Saturday, January 9, 2021

A case-control study of scrapie Nor98 in Norwegian sheep flocks

J Gen Virol . 2006 Dec;87(Pt 12):3729-3736. doi: 10.1099/vir.0.81951-0. 

A case-control study of scrapie Nor98 in Norwegian sheep flocks 

Petter Hopp 1, Mohamed K Omer 1, Berit T Heier 1 Affiliations expand PMID: 17098991 DOI: 10.1099/vir.0.81951-0 Abstract Scrapie is a fatal, neurological disease of sheep and goats and belongs to the transmissible spongiform encephalopathies. In 1998, a new type of scrapie, designated scrapie Nor98, was detected in Norway. Scrapie Nor98 differs from classical scrapie in the distribution of pathological changes and of the scrapie prion protein, the Western blot profile of the prion protein, and with isolated cases usually being observed in the case flocks. In 2004, a case-control study was conducted on scrapie Nor98 with 28 cases and 102 randomly selected controls. The questionnaire included questions on demographic data, animal contact between sheep flocks, indirect contact with equipment, use of concentrate feed and supplemental feeds, and use of medicines and vaccines. The data were analysed by using logistic regression with the sheep flock as the statistical unit. In the final model, the detection of scrapie Nor98 was related to the practice of not removing all afterbirths, the use of vitamin and mineral feed supplements, the absence of concentrate feed of swine or poultry on the farm and the presence of dogs on the farm. The results show that the epidemiology of scrapie Nor98 differs from that of classical scrapie in that no risk factors that indicate transmission of scrapie Nor98 between flocks by movement or direct contact between animals were found. Furthermore, the association between scrapie Nor98 and mineral intake shown herein should be explored further. Although the possibility that scrapie Nor98 has a low transmissibility between animals under natural conditions cannot be ruled out, the results would also be in accordance with a spontaneous aetiology.

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DISCUSSION

In this study, we did not find any significant risk factors indicating that scrapie Nor98 had been transmitted between sheep flocks by animal movement or animal-to-animal contact. This suggests that the transmissibility of scrapie Nor98 in natural conditions is low, if present at all. This was in contrast to the previous study on risk factors for scrapiepositive flocks based on material collected in 1995–1997 in Norway (Hopp et al., 2001), where factors such as purchase of female sheep from scrapie flocks, sharing pastures with scrapie flocks, and sharing breeding rams increased the odds for scrapie in the flock. Based upon the pathological changes and the PrP genotypes affected, it is now assumed that most of the case flocks included in the previous study had classical scrapie (B. Bratberg, personal communication). Therefore, the conflicting results between these two studies are probably due to two different types of scrapie being examined, with different abilities to transmit between animals.

In classical scrapie, the prion protein PrPSc has been found in the placenta and amniotic fluids and the afterbirth is considered as an infectious source for other animals and for contamination of the environment (Andre´olettiet al., 2002). In a previous case–control study on scrapie in Irish sheep flocks, it was found that failure to retrieve the placenta from the lambing pen or disposal of placenta in the compost increased the odds of (classical) scrapie (Healy et al., 2004).

Our finding that the practice of not removing all afterbirths increased the risk of scrapie Nor98 might suggest that the agent of scrapie Nor98 is also found in the placenta of infected dams. In classical scrapie, the detection of PrPSc in the placenta has been reported in dams with the PrP genotypes ARQ/ARQ, ARQ/VRQ and VRQ/VRQ. For these genotypes, PrPSc has also been found in the lymphoid tissue (Andre´oletti et al., 2002; Tuo et al., 2002). To our knowledge, the scrapie Nor98 agent has so far only been detected in the central nervous system and not in lymphoid tissues (Benestad et al., 2003), which might indicate that PrPSc is not found in the placenta in scrapie Nor98. The examination of the placenta of dams infected with scrapie for PrPSc might give insight into the possibility of the placenta being an infectious source of scrapie Nor98.

