Estimating relative CWD susceptibility and disease progression in farmed white-tailed deer with rare PRNP alleles
Estimating relative CWD susceptibility and disease progression in farmed white-tailed deer with rare PRNP alleles
Nicholas J. Haley ,Kahla Merrett,Amy Buros Stein,Dennis Simpson,Andrew Carlson,Gordon Mitchell,Antanas Staskevicius,Tracy Nichols,Aaron D. Lehmkuhl,Bruce V. Thomsen
Estimating relative CWD susceptibility and disease progression in farmed white-tailed deer with rare PRNP alleles
Nicholas J. Haley, Kahla Merrett, Amy Buros Stein, Dennis Simpson, Andrew Carlson, Gordon Mitchell, Antanas Staskevicius, …PLOS x Published: December 2, 2019https://doi.org/10.1371/journal.pone.0224342
Abstract
Chronic wasting disease is a prion disease affecting both free-ranging and farmed cervids in North America and Scandinavia. A range of cervid species have been found to be susceptible, each with variations in the gene for the normal prion protein, PRNP, reportedly influencing both disease susceptibility and progression in the respective hosts.
Despite the finding of several different PRNP alleles in white-tailed deer, the majority of past research has focused on two of the more common alleles identified—the 96G and 96S alleles.
In the present study, we evaluate both infection status and disease stage in nearly 2100 farmed deer depopulated in the United States and Canada, including 714 CWD-positive deer and correlate our findings with PRNP genotype, including the more rare 95H, 116G, and 226K alleles.
We found significant differences in either likelihood of being found infected or disease stage (and in many cases both) at the time of depopulation in all genotypes present, relative to the most common 96GG genotype.
Despite high prevalence in many of the herds examined, infection was not found in several of the reported genotypes.
These findings suggest that additional research is necessary to more properly define the role that these genotypes may play in managing CWD in both farmed and free-ranging white-tailed deer, with consideration for factors including relative fitness levels, incubation periods, and the kinetics of shedding in animals with these rare genotypes.
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Discussion
A significant amount of research over the past two decades has been conducted on PRNP gene frequencies in both wild and farmed white-tailed deer populations affected by CWD, which cumulatively has led to the understanding that animals with different PRNP alleles are differentially susceptible to CWD infection. [8,26,50,51,57] Recent research has pointed to slower disease progression in animals with several of the more common genotypes, notably those carrying the 96S allele, in addition to their reduced susceptibility. [56,57] Each of these previous studies, however, have suffered from limitations which may hinder broader interpretation, including low disease prevalence and/or negligible or absent populations of animals representing rarer genotypes. [50–52,61] The present study represents one of the largest in-depth evaluations of the relationship between PRNP genotype and both CWD status and disease stage in white-tailed deer, and the relatively high disease prevalence in many of these populations provided us with important insight into susceptibility and disease progression in some of the more rare genotypes.
Previous studies have typically focused on two of the most common alleles—commonly referred to as the 96G and 96S alleles, and the corresponding 96GG, 96GS, and 96SS genotypes. Occasionally these studies make use of genotyping strategies that might ignore the contribution of other, rarer alleles. [57,62] In the present study, as in past studies, the 96G and 96S alleles made up a substantial percentage of total alleles in a population, making statistical comparisons easier even with small population sizes. [26,56] We found that, in line with previous studies, animals with the 96GS and 96SS genotypes were at a significantly reduced risk of being found CWD positive at the time of depopulation, and were generally in a significantly earlier stage of disease when infected compared to animals with the 96GG genotype.
We extended our analyses to rarer alleles, including the 95H, 116G, and 226K alleles, which to date have only garnered passing interest in susceptibility studies. [46,50,61,63] We report that the animals evaluated in this study with the 95H/96G and 96G/116G genotypes not only appear to face significantly lower risk of being found CWD positive, they, like their 96GS and 96SS counterparts, were also found to be in significantly earlier stages of disease at the time of depopulation. While there was a trend towards reduced susceptibility in animals with the 96G/226K genotype, their differences compared to animals with the 96GG genotype were not statistically significant. The 96G/226K genotype was, however, found to correlate with significantly lower disease scores than 96GG homozygous animals in the study. Models extending available data to 95HH, 116GG, and 226KK homozygous genotypes suggest the potential for an even further reduction in both susceptibility and disease progression.
