need for large sample sizes for rare diseases, animals of unknown
pedigrees create a serious risk of spurious results due to population admixture,
and the inability to control disease exposure or dose. We used an innovative
matched case-control design and conditional logistic regression to evaluate
associations between polymorphisms of complement C1q and prion protein genes
(Prnp), and CWD infection. Our approach minimized the risk of problems due to
admixture or disease-risk confounding. We used neutral genetic(microsatellite)
data to identify closely related CWD-positive and CWD-negative deer to serve as
matched cases and controls. Cases and controls were also matched on factors
(age, sex, location) previously demonstrated to affect CWD infection risk. For
Prnp, deer with at least one Serine (S) at amino acid 96 were significantly less
likely to be CWD-positive relative to deer homozygous for Glycine (G). No tests
for association between any C1q polymorphism and CWD infection were significant.
After controlling for Prnp, we found weak support for an elevated risk of CWD
infection in deer with at least one Glycine (G) at amino acid 56 of the C1qC
gene. This is the first characterization of genes associated with the complement
system in white-tailed deer. While, we detected numerous amino acid
polymorphisms in these genes none appear to be strongly associated with CWD
susceptibility.
Chronic Wasting Disease Susceptibility of Four North American Rodents
Chad J. Johnson1*, Jay R. Schneider2, Christopher J. Johnson2, Natalie A.
Mickelsen2, Julia A. Langenberg3, Philip N. Bochsler4, Delwyn P. Keane4, Daniel
J. Barr4, and Dennis M. Heisey2 1University of Wisconsin School of Veterinary
Medicine, Department of Comparative Biosciences, 1656 Linden Drive, Madison WI
53706, USA 2US Geological Survey, National Wildlife Health Center, 6006
Schroeder Road, Madison WI 53711, USA 3Wisconsin Department of Natural
Resources, 101 South Webster Street, Madison WI 53703, USA 4Wisconsin Veterinary
Diagnostic Lab, 445 Easterday Lane, Madison WI 53706, USA
*Corresponding author email: cjohnson@svm.vetmed.wisc.edu
We intracerebrally challenged four species of native North American rodents
that inhabit locations undergoing cervid chronic wasting disease (CWD)
epidemics. The species were: deer mice (Peromyscus maniculatus), white-footed
mice (P. leucopus), meadow voles (Microtus pennsylvanicus), and red-backed voles
(Myodes gapperi). The inocula were prepared from the brains of hunter-harvested
white-tailed deer from Wisconsin that tested positive for CWD. Meadow voles
proved to be most susceptible, with a median incubation period of 272 days.
Immunoblotting and immunohistochemistry confirmed the presence of PrPd in the
brains of all challenged meadow voles. Subsequent passages in meadow voles lead
to a significant reduction in incubation period. The disease progression in
red-backed voles, which are very closely related to the European bank vole (M.
glareolus) which have been demonstrated to be sensitive to a number of TSEs, was
slower than in meadow voles with a median incubation period of 351 days. We
sequenced the meadow vole and red-backed vole Prnp genes and found three amino
acid (AA) differences outside of the signal and GPI anchor sequences. Of these
differences (T56-, G90S, S170N; read-backed vole:meadow vole), S170N is
particularly intriguing due its postulated involvement in “rigid loop” structure
and CWD susceptibility. Deer mice did not exhibit disease signs until nearly 1.5
years post-inoculation, but appear to be exhibiting a high degree of disease
penetrance. White-footed mice have an even longer incubation period but are also
showing high penetrance. Second passage experiments show significant shortening
of incubation periods. Meadow voles in particular appear to be interesting lab
models for CWD. These rodents scavenge carrion, and are an important food source
for many predator species. Furthermore, these rodents enter human and domestic
livestock food chains by accidental inclusion in grain and forage. Further
investigation of these species as potential hosts, bridge species, and
reservoirs of CWD is required.
SNIP...
Differential Characteristics of Experimental BSE and CWD in European Red
Deer (Cervus elaphus elaphus)
Stuart Martin1, Martin Jeffrey1, Lorenzo González1*, Sílvia Sisó1, Hugh W.