The increased risk for scrapie Nor98 in flocks in which vitamin and mineral feed supplements had been used might be explained by the feed supplements that either included factors predisposing for scrapie Nor98 or had been contaminated with the scrapie Nor98 agent. Both minerals and vitamins might be potential predisposing factors from the feed and, on the molecular level, it is shown that PrPC has metal-binding properties. It has been suggested that manganese may induce the conformational change from PrPC to PrPSc (Kim et al., 2005), and copper may induce, as well as reduce, this conformational change (reviewed by Cerpa et al., 2005). Furthermore, an increased level of manganese in brain material from human cases with Creutzfeldt–Jakob disease and hamsters with scrapie has been reported (Kim et al., 2005; Wong et al., 2001). Therefore, the association found between scrapie Nor98 and feed supplements might be explained biologically by the intake of essential elements that influence the development of the disease.

A few epidemiological studies have investigated the associations between mineral intake and TSEs. In a study on risk factors for BSE, no association between BSE and mineral intake was found (Wilesmith et al., 1988). Chihota et al. (2004) investigated potential associations between mineral content in pasture and scrapie in the UK and found that farms with an excess of molybdenum had higher odds of having scrapie. However, the authors suggested that this might be a false-positive result (type I error). Although previous epidemiological studies have not been able to confirm any association between mineral intake and TSEs, we cannot rule out the possibility that this might be biologically plausible. We suggest that this relationship should be explored further in studies with a design suitable for the purpose.

The feeding regime of sheep in Norway varies considerably and the sources for essential elements are concentrate feed, lick stones, forage and grazing, in addition to the vitamin and mineral feed supplement. We would expect sheep given vitamin and mineral feed supplements to have a higher mineral intake than sheep not fed supplemental feed. Both the vitamin and mineral feed supplements and the salt lick stones produced for sheep generally included the essential elements: calcium, magnesium, manganese, selenium, iodine, cobalt, zinc and iron. When the farmer had used feed supplements produced for other ruminants, copper was also included. It would have been preferable to perform the analysis by using information on the quantitative intake of the different essential elements, but in our study design, the data only allowed differentiation between use of feedstuffs with and without copper. The fact that there was no significant association between scrapie Nor98 and feedstuffs with or without added copper indicates that the increased risk for scrapie Nor98 was not related specifically to the copper content of the feed. The result that the use of feed supplements gave a larger risk for scrapie Nor98 raises the question as to whether these might have been contaminated with the scrapie Nor98 agent through raw materials of animal origin. In Europe, BSE (Wilesmith et al., 1988) and perhaps also (classical) scrapie (Philippe et al., 2005) have spread through concentrate with meat-and-bone meal contaminated with the respective agent. In Norway, meat-and-bone meal was prohibited in commercial feed for ruminants in November 1990, and products of ruminant origin were prohibited as feed for ruminants in June 1994 (Høga˚sen & Hopp, 2002). Although meat-and-bone meal has been excluded from ruminant concentrate feed since 1994, meat-and-bone meal was allowed in concentrate feeds for poultry and swine until 2001 (Høga˚sen & Hopp, 2002) and some crosscontamination cannot be ruled out. However, the fact that the practice of keeping concentrate feeds for poultry or swine on the farm reduced the risk for scrapie Nor98 suggests that such feed has not been a source of the scrapie Nor98 agent. The finding that the presence of dog(s) on the farm represented a higher risk for scrapie indicates that feed offered to dogs might have been contaminated with the scrapie Nor98 agent, analogous to feline spongiform encephalopathy in cat, which is suggested to originate from cat feed contaminated with the BSE agent (Bradley, 1997). However, when asked about the feeding practices for dogs, only three case and eight control farmers admitted having fed their dog(s) in the sheep barns. To our knowledge, there is no report describing any relationship between the risk of scrapie and contact between sheep and dogs. Therefore, the association found is not explained easily and we think that the result must be considered in the context of a study with a limited number of cases and controls and with the possibility of a false-positive result.

The positive association between scrapie Nor98 and PrP genotypes with the alleles AHQ and AF141RQ has been documented previously (Moum et al., 2005). We were not able to find any relationship between the breed represented in the flock and the risk of scrapie Nor98 that could support the findings of the previous Norwegian study. However, in our study, the flock level was the unit of concern, which might not have been an optimal design for measuring this relationship. In future, such a relationship might be studied on the animal level and by using the PrP genotype as a measure of genetic susceptibility.