To a limited extent, both the 95H and 116G alleles have been evaluated in prior studies for CWD susceptibility in either free-ranging or farmed white-tailed deer herds. A study of a wild deer population in Illinois found that animals with the 95H allele faced a risk of being found CWD-positive 1/5th that of the herd at large, similar to data reported in the present study (OR = 0.257, Table 4). [51] A limited bioassay study including two animals with the 95H allele found that CWD incubation periods were nearly double that of their 96GG and 96GS counterparts. [61] Subsequent examinations of animals in that report suggested differences in CWD prion protease sensitivity which might affect diagnostic test results—an important factor to consider when evaluating the results from the present study. [64] An evaluation of a farmed herd in Nebraska, meanwhile, found that white-tailed deer with the 116G allele were roughly half as likely to be found CWD positive compared to the herd at large, again very similar to the results reported here (OR = 0.440, Table 4). [46] Little information is available regarding the 226K allele in the natural host; however, in vitro misfolding studies have shown that, like several other rare cervid PRNP alleles, recombinant 226K prion protein is significantly limited in its ability to misfold in the presence of CWD prions. [65] Additional work is needed to more adequately define relative infection odds ratio and disease staging in not only the 96G/226K genotype, but other rare alleles as well—especially in animals homozygous for 95H, 116G, or 226K alleles.
While our findings, and those of past research efforts, suggest that deer with specific alleles face a significantly lower risk of being found CWD positive at depopulation—as well as a significant deceleration in disease progression when infected—it seems likely that deer carrying these alleles are not completely resistant to the disease. It is therefore uncertain what role, if any, PRNP genetics may play in the management of CWD in both farmed and free-ranging deer. From a diagnostic perspective, animals with more susceptible alleles exhibit a more rapid progression of the disease, and are thus more readily identified on antemortem testing. This particular factor may prove helpful in more quickly identifying infected herds and placing them under quarantine. [56,57] The increased diagnostic sensitivity offered by animals with susceptible genotypes, however, should be carefully weighed against the drawbacks of raising highly susceptible animals, especially in areas where CWD is highly endemic.
Apart from the diagnostic challenges noted above, additional factors that should be considered include the role that less susceptible alleles may have on general animal health, any delays in disease progression, and the resultant kinetics of prion shedding in infected animals carrying them. At present, there is almost no objective information available on the fitness of various PRNP genotypes in cervids [54], and while there are several limited reports of CWD prion shedding in more common white-tailed deer genotypes [66–68], the biological relevance of prions likely shed in biological fluids has proven more difficult to assess. [10,15,69] The lifespan of the host is also relevant when considering incubation periods of the disease—particularly in farmed deer, where age may be useful as a selective management factor, similar to strategies used to address concerns for zoonotic transmission of BSE from cattle. [70] Lastly, it is critical to understand the mutable nature of the CWD prion agent itself in the face of shifting host genetic background, and whether any novel strains that may arise have any notable differences in disease manifestation and zoonotic potential. [71–74]
In free-ranging herds, it is even less clear if there is a role for human intervention, and more importantly whether CWD may be actively shaping PRNP allele frequencies in wild populations. [26] At least one study has found that the less susceptible 96S allele may provide a significant fitness advantage in a CWD endemic area, making it especially valuable to reevaluate the current frequencies of PRNP alleles in areas hard hit by the CWD epidemic. [62] As with farmed deer, understanding the relationship between PRNP genotype, fitness, prion shedding, and incubation periods would prove useful to those seeking to manage the disease in wild herds as allele frequencies shift over time. Our surveillance efforts in farmed populations shows that rare alleles are fairly well distributed across North America, with potential regional variation in frequencies, and similar efforts in wild cervids in both North America and Scandinavia may prove both useful and informative.
In summary, we provide further evidence that specific and often rare PRNP alleles of white-tailed deer appear to correlate strongly to both CWD susceptibility and progression. Though rare, these alleles may be found in farmed deer herds across the United States and Canada, with potential, as yet unexplained, regional variations observed. Ongoing studies in farmed deer should provide some insight into both the relative fitness of animals carrying these alleles and their utility in managing CWD in endemic areas. The role these genotypes may have in managing the disease in free-ranging white-tailed deer should likewise continue to be explored, within the context of those considerations noted above.
''While our findings, and those of past research efforts, suggest that deer with specific alleles face a significantly lower risk of being found CWD positive at depopulation—as well as a significant deceleration in disease progression when infected—it seems likely that deer carrying these alleles are not completely resistant to the disease. It is therefore uncertain what role, if any, PRNP genetics may play in the management of CWD in both farmed and free-ranging deer.''
you better not mess with mother nature, you are playing with fire imo...terry
***> at present, no PrPC allele conferring absolute resistance in cervids has been identified.
J Gen Virol. 2017 Nov; 98(11): 2882–2892.