Reid2, Philip Steele2, Mark P. Dagleish2, Michael Stack3, Melanie Chaplin3 and
Aru Balachandran4 1Veterinary Laboratories Agency (VLA-Lasswade), Pentlands
Science Park, Midlothian EH26 0PZ, UK. 2Moredun Research Institute, Pentlands
Science Park, Midlothian EH26 0PZ, UK. 3VLA-Weybridge, Addlestone KT15 3NB, UK.
4Animal Diseases Research Institute, Canadian Food Inspection Agency,
Ottawa, Ontario, Canada K2H 8P9 *Corresponding author e-mail:
l.gonzalez@vla.defra.gsi.gov.uk
The cause of the bovine spongiform encephalopathy (BSE) epidemic in the
United Kingdom (UK) was the inclusion of contaminated meat and bone meal in the
protein rations fed to cattle. Contaminated feedstuffs were also fed to other
livestock including farmed and free living deer. BSE has been shown to be
naturally or experimentally transmissible to a wide range of different ungulates
although to date there are no reported cases of natural BSE infections in
European deer. In North America, however, several cervid species are highly
susceptible to chronic wasting disease (CWD), an endemic transmissible
spongiform encephalopathy. Should BSE infection have been introduced into the UK
deer population, the CWD precedent would suggest that there is a danger for
spread and maintenance of the disease in both free living and captive UK deer
populations. This study compares the immunohistochemical and biochemical
characteristics of BSE and CWD in experimentally-infected European red deer
(Cervus elaphus elaphus). Six out of six red deer challenged intracerebrally and
one of six dosed orally with 25 g of cattle BSE developed TSE-confirmed disease
at 26-42 and 58 months post-infection, respectively. Four out of four deer
challenged orally with 5 g of elk CWD developed TSE-confirmed disease at 18-20
months post-infection. In terms of abnormal PrP distribution, BSE in red deer
more closely resembled natural infection in cattle rather than experimental BSE
in small ruminants,
SNIP...
Potential Venison Exposure Among FoodNet Population Survey Respondents,
2006-2007
Ryan A. Maddox1*, Joseph Y. Abrams1, Robert C. Holman1, Lawrence B.
Schonberger1, Ermias D. Belay1 Division of Viral and Rickettsial Diseases,
National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for
Disease Control and Prevention, Atlanta, GA *Corresponding author e-mail:
rmaddox@cdc.gov
The foodborne transmission of bovine spongiform encephalopathy to humans,
resulting in variant Creutzfeldt-Jakob disease, indicates that humans can be
susceptible to animal prion diseases. However, it is not known whether foodborne
exposure to the agent causing chronic wasting disease (CWD) in cervids can cause
human disease. The United States Foodborne Diseases Active Surveillance Network
(FoodNet) conducts surveillance for foodborne diseases through an extensive
survey administered to respondents in selected states. To describe the frequency
of deer and elk hunting and venison consumption, five questions were included in
the 2006-2007 FoodNet survey. This survey included 17,372 respondents in ten
states: California, Colorado, Connecticut, Georgia, Maryland, Minnesota, New
Mexico, New York, Oregon, and Tennessee. Of these respondents, 3,220 (18.5%)
reported ever hunting deer or elk, with 217 (1.3%) reporting hunting in a
CWD-endemic area (northeastern Colorado, southeastern Wyoming, and southwestern
Nebraska). Of the 217 CWD-endemic area hunters, 74 (34.1%) were residents of
Colorado. Respondents reporting hunting were significantly more likely to be
male than female (prevalence ratio: 3.3, 95% confidence interval: 3.1-3.6) and,
in general, older respondents were significantly more likely to report hunting
than younger respondents. Venison consumption was reported by more than half
(67.4%) of the study population, and most venison consumers (94.1%) reported
that at least half of their venison came from the wild. However, more than half
(59.1%) of the consumers reported eating venison only one to five times in their
life or only once or twice a year. These findings indicate that a high
percentage of the United States population engages in hunting and/or venison
consumption. If CWD continues to spread to more areas across the country, a
substantial number of people could potentially be exposed to the infectious
agent.
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 ;
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
2010
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.
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.
PPo2-7:
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.
SEE MORE BELOW ;
UPDATED DATA ON 2ND CWD STRAIN
Wednesday, September 08, 2010
CWD PRION CONGRESS SEPTEMBER 8-11 2010
2011
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.
www.landesbioscience.com Prion
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.