The latent period for scrapie is long and, for some factors, we considered it important to collect historical information and recall bias cannot be excluded. The questionnaire included questions for a period of up to 10 years, in accordance with the time period for which the farmers were obliged to keep the economic records, to allow the use of information collected from written sources and thereby reduce recall bias. Farmers with scrapie-affected flocks have been obliged to collect information on all trade for the authorities, and knowing that (classical) scrapie is transmitted through animal-to-animal contact, they probably would have tried to recollect any contact with other flocks. The control farmers would not necessarily have done so, which might have generated a differentiated recall bias. This would potentially exaggerate the effect from these factors. Despite this, no factors indicating transmission between animals were found to be significant in the final model.

The case flocks were asked for the last year of activity at the farm and then 10 years back, whereas the control flocks were asked for the time period 1994–2004. The different time periods of cases and controls might have introduced a problem if the exposure of the risk factors has changed during the time period. However, the cases differ from the controls by a maximum of 3 years, which, with regard to Norwegian sheep farming, we would consider a short time period for the risk factors investigated. Nevertheless, when considering the different time periods of the cases, a design where the cases and controls were matched for time period would have been preferable.

This study was designed as a case–control study in which the control flocks were selected randomly. However, for practical reasons, some adjustments were made to a true random sample of the total Norwegian sheep population. In order to reduce the cost of information collection, potential control flocks in the northern-most part of Norway, a total of 623 flocks (4 %), were excluded from the study. Northern Norway has a harsh climate and different management routines would be expected. Therefore, extrapolation of the results to the northern-most part of Norway is not necessarily valid. Furthermore, if a control refused to participate in the study, it was replaced by a reserve from the same municipality as the control that it replaced. This selection procedure was chosen to avoid (expensive) changes in the travel itinerary during the collection of the data. We do not know of any factor that might be affected by this as a result. Despite the low number of cases used in this study, we were able to reveal several factors that were associated significantly with scrapie Nor98. The study has shown to be a costeffective way of screening a large number of potential risk factors representing several hypotheses on the origin of the disease. The results of the study support the hypothesis that the epidemiology of scrapie Nor98 differs from that of classical scrapie. Scrapie Nor98 has a low transmissibility or might not be transmitted between animals under natural conditions. Furthermore, an association between mineral intake and scrapie Nor98 is biologically plausible and should be explored further in studies designed for the purpose. The association with mineral intake would be in accordance with a spontaneous aetiology of scrapie Nor98. 


''Furthermore, an association between mineral intake and scrapie Nor98 is biologically plausible and should be explored further in studies designed for the purpose. The association with mineral intake would be in accordance with a spontaneous aetiology of scrapie Nor98.''

this myth has been proven false time and time again...tss

 IBNC Tauopathy or TSE Prion disease, it appears, no one is sure 

Terry S. Singeltary Sr., 03 Jul 2015 at 16:53 GMT

PLOS ONE Journal 

IBNC Tauopathy or TSE Prion disease, it appears, no one is sure 

Terry S. Singeltary Sr., 03 Jul 2015 at 16:53 GMT

***however in 1 C-type challenged animal, Prion 2015 Poster Abstracts S67 PrPsc was not detected using rapid tests for BSE.

***Subsequent testing resulted in the detection of pathologic lesion in unusual brain location and PrPsc detection by PMCA only.

*** IBNC Tauopathy or TSE Prion disease, it appears, no one is sure ***

snip...

SEAC, FatPride, BSE Inquiry, have never found a link to pesticides, or OP’s, or metals, as a _cause_, to any TSE prion disease.

I have also followed the metals, pesticide debate as a cause for the TSE prion disease. to date, this has proven to be fruitless for any _cause_ of the TSE prion disease. not to say the potential for these factors for one to be more susceptible to a TSE prion from surrounding environmental factors i.e. surrounding TSE prion exposures from the various routes and sources of the TSE prion disease (see metals and pesticide i.e. FatePride towards the bottom). from Mark Purdey and his research, to a farmer with BSE that treated his kids with OP’s for head lice, and nothing scientific to date has confirmed a link to the TSE prion disease as a _cause_.