Published online 2017 Oct 23. doi: 10.1099/jgv.0.000952
PMCID: PMC5845664
PMID: 29058651
Estimating chronic wasting disease susceptibility in cervids using real-time quaking-induced conversion
Chronic wasting disease (CWD) resistance in cervids is often characterized as decreased prevalence and/or protracted disease progression in individuals with specific alleles; at present, no PrPC allele conferring absolute resistance in cervids has been identified.
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In summary, evaluating the amplification rates and efficiencies of recombinant PrPC substrates by RT-QuIC could be a useful tool for estimating the susceptibility of rare or newly discovered PRNP alleles, allowing researchers to target specific alleles for downstream evaluation in challenge studies. In the face of an ever-expanding CWD-endemic area, it is increasingly important to characterize the natural susceptibility of these alleles, as well as their geographical distribution and the evolutionary basis for their rarity. Do the QGAK, 225F and 225Y alleles represent recent, random anomalies, or are they more primitive mutations that adversely affect reproductive fitness? Perhaps they are an indication that cervids with these rare alleles were themselves once the target of a primordial prion strain. While some evidence has been presented for distinct strains of CWD, little is known about their geographical distribution or virulence in cervid hosts of diverse PRNP backgrounds. It is possible that, with the appropriate framework, RT-QuIC could allow for the discrimination of known and novel prion strains. Without further research into disease management and prevention, including resistance, the only certainty seems to be that CWD will continue its insidious spread, with further discoveries in new hosts and geographical locations.
P-145 Estimating chronic wasting disease resistance in cervids using real time quaking- induced conversion
Nicholas J Haley1, Rachel Rielinqer2, Kristen A Davenport3, W. David Walter4, Katherine I O'Rourke5, Gordon Mitchell6, Juergen A Richt2 1
Department of Microbiology and Immunology, Midwestern University, United States; 2Department of Diagnostic Medicine and Pathobiology, Kansas State University; 3Prion Research Center; Colorado State University; 4U.S. Geological Survey, Pennsylvania Cooperative Fish and Wildlife Research Unit; 5Agricultural Research Service, United States Department of Agriculture; 6Canadian Food Inspection Agency, National and OlE Reference Laboratory for Scrapie and CWO
In mammalian species, the susceptibility to prion diseases is affected, in part, by the sequence of the host's prion protein (PrP). In sheep, a gradation from scrapie susceptible to resistant has been established both in vivo and in vitro based on the amino acids present at PrP positions 136, 154, and 171, which has led to global breeding programs to reduce the prevalence of scrapie in domestic sheep. In cervids, resistance is commonly characterized as a delayed progression of chronic wasting disease (CWD); at present, no cervid PrP allele conferring absolute resistance to prion infection has been identified. To model the susceptibility of various naturally-occurring and hypothetical cervid PrP alleles in vitro, we compared the amplification rates and efficiency of various CWD isolates in recombinant PrPC using real time quaking-induced conversion. We hypothesized that amplification metrics of these isolates in cervid PrP substrates would correlate to in vivo susceptibility - allowing susceptibility prediction for alleles found at 10 frequency in nature, and that there would be an additive effect of multiple resistant codons in hypothetical alleles. Our studies demonstrate that in vitro amplification metrics predict in vivo susceptibility, and that alleles with multiple codons, each influencing resistance independently, do not necessarily contribute additively to resistance. Importantly, we found that the white-tailed deer 226K substrate exhibited the slowest amplification rate among those evaluated, suggesting that further investigation of this allele and its resistance in vivo are warranted to determine if absolute resistance to CWD is possible. ***at present, no cervid PrP allele conferring absolute resistance to prion infection has been identified.
PRION 2016 CONFERENCE TOKYO
***at present, no cervid PrP allele conferring absolute resistance to prion infection has been identified.
''There are no known familial or genetic TSEs of animals, although polymorphisms in the PRNP gene of some species (sheep for example) may influence the length of the incubation period and occurrence of disease.''
c) The commonest form of CJD occurs as a sporadic disease, the cause of which is unknown, although genetic factors (particularly the codon 129 polymorphism in the prion protein gene (PRNP)) influence disease susceptibility. The familial forms of human TSEs (see Box 1) appear to have a solely genetic origin and are closely associated with mutations or insertions in the PRNP gene. Most, but not all, of the familial forms of human TSEs have been transmitted experimentally to animals. There are no known familial or genetic TSEs of animals, although polymorphisms in the PRNP gene of some species (sheep for example) may influence the length of the incubation period and occurrence of disease.
''There are no known familial or genetic TSEs of animals, although polymorphisms in the PRNP gene of some species (sheep for example) may influence the length of the incubation period and occurrence of disease.''