Volume 18, Number 3—March 2012
Samuel E. Saunders1, Shannon L. Bartelt-Hunt, and Jason C. Bartz
Author affiliations: University of Nebraska-Lincoln, Omaha, Nebraska, USA
(S.E. Saunders, S.L. Bartelt-Hunt); Creighton University, Omaha (J.C. Bartz)
Synopsis
Occurrence, Transmission, and Zoonotic Potential of Chronic Wasting Disease
Originally recognized only in southeastern Wyoming and northeastern
Colorado, USA, CWD was reported in Canada in 1996 and Wisconsin in 2001 and
continues to be identified in new geographic locations (Figure 1, panel A).
CWD has been identified in free-ranging cervids in 15 US states and 2
Canadian provinces and in ≈100 captive herds in 15 states and provinces and in
South Korea (Figure 1, panel B). Except in South Korea, CWD has not been
detected outside North America. In most locations reporting CWD cases in
free-ranging animals, the disease continues to emerge in wider geographic areas,
and prevalence appears to be increasing in many disease-endemic areas.
Areas of Wyoming now have an apparent CWD prevalence of near 50% in mule
deer, and prevalence in areas of Colorado and Wisconsin is <15 deer.="deer." div="div" in="in">
However, prevalence in many areas remains between 0% and 5% according to
reports and data obtained from state and provincial wildlife agencies.
Prevalence in elk is lower than in deer but reaches 10% in parts of
Wyoming.
Known risk factors for CWD include sex and age, and adult male deer show
the highest prevalence (5).
Polymorphisms in the PrP (PRNP) gene appear to influence susceptibility in
deer and elk (2,6,7), but remain less understood than the strong genetic
influences for scrapie.
snip...
Most epidemiologic studies and experimental work have suggested that the
potential for CWD transmission to humans is low, and such transmission has not
been documented through ongoing surveillance (2,3). In vitro prion replication
assays report a relatively low efficiency of CWD PrPSc-directed conversion of
human PrPc to PrPSc (30), and transgenic mice overexpressing human PrPc are
resistant to CWD infection (31); these findings indicate low zoonotic potential.
However, squirrel monkeys are susceptible to CWD by intracerebral and oral
inoculation (32). Cynomolgus macaques, which are evolutionarily closer to humans
than squirrel monkeys, are resistant to CWD infection (32). Regardless, the
finding that a primate is orally susceptible to CWD is of concern...
snip...
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,...
snip...
NEVER SAY NEVER !
> Cynomolgus macaques, which are evolutionarily closer to humans than
squirrel monkeys, are resistant to CWD infection (32).
THIS statement seems to be a bit premature to me. kinda like the rabbit and
how it was suppose to be resistant to TSE, until transmission was confirmed
later in more studies.
for one, how many to date, of the Cynomolgus macaques, have been attempted
at transmission of CWD, and to how many strains of CWD were used in said test
??? ...tss
Rabbits are not resistant to prion infection
The ability of prions to infect some species and not others is determined
by the transmission barrier. This unexplained phenomenon has led to the belief
that certain species were not susceptible to transmissible spongiform
encephalopathies (TSEs) and therefore represented negligible risk to human
health if consumed. Using the protein misfolding cyclic amplification (PMCA)
technique, we were able to overcome the species barrier in rabbits, which have
been classified as TSE resistant for four decades. Rabbit brain homogenate,
either unseeded or seeded in vitro with disease-related prions obtained from
different species, was subjected to serial rounds of PMCA. De novo rabbit prions
produced in vitro from unseeded material were tested for infectivity in rabbits,
with one of three intracerebrally challenged animals succumbing to disease at
766 d and displaying all of the characteristics of a TSE, thereby demonstrating
that leporids are not resistant to prion infection. Material from the brain of
the clinically affected rabbit containing abnormal prion protein resulted in a
100% attack rate after its inoculation in transgenic mice overexpressing rabbit
PrP. Transmissibility to rabbits (>470 d) has been confirmed in 2 of 10
rabbits after intracerebral challenge. Despite rabbits no longer being able to
be classified as resistant to TSEs, an outbreak of “mad rabbit disease” is
unlikely.
snip...
Discussion
Slightly more than 25 y ago, cattle were considered free of prion diseases.