We MUST not abandon transmission studies, and or any link to the TSE prion disease.

IT appears, in the absence of any scientific link to any specific herbicides, insecticides, parasiticides and other chemicals to date to IBNC, to just explore other options instead of the transmission studies to prove one way or the other whether or not the IBNC or BBD or whatever you want to call this, while ignoring the existing epidemiology and knowledge of the TSE prion disease with the primitive TSE prion testing to date, it appears all this would be foolish, it appears this would be very questionable, in my opinion. ...


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. 

snip..... 

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..... 


***> 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, APRIL 18, 2017 

*** EXTREME USA FDA PART 589 TSE PRION FEED LOOP HOLE STILL EXIST, AND PRICE OF POKER GOES UP *** 


*** Singeltary reply ; Molecular, Biochemical and Genetic Characteristics of BSE in Canada Singeltary reply ;


2.3.2. New evidence on the zoonotic potential of atypical BSE and atypical scrapie prion strains

PLEASE NOTE;

2.3.2. New evidence on the zoonotic potential of atypical BSE and atypical scrapie prion strains

Olivier Andreoletti, INRA Research Director, Institut National de la Recherche Agronomique (INRA) – École Nationale Vétérinaire de Toulouse (ENVT), invited speaker, presented the results of two recently published scientific articles of interest, of which he is co-author: ‘Radical Change in Zoonotic Abilities of Atypical BSE Prion Strains as Evidenced by Crossing of Sheep Species Barrier in Transgenic Mice’ (MarinMoreno et al., 2020) and ‘The emergence of classical BSE from atypical/Nor98 scrapie’ (Huor et al., 2019).

In the first experimental study, H-type and L-type BSE were inoculated into transgenic mice expressing all three genotypes of the human PRNP at codon 129 and into adapted into ARQ and VRQ transgenic sheep mice. The results showed the alterations of the capacities to cross the human barrier species (mouse model) and emergence of sporadic CJD agents in Hu PrP expressing mice: type 2 sCJD in homozygous TgVal129 VRQ-passaged L-BSE, and type 1 sCJD in homozygous TgVal 129 and TgMet129 VRQ-passaged H-BSE.


THURSDAY, AUGUST 20, 2020 

***> Why is USDA "only" BSE TSE Prion testing 25,000 samples a year? <***


MONDAY, DECEMBER 14, 2020 

Experimental oral transmission of chronic wasting disease to sika deer (Cervus nippon)


Transmissible Spongiform Encephalopathy TSE Prion End of Year Report

CJD FOUNDATION VIRTUAL CONFERENCE CJD Foundation Research Grant Recipient Reports Panel 2 Nov 3, 2020

zoonotic potential of PMCA-adapted CWD PrP 96SS inoculum


4 different CWD strains, and these 4 strains have different potential to induce any folding of the human prion protein. 


***> PIGS, WILD BOAR, CWD <***

***> POPULATIONS OF WILD BOARS IN THE UNITED STATES INCREASING SUPSTANTUALLY AND IN MANY AREAS WE CAN SEE  A HIGH DENSITY OF WILD BOARS AND HIGH INCIDENT OF CHRONIC WASTING DISEASE

HYPOTHOSIS AND SPECIFIC AIMS

HYPOTHOSIS 

BSE, SCRAPIE, AND CWD, EXPOSED DOMESTIC PIGS ACCUMULATE DIFFERENT QUANTITIES AND STRAINS OF PRIONS IN PERIPHERAL TISSUES, EACH ONE OF THEM WITH PARTICULAR ZOONOTIC POTENTIALS


Final Report – CJD Foundation Grant Program A. 

Project Title: Systematic evaluation of the zoonotic potential of different CWD isolates. Principal Investigator: Rodrigo Morales, PhD.