ADOPTED: 26 September 2019 doi: 10.2903/j.efsa.2019.5863 Update on chronic wasting disease (CWD) III
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3.2.1.2. Non-cervid domestic species
The remarkably high rate of natural CWD transmission in the ongoing NA epidemics raises the question of the risk to livestock grazing on CWD-contaminated shared rangeland and subsequently developing a novel CWD-related prion disease. This issue has been investigated by transmitting CWD via experimental challenge to cattle, sheep and pigs and to tg mouse lines expressing the relevant species PrP.
For cattle challenged with CWD, PrPSc was detected in approximately 40% of intracerebrally inoculated animals (Hamir et al., 2005, 2006a, 2007). Tg mice expressing bovine PrP have also been challenged with CWD and while published studies have negative outcomes (Tamguney et al., 2009b), unpublished data provided for the purposes of this Opinion indicate that some transmission of individual isolates to bovinised mice is possible (Table 1).
In small ruminant recipients, a low rate of transmission was reported between 35 and 72 months post-infection (mpi) in ARQ/ARQ and ARQ/VRQ sheep intracerebrally challenged with mule deer CWD (Hamir et al., 2006b), while two out of two ARQ/ARQ sheep intracerebrally inoculated with elk CWD developed clinical disease after 28 mpi (Madsen-Bouterse et al., 2016). However, tg mice expressing ARQ sheep PrP were resistant (Tamguney et al., 2006) and tg mice expressing the VRQ PrP allele were poorly susceptible to clinical disease (Beringue et al., 2012; Madsen-Bouterse et al., 2016). In contrast, tg mice expressing VRQ sheep PrP challenged with CWD have resulted in highly efficient, life-long asymptomatic replication of these prions in the spleen tissue (Beringue et al., 2012).
A recent study investigated the potential for swine to serve as hosts of the CWD agent(s) by intracerebral or oral challenge of crossbred piglets (Moore et al., 2016b, 2017). Pigs sacrificed at 6 mpi, approximately the age at which pigs reach market weight, were clinically healthy and negative by diagnostic tests, although low-level CWD agent replication could be detected in the CNS by bioassay in tg cervinised mice. Among pigs that were incubated for up to 73 mpi, some gave diagnostic evidence of CWD replication in the brain between 42 and 72 mpi. Importantly, this was observed also in one orally challenged pig at 64 mpi and the presence of low-level CWD replication was confirmed by mouse bioassay. The authors of this study argued that pigs can support low-level amplification of CWD prions, although the species barrier to CWD infection is relatively high and that the detection of infectivity in orally inoculated pigs with a mouse bioassay raises the possibility that naturally exposed pigs could act as a reservoir of CWD infectivity.
3.2.1.3. Other species
Studies have demonstrated that the CWD agent(s) can be transmitted by the IC route in several species of rodents, such as voles (Subfamily Arvicolinae), deer mice (Peromyscus maniculatus), mice and hamsters (Subfamily Cricetinae). The susceptibility was, however, variable, being high in voles and deer mice but lower in mice and hamsters (Raymond et al., 2007; Heisey et al., 2010; Kurt et al., 2011; Di et al., 2013; Lee et al., 2013). Mink (subfamily Mustelinae) (Harrington et al., 2008), ferrets (Mustela putorius) (Bartz et al., 1998; Sigurdson et al., 2008) and cats (Mathiason et al., 2013) were susceptible to IC challenge with NA CWD sources, while CWD transmitted poorly to raccoons (Procyon lotor) by the IC route (Moore et al., 2019).
3.2.2. European isolates
The host range of CWD in Europe has been much less investigated so far, due to its recent identification. Among the cervid species involved in the CWD epidemics in North America, only some species (such as moose and reindeer) inhabit Europe; mule deer, white-tailed deer and elk/wapiti are American cervid species, although a few populations of white-tailed deer have been introduced into Europe. Others cervids that mainly inhabit Europe are red deer and roe deer. After the first detection in a reindeer in Norway in 2016 (Benestad et al., 2016), CWD has been detected in wild reindeer, moose and one red deer in Norway (Mysterud and Edmunds, 2019), in a moose in Finland in March 2018 and in three moose in Sweden in March, May and September 2019. CWD has not been detected
Chronic Wasting Disease (CWD) III www.efsa.europa.eu/efsajournal 14 EFSA Journal 2019;17(11):5863
so far in wild roe deer, fallow deer or white-tailed deer nor in any farmed cervid species. However, for fallow deer and white-tailed deer, the number of animals tested by the surveillance systems is still very low.
