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Susceptibility Chronic Wasting Disease (CWD) in wild cervids to Humans 2005 - December 14, 2012

Posted Dec 14 2012 3:09pm
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.



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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.



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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.



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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.



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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.



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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.



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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.



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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.



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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.




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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,




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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.


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*** twenty-seven CJD patients who regularly consumed venison were reported to the Surveillance Center***,



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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.







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






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




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














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
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