Systematic evaluation of the zoonotic potential of different CWD isolates. Rodrigo Morales, PhD Assistant Professor Protein Misfolding Disorders lab Mitchell Center for Alzheimer’s disease and Related Brain Disorders Department of Neurology University of Texas Health Science Center at Houston Washington DC. July 14th, 2018

Conclusions and Future Directions • We have developed a highly sensitive and specific CWD-PMCA platform to be used as a diagnostic tool. • Current PMCA set up allow us to mimic relevant prion inter-species transmission events. • Polymorphic changes at position 96 of the prion protein apparently alter strain properties and, consequently, the zoonotic potential of CWD isolates. • Inter-species and inter-polymorphic PrPC → PrPSc conversions further increase the spectrum of CWD isolates possibly present in nature. • CWD prions generated in 96SS PrPC substrate apparently have greater inter-species transmission potentials. • Future experiments will explore the zoonotic potential of CWD prions along different adaptation scenarios, including inter-species and inter-polymorphic.



Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES Location: Virus and Prion Research

Title: Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease 

Author item MOORE, SARAH - Orise Fellow item Kunkle, Robert item KONDRU, NAVEEN - Iowa State University item MANNE, SIREESHA - Iowa State University item SMITH, JODI - Iowa State University item KANTHASAMY, ANUMANTHA - Iowa State University item WEST GREENLEE, M - Iowa State University item Greenlee, Justin Submitted to: Prion Publication Type: Abstract Only Publication Acceptance Date: 3/15/2017 Publication Date: N/A Citation: N/A Interpretive Summary:

Technical Abstract: Aims: Chronic wasting disease (CWD) is a naturally-occurring, fatal neurodegenerative disease of cervids. We previously demonstrated that disease-associated prion protein (PrPSc) can be detected in the brain and retina from pigs challenged intracranially or orally with the CWD agent. In that study, neurological signs consistent with prion disease were observed only in one pig: an intracranially challenged pig that was euthanized at 64 months post-challenge. The purpose of this study was to use an antigen-capture immunoassay (EIA) and real-time quaking-induced conversion (QuIC) to determine whether PrPSc is present in lymphoid tissues from pigs challenged with the CWD agent. 

Methods: At two months of age, crossbred pigs were challenged by the intracranial route (n=20), oral route (n=19), or were left unchallenged (n=9). At approximately 6 months of age, the time at which commercial pigs reach market weight, half of the pigs in each group were culled (<6 month challenge groups). The remaining pigs (>6 month challenge groups) were allowed to incubate for up to 73 months post challenge (mpc). The retropharyngeal lymph node (RPLN) was screened for the presence of PrPSc by EIA and immunohistochemistry (IHC). The RPLN, palatine tonsil, and mesenteric lymph node (MLN) from 6-7 pigs per challenge group were also tested using EIA and QuIC. 

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 month group was positive by EIA. PrPSc was detected by QuIC in at least one of the lymphoid tissues examined in 5/6 pigs in the intracranial <6 months group, 6/7 intracranial >6 months group, 5/6 pigs in the oral <6 months group, and 4/6 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.



Research Project: Pathobiology, Genetics, and Detection of Transmissible Spongiform Encephalopathies Location: Virus and Prion Research

Title: The agent of chronic wasting disease from pigs is infectious in transgenic mice expressing human PRNP 

Author item MOORE, S - Orise Fellow item Kokemuller, Robyn item WEST-GREENLEE, M - Iowa State University item BALKEMA-BUSCHMANN, ANNE - Friedrich-Loeffler-institut item GROSCHUP, MARTIN - Friedrich-Loeffler-institut item Greenlee, Justin Submitted to: Prion Publication Type: Abstract Only Publication Acceptance Date: 5/10/2018 Publication Date: 5/22/2018 Citation: Moore, S.J., Kokemuller, R.D., West-Greenlee, M.H., Balkema-Buschmann, A., Groschup, M.H., Greenlee, J.J. 2018. The agent of chronic wasting disease from pigs is infectious in transgenic mice expressing human PRNP. Prion 2018, Santiago de Compostela, Spain, May 22-25, 2018. Paper No. WA15, page 44.