The potential host range of European CWD strains is under investigation by bioassay experiments in a range of model species; most of these studies are ongoing and there are no published data available so far. Data from the experiments that are known to be ongoing in different laboratories have been gathered for the purposes of this Opinion. Overall, reindeer CWD, moose CWD and red deer CWD brain isolates (and LRS isolates from some selected cases) are being tested for transmissibility in mice, hamsters, bank voles and in a range of tg mouse lines expressing PrP sequences from: cervids (Q226 or E226 deer PrP variants), small ruminants (ARQ, VRQ, AHQ and ARR PrP polymorphic variants), cattle, pig, vulture and human (M129 and V129 PrP polymorphic variants) (see Section 3.3.1). Importantly, in most of these animal models, the transmissibility of European CWD isolates will be directly comparable with the outcome of similar (published or ongoing) experiments with CWD isolates from North America.
While most of these studies are still ongoing, some experiments with CWD isolates from Europe have already produced evidence of transmission in some recipient species (Table 1). These include bank voles, conventional laboratory mice and tg mice expressing cervid PrP, sheep PrP and mouse PrP. The same rodent models are also susceptible to NA CWD isolates and will therefore allow comparative strain typing of NA and European CWD strains in due course. There is no strong evidence so far for rodent models being widely susceptible to NA isolates but not to European isolates or vice versa.
Table 1 summarises more than 500 ongoing, published or unpublished primary transmission experiments of NA or European CWD isolates from different cervids into various rodent models, which have been gathered following the requests described in Section 2.2. The CWD isolates are grouped according to geographical origin and cervid species, with each column summarising the results obtained with one or more CWD isolates from a given species and country. Rodent models are grouped according to the PrP species expressed. Some species have polymorphic PrP sequences, so more than one PrP sequence per species has been modelled. In these cases, each row summarises the data obtained with more than one PrP variant of a given species. Therefore, conventional mice include wt mice expressing PRNPa or PRNPb mouse PrP variants; bank voles include two genetic lines with different amino acids at codon 109 (Bv109M and Bv109I); tg-cervidPrP mice include mouse lines expressing several cervid PrP variants (the deer wt Q226, the elk wt E226, the WTD variant S96, the elk variant M132); tg-sheepPrP mice include mouse lines expressing the ARQ, VRQ, AHQ or ARR small ruminant PrP variants; finally, tg-humanPrP mice include mouse lines expressing M or V at the human PrP polymorphic codon 129. Therefore, each box in the Table 1 summarises the outcome of bioassay experiments with one or more CWD isolates (from the same species and origin) in one or more recipient rodent models (expressing PrP from a single given species).
Chronic Wasting Disease (CWD) III www.efsa.europa.eu/efsajournal 15 EFSA Journal 2019;17(11):5863
Most of the studies conducted by molecular/biochemical methods are still ongoing. The preliminary data obtained by molecular/biochemical methods were difficult to summarise and will not be reported in the present Opinion. This was mainly due to lack of detail in the results obtained by direct PrPSc analyses (PrPres typing, conformational stability, proteinase K resistance, which are intended to investigate CWD strains) and to the different methodological approaches employed in amplification assays (PMCA and RT-QuIC). The information gathered by this activity shows that experiments aimed at modelling the species barrier for NA or European CWD isolates into different animal species, including humans, are underway in different laboratories and will be of help for understanding the potential host range of CWD strains.
3.2.3 Impact of the PRNP gene on transmissibility
Polymorphisms in the PRNP gene are known to influence susceptibility/resistance to prion disease in both small ruminants and humans (for recent review, see EFSA BIOHAZ Panel 2014, EFSA BIOHAZ Panel, 2017; Diack et al., 2014). Effects of host PRNP polymorphisms on CWD susceptibility/resistance have also been described in a number of cervid species (reviewed in EFSA BIOHAZ Panel, 2017, 2018).
However, deer and elk wild-type PrP primary structures are equivalent, except at residue 226, which is glutamate in elk and glutamine in deer. The effect of this difference on CWD pathogenesis has been recently investigated using a gene-targeting approach in which the mouse PrP coding sequence was replaced with elk or deer PrP. The results obtained following experimental challenge with deer and elk CWD inocula from NA showed that the resulting GtE226 and GtQ226 mice had distinct kinetics of disease onset, with incubation times shorter in GtE226 than in GtQ226 mice, indicating that amino acid differences at PrP residue 226 dictate the selection and propagation of divergent strains in deer and elk with CWD. As prion strain properties largely dictate host range potential, these findings suggest that prion strains from elk and deer might pose distinct risks to sympatric species or humans exposed to CWD (Bian et al., 2019).