No one would have predicted the BSE epidemic with the considerable human and
animal health repercussions, and the political and economic impacts that it had
in Europe during the 1990s. At that time, the scientific knowledge of prions was
too limited to determine its role in the development of spontaneous cases of BSE
and their subsequent impact on human health. By 2011, however, several new prion
strains, naturally occurring (19, 20) or artificially generated (10), have been
described, indicating that their number has increased and that a species should
be considered resistant to disease only after careful consideration. The degree
of resistance and susceptibility to prion disease(s) differs within species.
Animals can be both extremely susceptible to the majority of prion diseases or
strains yet remain resistant to others on first passage (21). Therefore, it
would be unwise to assume that a species generally resistant to TSEs would
represent a minor risk to human health, as new TSEs and strains are continually
being detected.
It is notoriously difficult to predict how a new TSE or strain will behave
in different species, so great caution must be exercised when determining the
transmissibility of prions between species. To evaluate the potential risk of
transmission, every tool in the prion toolkit is essential, including artificial
methods, such as the use of transgenic animals, or secondary in vivo
transmission, which can exaggerate the possibility of infection (2, 22). Even
these extreme measures, which probably do not reflect the normal mechanisms of
infection, have to be considered to avoid future epidemics similar to that
observed with the new variant Creutzfeldt-Jakob disease (vCJD). For this reason,
we selected PMCA with its associated advantages, including the ability to
overcome the transmission barrier (8), as the preferred tool to evaluate the
absolute susceptibility of rabbits to TSEs.
In summary, after 3 y postchallenge with three different rabbitderived
inocula, we have obtained one positive clinical case, one possible preclinical
case, two intercurrent deaths, and six animals that have remained healthy.
Although the incubation periods do not directly correlate with the degree of
susceptibility, these data might indicate that rabbits are poorly susceptible to
prion infection. Although the rabbits used in this study were not inbred, they
all had identical full-length PrP sequences and, to date, no difference has been
detected in the ORF PrP sequence in any other published rabbit PrP sequence
placed in GenBank. To further investigate this, two types of second passage
experiment were performed; three raPrPTg mice and 10 rabbits were all
intracerebrally inoculated using brain homogenate from the clinically affected
rabbit. In contrast to 100% of the de novo RaPrPSc-inoculated transgenic mice
having succumbed to a standard clinical prion disease and thereby demonstrating
a high rate of transmissibility in vivo, two of 10 rabbits developed a TSE (477
and 540 dpi, respectively) to date. A plausible explanation for the evident
differences between these two transmission studies would be the high level of
rabbit PrPC expression (4- to 6-fold) in the murine model. In addition, it is
well known that even if overexpression does not increase susceptibility, it can
significantly reduce the incubation time of disease (2). However, the two
positive TSE cases in the second rabbit passage, even though 8 rabbits remained
clinically normal at 560 dpi, have led us to conclude that rabbits can no longer
be considered a prionresistant species. The long incubation times, even after a
second passage, might be due to the presence of some unknown, and probably rare,
susceptibility factor in rabbits, which may also be present, for example, in
equids and canids...
snip...
see full text ;
Friday, November 09, 2012
*** Chronic Wasting Disease CWD in cervidae and transmission to other
species
Saturday, October 6, 2012
**** TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF TRANSMISSIBLE
SPONGIFORM ENCEPHALOPATHIES 2011 Annual Report
Friday, August 24, 2012
Diagnostic accuracy of rectal mucosa biopsy testing for chronic wasting
disease within white-tailed deer (Odocoileus virginianus) herds in North America
Friday, August 31, 2012
COMMITTEE ON CAPTIVE WILDLIFE AND ALTERNATIVE LIVESTOCK and CWD 2009-2012 a
review
Tuesday, June 05, 2012
Captive Deer Breeding Legislation Overwhelmingly Defeated During 2012
Legislative Session
***Subject: DOCKET-- 03D-0186 -- FDA Issues Draft Guidance on Use of
Material From Deer and Elk in Animal Feed; Availability
Date: Fri, 16 May 2003 11:47:37 –0500
From: "Terry S. Singeltary Sr."