Interpretive Summary:

Technical Abstract: We have previously shown that the chronic wasting disease (CWD) agent from white-tailed deer can be transmitted to domestic pigs via intracranial or oral inoculation although with low attack rates and restricted PrPSc accumulation. The objective of this study was to assess the potential for cross-species transmission of pig-passaged CWD using bioassay in transgenic mice. Transgenic mice expressing human (Tg40), bovine (TgBovXV) or porcine (Tg002) PRNP were inoculated intracranially with 1% brain homogenate from a pig that had been intracranially inoculated with a pool of CWD from white-tailed deer. This pig developed neurological clinical signs, was euthanized at 64 months post-inoculation, and PrPSc was detected in the brain. Mice were monitored daily for clinical signs of disease until the end of the study. Mice were considered positive if PrPSc was detected in the brain using an enzyme immunoassay (EIA). In transgenic mice expressing porcine prion protein the average incubation period was 167 days post-inoculation (dpi) and 3/27 mice were EIA positive (attack rate = 11%). All 3 mice were found dead and clinical signs were not noted prior to death. One transgenic mouse expressing bovine prion protein was euthanized due to excessive scratching at 617 dpi and 2 mice culled at the end of the study at 700 dpi were EIA positive resulting in an overall attack rate of 3/16 (19%). None of the transgenic mice expressing human prion protein that died or were euthanized up to 769 dpi were EIA positive and at study end point at 800 dpi 2 mice had positive EIA results (overall attack rate = 2/20 = 10%). The EIA optical density (OD) readings for all positive mice were at the lower end of the reference range (positive mice range, OD = 0.266-0.438; test positive reference range, OD = 0.250-4.000). To the authors’ knowledge, cervid-derived CWD isolates have not been successfully transmitted to transgenic mice expressing human prion protein. The successful transmission of pig-passaged CWD to Tg40 mice reported here suggests that passage of the CWD agent through pigs results in a change of the transmission characteristics which reduces the transmission barrier of Tg40 mice to the CWD agent. If this biological behavior is recapitulated in the original host species, passage of the CWD agent through pigs could potentially lead to increased pathogenicity of the CWD agent in humans.


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 month group was positive by EIA. PrPSc was detected by QuIC in at least one of the lymphoid tissues examined in 5/6 pigs in the intracranial <6 months group, 6/7 intracranial >6 months group, 5/6 pigs in the oral <6 months group, and 4/6 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. 




SUNDAY, OCTOBER 11, 2020 

Bovine adapted transmissible mink encephalopathy is similar to L-BSE after passage through sheep with the VRQ/VRQ genotype but not VRQ/ARQ 


SUNDAY, OCTOBER 4, 2020 

Cattle Meat and Offal Imported from the United States of America, Canada and Ireland to Japan (Prions) Food Safety Commission of Japan


TUESDAY, SEPTEMBER 29, 2020 

ISO's Updated 22442 Animal Tissue Standards — What Changed? TSE Prion!


TUESDAY, SEPTEMBER 22, 2020 

APHIS USDA MORE SCRAPIE ATYPICAL Nor-98 Confirmed USA September 15 2020

17 cases of the Nor98 in the USA to date, location, unknown...tss

17 Nor98-like cases since the beginning of RSSS.



***Our transmission study demonstrates that CH 1641-like scrapie is likely to be more virulent than classical scrapie in cattle. 

In the US, scrapie is reported primarily in sheep homozygous for 136A/171Q (AAQQ) and the disease phenotype is similar to that seen with experimental strain CH1641.


***Our transmission study demonstrates that CH 1641-like scrapie is likely to be more virulent than classical scrapie in cattle. 

P-088 Transmission of experimental CH1641-like scrapie to bovine PrP overexpression mice

Kohtaro Miyazawa1, Kentaro Masujin1, Hiroyuki Okada1, Yuichi Matsuura1, Takashi Yokoyama2

1Influenza and Prion Disease Research Center, National Institute of Animal Health, NARO, Japan; 2Department of Planning and General Administration, National Institute of Animal Health, NARO

Introduction: Scrapie is a prion disease in sheep and goats. CH1641-lke scrapie is characterized by a lower molecular mass of the unglycosylated form of abnormal prion protein (PrpSc) compared to that of classical scrapie. It is worthy of attention because of the biochemical similarities of the Prpsc from CH1641-like and BSE affected sheep. We have reported that experimental CH1641-like scrapie is transmissible to bovine PrP overexpression (TgBoPrP) mice (Yokoyama et al. 2010). We report here the further details of this transmission study and compare the biological and biochemical properties to those of classical scrapie affected TgBoPrP mice.