The most common cervid species in Europe (moose, red deer, reindeer and roe deer) share the same PrP primary structure, i.e. Q226. However, red deer PrP is polymorphic at residue 226 and can therefore code for either Q226 or E226. Interestingly, CWD cases detected so far in four Norwegian moose, the first Swedish moose and one Norwegian reindeer are all homozygous for Q226 (Benestad, 2019b,c,d), but the CWD case in red deer is instead homozygous for E226 (Vikøren et al., 2019). The impact of these differences in PrP genotype on the transmissibility and strain properties of European CWD isolates is currently under investigation using GtE226 and GtQ226 mice (Bian et al., 2019). PRNP genotypes of the other reindeer from Norway and of the other moose cases in Sweden and Finland are not in the public domain.
Data on the transmissibility of CWD in species with different PrP sequences obtained by in vivo or in vitro modelling allow the investigation of the structural basis of the transmission barriers for CWD. This in turn could provide hints for predicting, to some extent, the susceptibility of non-cervid species to CWD. Taken together, studies with CWD isolates from NA suggest that the 165–175 sequence similarity between cervid and host PrP is one important factor governing the susceptibility of different species to CWD (reviewed by Kurt et al., 2016). In particular, polymorphisms at N/S170 in the recipient species might be important for susceptibility, with species that have N170 being more susceptible than those with S170 (Kurt et al., 2016). However, this must not be seen as an absolute rule, as species having S170 in their PrP, such as squirrel monkeys, have also been reported to be susceptible to CWD. It is however pertinent to note that all livestock species and humans have PrP sequences with S170, so they should not be considered among the species with supposedly high susceptibility to NA CWD isolates. Ongoing experiments in rodent models seem to indicate a similar trend for European CWD isolates, as rodent models, apparently more susceptible to European CWD isolates such as bank voles and tg mice expressing deer PrP, are N170.
Little information is currently known about the genetics of either wild or farmed cervid populations in Europe. A recent published study of several deer species (mostly in Great Britain) reported that red deer showed the most PRNP gene variation, with polymorphisms at codons 98, 168, 226 and 247 and marked variability in genotype frequencies in different regions. Other deer species showed less variation, with roe and fallow deer having identical PRNP gene sequences in all the animals sampled. Based on comparison with PRNP sequences of NA cervids affected by CWD and limited experimental challenge data, the authors conclude that a high proportion of wild deer in Great Britain may be susceptible to CWD (Robinson et al., 2019). A similar conclusion was reached by a previous study of 715 genotyped cervids (red deer, roe deer and chamois) from the UK and Italy (Peletto et al., 2009).
3.2.4. Concluding remarks
• The transmission of prions between species is limited by the ‘transmission barrier’ and the amino acid sequence of the host PrP plays a very key role in the overall susceptibility to TSE. Even for prions deriving from the same species, the host range may vary according to the prion strain, implying that different CWD strains might have different host ranges and different potential for transmitting to livestock species and to humans.
• Whether the natural host range of CWD in NA extends beyond the family Cervidae is currently unclear and no natural infections have been reported so far in other wildlife species (e.g. predators and scavengers) with overlapping geographical ranges.
• NA CWD has been transmitted experimentally to cattle and sheep, but with incomplete attack rates. The species barrier appears higher for pigs, although challenged animals can support low-level prion amplification.
• Experimental transmission to tg mice and other rodent models shows some difference in the host ranges of different isolates but, particularly for the European isolates, many bioassays are still ongoing and data are not yet available.
• The number of strains, the strain diversity, the prevalence and the potential host range of disease in both NA and Europe CWD may be underestimated.
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FRIDAY, NOVEMBER 08, 2019
EFSA Panel on Biological Hazards (BIOHAZ) Update on chronic wasting disease (CWD) III
***> cattle, pigs, sheep, cwd, tse, prion, oh my!
***> In contrast, cattle are highly susceptible to white-tailed deer CWD and mule deer CWD in experimental conditions but no natural CWD infections in cattle have been reported (Sigurdson, 2008; Hamir et al., 2006).