To: fdadockets@oc.fda.gov
***Monday, March 26, 2012
CANINE SPONGIFORM ENCEPHALOPATHY: A NEW FORM OF ANIMAL PRION DISEASE
http://caninespongiformencephalopathy.blogspot.com/2012/03/canine-spongiform-encephalopathy-new.html
FELINE SPONGIFORM ENCEPHALOPATHY FSE
TSE & HOUNDS
GAH WELLS (very important statement here...TSS)
HOUND STUDY
AS implied in the Inset 25 we must not _ASSUME_ that transmission of BSE to
other species will invariably present pathology typical of a scrapie-like
disease.
snip...
76 pages on hound study;
snip...
The spongiform changes were not pathognomonic (ie. conclusive proof) for
prion disease, as they were atypical, being largely present in white matter
rather than grey matter in the brain and spinal cord. However, Tony Scott, then
head of electron microscopy work on TSEs, had no doubt that these SAFs were
genuine and that these hounds therefore must have had a scrapie-like disease. I
reviewed all the sections myself (original notes appended) and although the
pathology was not typical, I could not exclude the possibility that this was a
scrapie-like disorder, as white matter vacuolation is seen in TSEs and Wallerian
degeneration was also present in the white matter of the hounds, another feature
of scrapie.
38.I reviewed the literature on hound neuropathology, and discovered that
micrographs and descriptive neuropathology from papers on 'hound ataxia'
mirrored those in material from Robert Higgins' hound survey. Dr Tony Palmer
(Cambridge) had done much of this work, and I obtained original sections from
hound ataxia cases from him. This enabled me provisionally to conclude that
Robert Higgins had in all probability detected hound ataxia, but also that hound
ataxia itself was possibly a TSE. Gerald Wells confirmed in 'blind' examination
of single restricted microscopic fields that there was no distinction between
the white matter vacuolation present in BSE and scrapie cases, and that
occurring in hound ataxia and the hound survey cases.
39.Hound ataxia had reportedly been occurring since the 1930's, and a known
risk factor for its development was the feeding to hounds of downer cows, and
particularly bovine offal. Circumstantial evidence suggests that bovine offal
may also be causal in FSE, and TME in mink. Despite the inconclusive nature of
the neuropathology, it was clearly evident that this putative canine spongiform
encephalopathy merited further investigation.
40.The inconclusive results in hounds were never confirmed, nor was the
link with hound ataxia pursued. I telephoned Robert Higgins six years after he
first sent the slides to CVL. I was informed that despite his submitting a
yearly report to the CVO including the suggestion that the hound work be
continued, no further work had been done since 1991. This was surprising, to say
the very least.
41.The hound work could have provided valuable evidence that a scrapie-like
agent may have been present in cattle offal long before the BSE epidemic was
recognised. The MAFF hound survey remains unpublished.
Histopathological support to various other published MAFF experiments
42.These included neuropathological examination of material from
experiments studying the attempted transmission of BSE to chickens and pigs (CVL
1991) and to mice (RVC 1994).
It was thought likely that at least some, and probably all, of the cases in
zoo animals were caused by the BSE agent. Strong support for this hypothesis
came from the findings of Bruce and others (1994) ( Bruce, M.E., Chree, A.,
McConnell, I., Foster, J., Pearson, G. & Fraser, H. (1994) Transmission of
bovine spongiform encephalopathy and scrapie to mice: strain variation and
species barrier. Philosophical Transactions of the Royal Society B 343, 405-411:
J/PTRSL/343/405 ), who demonstrated that the pattern of variation in incubation
period and lesion profile in six strains of mice inoculated with brain
homogenates from an affected kudu and the nyala, was similar to that seen when
this panel of mouse strains was inoculated with brain from cattle with BSE. The
affected zoo bovids were all from herds that were exposed to feeds that were
likely to have contained contaminated ruminant-derived protein and the zoo
felids had been exposed, if only occasionally in some cases, to tissues from
cattle unfit for human consumption.
snip...
SEE NEW URL ;
2005
DEFRA Department for Environment, Food & Rural Affairs
Area 307, London, SW1P 4PQ Telephone: 0207 904 6000 Direct line: 0207 904
6287 E-mail: h.mcdonagh.defra.gsi.gov.uk
GTN: FAX:
Mr T S Singeltary P.O. Box 42 Bacliff Texas USA 77518
21 November 2001
Dear Mr Singeltary
TSE IN HOUNDS
Thank you for e-mail regarding the hounds survey. I am sorry for the long
delay in responding.