Methods: The details of sheep brain homogenates used in this study are described in our previous report (Yokoyama et al. 2010). TgBoPrP mice were intracerebrally inoculated with a 10% brain homogenate of each scrapie strain. The brains of mice were subjected to histopathological and biochemical analyses.

Results: Prpsc banding pattern of CH1641-like scrapie affected TgBoPrP mice was similar to that of classical scrapie affected mice. Mean survival period of CH1641-like scrapie affected TgBoPrP mice was 170 days at the 3rd passage and it was significantly shorter than that of classical scrapie affected mice (439 days). Lesion profiles and Prpsc distributions in the brains also differed between CH1641-like and classical scrapie affected mice.

Conclusion: We succeeded in stable transmission of CH1641-like scrapie to TgBoPrP mice. Our transmission study demonstrates that CH 1641-like scrapie is likely to be more virulent than classical scrapie in cattle.

snip... 

In the US, scrapie is reported primarily in sheep homozygous for 136A/171Q (AAQQ) and the disease phenotype is similar to that seen with experimental strain CH1641.


CH1641


***Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility.***

Even if the prevailing view is that sporadic CJD is due to the spontaneous formation of CJD prions, it remains possible that its apparent sporadic nature may, at least in part, result from our limited capacity to identify an environmental origin.

https://www.nature.com/articles/srep11573 

O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations 
Emmanuel Comoy, Jacqueline Mikol, Valerie Durand, Sophie Luccantoni, Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys Atomic Energy Commission; Fontenay-aux-Roses, France 

Prion diseases (PD) are the unique neurodegenerative proteinopathies reputed to be transmissible under field conditions since decades. The transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that an animal PD might be zoonotic under appropriate conditions. Contrarily, in the absence of obvious (epidemiological or experimental) elements supporting a transmission or genetic predispositions, PD, like the other proteinopathies, are reputed to occur spontaneously (atpical animal prion strains, sporadic CJD summing 80% of human prion cases). 

Non-human primate models provided the first evidences supporting the transmissibiity of human prion strains and the zoonotic potential of BSE. Among them, cynomolgus macaques brought major information for BSE risk assessment for human health (Chen, 2014), according to their phylogenetic proximity to humans and extended lifetime. We used this model to assess the zoonotic potential of other animal PD from bovine, ovine and cervid origins even after very long silent incubation periods. 

*** We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period, 

***with features similar to some reported for human cases of sporadic CJD, albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014), 

***is the third potentially zoonotic PD (with BSE and L-type BSE), 

***thus questioning the origin of human sporadic cases. 

We will present an updated panorama of our different transmission studies and discuss the implications of such extended incubation periods on risk assessment of animal PD for human health. 

=============== 

***thus questioning the origin of human sporadic cases*** 

=============== 

***our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals. 

============== 

https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf 

***Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice. 

***Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion. 

***These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions. 

http://www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20 

PRION 2016 TOKYO

Saturday, April 23, 2016

SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016

Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X online

Taylor & Francis

Prion 2016 Animal Prion Disease Workshop Abstracts

WS-01: Prion diseases in animals and zoonotic potential

Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion. 

These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions. 

http://www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20

Title: Transmission of scrapie prions to primate after an extended silent incubation period) 

*** In complement to the recent demonstration that humanized mice are susceptible to scrapie, we report here the first observation of direct transmission of a natural classical scrapie isolate to a macaque after a 10-year incubation period. Neuropathologic examination revealed all of the features of a prion disease: spongiform change, neuronal loss, and accumulation of PrPres throughout the CNS. 

*** This observation strengthens the questioning of the harmlessness of scrapie to humans, at a time when protective measures for human and animal health are being dismantled and reduced as c-BSE is considered controlled and being eradicated. 

*** Our results underscore the importance of precautionary and protective measures and the necessity for long-term experimental transmission studies to assess the zoonotic potential of other animal prion strains. 

http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=313160

1: J Infect Dis 1980 Aug;142(2):205-8

Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.

Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.

Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.

snip...

The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.

PMID: 6997404


Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias"

Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously.

snip...

76/10.12/4.6


Nature. 1972 Mar 10;236(5341):73-4.

Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis).