Sheep and cattle may be exposed to CWD via common grazing areas with affected deer but so far, appear to be poorly susceptible to mule deer CWD (Sigurdson, 2008). In contrast, cattle are highly susceptible to white-tailed deer CWD and mule deer CWD in experimental conditions but no natural CWD infections in cattle have been reported (Sigurdson, 2008; Hamir et al., 2006). It is not known how susceptible humans are to CWD but given that the prion can be present in muscle, it is likely that humans have been exposed to the agent via consumption of venison (Sigurdson, 2008). Initial experimental research suggests that human susceptibility to CWD is low and there may be a robust species barrier for CWD transmission to humans (Sigurdson, 2008), however the risk appetite for a public health threat may still find this level unacceptable.
cwd scrapie pigs oral routes
***> However, at 51 months of incubation or greater, 5 animals were positive by one or more diagnostic methods. Furthermore, positive bioassay results were obtained from all inoculated groups (oral and intracranial; market weight and end of study) suggesting that swine are potential hosts for the agent of scrapie. <***
>*** Although the current U.S. feed ban is based on keeping tissues from TSE infected cattle from contaminating animal feed, swine rations in the U.S. could contain animal derived components including materials from scrapie infected sheep and goats. These results indicating the susceptibility of pigs to sheep scrapie, coupled with the limitations of the current feed ban, indicates that a revision of the feed ban may be necessary to protect swine production and potentially human health. <***
***> Results: PrPSc was not detected by EIA and IHC in any RPLNs. All tonsils and MLNs were negative by IHC, though the MLN from one pig in the oral <6 5="" 6="" at="" by="" detected="" eia.="" examined="" group="" in="" intracranial="" least="" lymphoid="" month="" months="" of="" one="" pigs="" positive="" prpsc="" quic="" the="" tissues="" was="">6 months group, 5/6 pigs in the oral <6 4="" and="" group="" months="" oral="">6 months group. Overall, the MLN was positive in 14/19 (74%) of samples examined, the RPLN in 8/18 (44%), and the tonsil in 10/25 (40%).
***> Conclusions: This study demonstrates that PrPSc accumulates in lymphoid tissues from pigs challenged intracranially or orally with the CWD agent, and can be detected as early as 4 months after challenge. CWD-infected pigs rarely develop clinical disease and if they do, they do so after a long incubation period. This raises the possibility that CWD-infected pigs could shed prions into their environment long before they develop clinical disease. Furthermore, lymphoid tissues from CWD-infected pigs could present a potential source of CWD infectivity in the animal and human food chains.
Friday, December 14, 2012
DEFRA U.K. What is the risk of Chronic Wasting Disease CWD being introduced into Great Britain? A Qualitative Risk Assessment October 2012
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In the USA, under the Food and Drug Administration's BSE Feed Regulation (21 CFR 589.2000) most material (exceptions include milk, tallow, and gelatin) from deer and elk is prohibited for use in feed for ruminant animals. With regards to feed for non-ruminant animals, under FDA law, CWD positive deer may not be used for any animal feed or feed ingredients. For elk and deer considered at high risk for CWD, the FDA recommends that these animals do not enter the animal feed system. However, this recommendation is guidance and not a requirement by law. Animals considered at high risk for CWD include:
1) animals from areas declared to be endemic for CWD and/or to be CWD eradication zones and
2) deer and elk that at some time during the 60-month period prior to slaughter were in a captive herd that contained a CWD-positive animal.
Therefore, in the USA, materials from cervids other than CWD positive animals may be used in animal feed and feed ingredients for non-ruminants.
The amount of animal PAP that is of deer and/or elk origin imported from the USA to GB can not be determined, however, as it is not specified in TRACES.
It may constitute a small percentage of the 8412 kilos of non-fish origin processed animal proteins that were imported from US into GB in 2011.
Overall, therefore, it is considered there is a __greater than negligible risk___ that (nonruminant) animal feed and pet food containing deer and/or elk protein is imported into GB.
There is uncertainty associated with this estimate given the lack of data on the amount of deer and/or elk protein possibly being imported in these products.
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36% in 2007 (Almberg et al., 2011). In such areas, population declines of deer of up to 30 to 50% have been observed (Almberg et al., 2011). In areas of Colorado, the prevalence can be as high as 30% (EFSA, 2011). The clinical signs of CWD in affected adults are weight loss and behavioural changes that can span weeks or months (Williams, 2005). In addition, signs might include excessive salivation, behavioural alterations including a fixed stare and changes in interaction with other animals in the herd, and an altered stance (Williams, 2005). These signs are indistinguishable from cervids experimentally infected with bovine spongiform encephalopathy (BSE). Given this, if CWD was to be introduced into countries with BSE such as GB, for example, infected deer populations would need to be tested to differentiate if they were infected with CWD or BSE to minimise the risk of BSE entering the human food-chain via affected venison. snip..... The rate of transmission of CWD has been reported to be as high as 30% and can approach 100% among captive animals in endemic areas (Safar et al., 2008).
snip.....