As you note, the hound survey remains unpublished. However the Spongiform
Encephalopathy Advisory Committee (SEAC), the UK Government's independent
Advisory Committee on all aspects related to BSE-like disease, gave the hound
study detailed consideration at their meeting in January 1994. As a summary of
this meeting published in the BSE inquiry noted, the Committee were clearly
concerned about the work that had been carried out, concluding that there had
clearly been problems with it, particularly the control on the histology, and
that it was more or less inconclusive. However was agreed that there should be a
re-evaluation of the pathological material in the study.
Later, at their meeting in June 95, The Committee re-evaluated the hound
study to see if any useful results could be gained from it. The Chairman
concluded that there were varying opinions within the Committee on further work.
It did not suggest any further transmission studies and thought that the lack of
clinical data was a major weakness.
Overall, it is clear that SEAC had major concerns about the survey as
conducted. As a result it is likely that the authors felt that it would not
stand up to r~eer review and hence it was never published. As noted above, and
in the detailed minutes of the SEAC meeting in June 95, SEAC considered whether
additional work should be performed to examine dogs for evidence of TSE
infection. Although the Committee had mixed views about the merits of conducting
further work, the Chairman noted that when the Southwood Committee made their
recommendation to complete an assessment of possible spongiform disease in dogs,
no TSEs had been identified in other species and hence dogs were perceived as a
high risk population and worthy of study. However subsequent to the original
recommendation, made in 1990, a number of other species had been identified with
TSE ( e.g. cats) so a study in hounds was less
critical. For more details see- http://www.bseinquiry.gov.uk/files/yb/1995/06/21005001.pdf
As this study remains unpublished, my understanding is that the ownership
of the data essentially remains with the original researchers. Thus
unfortunately, I am unable to help with your request to supply information on
the hound survey directly. My only suggestion is that you contact one of the
researchers originally involved in the project, such as Gerald Wells. He can be
contacted at the following address.
Dr Gerald Wells, Veterinary Laboratories Agency, New Haw, Addlestone,
Surrey, KT 15 3NB, UK
You may also wish to be aware that since November 1994 all suspected cases
of spongiform encephalopathy in animals and poultry were made notifiable. Hence
since that date there has been a requirement for vets to report any suspect SE
in dogs for further investigation. To date there has never been positive
identification of a TSE in a dog.
I hope this is helpful
Yours sincerely 4
HUGH MCDONAGH BSE CORRESPONDENCE SECTION
======================================
HOUND SURVEY
I am sorry, but I really could have been a co-signatory of Gerald's
minute.
I do NOT think that we can justify devoting any resources to this study,
especially as larger and more important projects such as the pathogenesis study
will be quite demanding.
If there is a POLITICAL need to continue with the examination of hound
brains then it should be passed entirely to the VI Service.
J W WILESMITH Epidemiology Unit 18 October 1991
Mr. R Bradley
cc: Mr. G A H Wells
3.3. Mr R J Higgins in conjunction with Mr G A Wells and Mr A C Scott would
by the end of the year, indentify the three brains that were from the
''POSITIVE'' end of the lesion spectrum.
Monday, March 26, 2012
CANINE SPONGIFORM ENCEPHALOPATHY: A NEW FORM OF ANIMAL PRION DISEASE
OR-09 15:10 - 15:25 CANINE SPONGIFORM ENCEPHALOPATHY: A NEW FORM OF ANIMAL
PRION DISEASE David
http://caninespongiformencephalopathy.blogspot.com/2012/03/canine-spongiform-encephalopathy-new.html
Thursday, December 13, 2012
Genetic Predictions of Prion Disease Susceptibility in Carnivore Species
Based on Variability of the Prion Gene
Friday, November 23, 2012
sporadic Creutzfeldt-Jakob Disease update As at 5th November 2012 UK, USA,
AND CANADA
Tuesday, November 6, 2012
Transmission of New Bovine Prion to Mice, Atypical Scrapie, BSE, and
Sporadic CJD, November-December 2012 update
RIP MOM 12/14/97 CONFIRMED hvCJD...
layperson
kind regards,
terry
posted by Terry S. Singeltary Sr. at
2:09 PM
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