In summary, in endemic areas, there is a medium probability that the soil and surrounding environment is contaminated with CWD prions and in a bioavailable form. In rural areas where CWD has not been reported and deer are present, there is a greater than negligible risk the soil is contaminated with CWD prion. snip..... In summary, given the volume of tourists, hunters and servicemen moving between GB and North America, the probability of at least one person travelling to/from a CWD affected area and, in doing so, contaminating their clothing, footwear and/or equipment prior to arriving in GB is greater than negligible... For deer hunters, specifically, the risk is likely to be greater given the increased contact with deer and their environment. However, there is significant uncertainty associated with these estimates.
snip.....
Therefore, it is considered that farmed and park deer may have a higher probability of exposure to CWD transferred to the environment than wild deer given the restricted habitat range and higher frequency of contact with tourists and returning GB residents.
snip.....
''In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) EFSA Panel on Biological Hazards (BIOHAZ) Antonia Ricci Ana Allende Declan Bolton Marianne Chemaly Robert Davies Pablo Salvador Fernández Escámez ... See all authors First published: 17 January 2018 https://doi.org/10.2903/j.efsa.2018.5132
ADOPTED: 6 December 2017 doi: 10.2903/j.efsa.2018.5132 Scientific opinion on chronic wasting disease (II)
Chronic wasting disease (CWD) in cervids chronic, wasting, cervids, surveillance, risk, introduction, spread
First published in the EFSA Journal: 18 January 2017 Adopted: 2 December 2016 Type: Scientific Opinion
''To rule out the presence of infectivity, the lymph nodes of two sheep genotypes, VRQ/VRQ and ARQ/ARQ, were bioassayed in transgenic mice expressing ovine prion protein.''
''Mice intracranially inoculated with retropharyngeal lymph node from a VRQ/VRQ sheep were EIA positive (3/17) indicating that sheep inoculated with the bovine TME agent harbor infectivity in their lymph nodes despite a lack of detection with conventional immunoassays.''
***> ''indicating that sheep inoculated with the bovine TME agent harbor infectivity in their lymph nodes despite a lack of detection with conventional immunoassays.''
WEDNESDAY, NOVEMBER 20, 2019
Sheep Are Susceptible to the Bovine Adapted Transmissible Mink Encephalopathy agent by Intracranial Inoculation and Have Evidence of Infectivity in Lymphoid Tissues
WEDNESDAY, NOVEMBER 20, 2019
Review: Update on Classical and Atypical Scrapie in Sheep and Goats
TUESDAY, MARCH 26, 2019
USDA ARS 2018 USAHA RESOLUTIONS Investigation of the Role of the Prion Protein Gene in CWD Resistance and Transmission of Disease
TUESDAY, MARCH 26, 2019
USDA ARS 2018 USAHA RESOLUTIONS TWO PRONGED APPROACH NEEDED FOR ADVANCING CATTLE TRACEABILITY
***> READ THIS VERY, VERY, CAREFULLY, AUGUST 1997 MAD COW FEED BAN WAS A SHAM, AS I HAVE STATED SINCE 1997! 3 FAILSAFES THE FDA ET AL PREACHED AS IF IT WERE THE GOSPEL, IN TERMS OF MAD COW BSE DISEASE IN USA, AND WHY IT IS/WAS/NOT A PROBLEM FOR THE USA, and those are;
BSE TESTING (failed terribly and proven to be a sham)
BSE SURVEILLANCE (failed terribly and proven to be a sham)
BSE 589.2001 FEED REGULATIONS (another colossal failure, and proven to be a sham)
these are facts folks. trump et al just admitted it with the feed ban.
see;
FDA Reports on VFD Compliance
John Maday
August 30, 2019 09:46 AM VFD-Form 007 (640x427)
Before and after the current Veterinary Feed Directive rules took full effect in January, 2017, the FDA focused primarily on education and outreach. ( John Maday ) Before and after the current Veterinary Feed Directive (VFD) rules took full effect in January, 2017, the FDA focused primarily on education and outreach to help feed mills, veterinarians and producers understand and comply with the requirements. Since then, FDA has gradually increased the number of VFD inspections and initiated enforcement actions when necessary. On August 29, FDA released its first report on inspection and compliance activities. The report, titled “Summary Assessment of Veterinary Feed Directive Compliance Activities Conducted in Fiscal Years 2016 – 2018,” is available online.
SUNDAY, SEPTEMBER 1, 2019
***> FDA Reports on VFD Compliance
TUESDAY, OCTOBER 29, 2019
America BSE 589.2001 FEED REGULATIONS, BSE SURVEILLANCE, BSE TESTING, and CJD TSE Prion
Terry S. Singeltary Sr.
posted by Terry S. Singeltary Sr. at
1:30 PM
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