Gibbs CJ Jr, Gajdusek DC.

Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0

Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)

C. J. GIBBS jun. & D. C. GAJDUSEK

National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland

SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).



Wednesday, February 16, 2011

IN CONFIDENCE

SCRAPIE TRANSMISSION TO CHIMPANZEES

IN CONFIDENCE


Evidence That Transmissible Mink Encephalopathy Results from Feeding Infected Cattle Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME. 

snip... 

The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle... 




I URGE EVERYONE TO READ IN FULL, THE OIE REPORT 2019 ABOUT ATYPICAL BSE TSE PRION, SRMs, SBOs, and feed...tss

''Experts could not rule out other causes due to the difficulty of investigating individual cases. Some constraints are the long incubation period of the disease and the lack of detailed information available from farms at the time of the trace-back investigation.''

Scientists investigate origin of isolated BSE cases 

The European response to bovine spongiform encephalopathy (BSE) after the crisis of the 1980s has significantly reduced prevalence of the disease in cattle. However, isolated cases are still being reported in the EU and for this reason the European Commission asked EFSA to investigate their origin.

The key measure for controlling BSE in the EU is a ban on the use of animal proteins in livestock feed. This is because BSE can be transmitted to cattle through contaminated feed, mainly in the first year of life.

Sixty cases of classical BSE have been reported in cattle born after the EU ban was enforced in 2001. None of these animals entered the food chain. Classical BSE is the type of BSE transmissible to humans. The Commission asked EFSA to determine if these cases were caused by contaminated feed or whether they occurred spontaneously, i.e. without an apparent cause.

EFSA experts concluded that contaminated feed is the most likely source of infection. This is because the infectious agent that causes BSE has the ability to remain active for many years. Cattle may have been exposed to contaminated feed because the BSE infectious agent was present where feed was stored or handled. A second possibility is that contaminated feed ingredients may have been imported from non-EU countries.

Experts could not rule out other causes due to the difficulty of investigating individual cases. Some constraints are the long incubation period of the disease and the lack of detailed information available from farms at the time of the trace-back investigation.

EFSA experts made a series of recommendations to maintain and strengthen the EU monitoring and reporting system, and to evaluate new scientific data that become available.

The European response to BSE

The coordinated European response to BSE has succeeded in reducing the prevalence of the disease. Between 2005 and 2015 about 73,000,000 cattle were tested for BSE in the EU, out of which 60 born after the ban tested positive for classical BSE. The number of affected animals rises to 1,259 if cattle born before the ban are included. The number of classical BSE cases has dropped significantly in the EU over time, from 554 cases reported in 2005 to just two in 2015 (both animals born after the ban). Moreover the EU food safety system is designed to prevent the entry of BSE-contaminated meat into the food chain.


MONDAY, NOVEMBER 30, 2020 

***> REPORT OF THE MEETING OF THE OIE SCIENTIFIC COMMISSION FOR ANIMAL DISEASES Paris, 9–13 September 2019 BSE, TSE, PRION

see updated concerns with atypical BSE from feed and zoonosis...terry


WEDNESDAY, DECEMBER 23, 2020 

BSE research project final report 2005 to 2008 SE1796 SID5


THURSDAY, SEPTEMBER 26, 2019 

Veterinary Biologics Guideline 3.32E: Guideline for minimising the risk of introducing transmissible spongiform encephalopathy prions and other infectious agents through veterinary biologics


U.S.A. 50 STATE BSE MAD COW CONFERENCE CALL Jan. 9, 2001

Subject: BSE--U.S. 50 STATE CONFERENCE CALL Jan. 9, 2001

Date: Tue, 9 Jan 2001 16:49:00 -0800

From: "Terry S. Singeltary Sr."

Reply-To: Bovine Spongiform Encephalopathy


snip...

[host Richard Barns] and now a question from Terry S. Singeltary of CJD Watch.

[TSS] yes, thank you, U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?

[no answer, you could hear in the back ground, mumbling and 'we can't. have him ask the question again.]

[host Richard] could you repeat the question?

[TSS] U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?

[not sure whom ask this] what group are you with?

[TSS] CJD Watch, my Mom died from hvCJD and we are tracking CJD world-wide.

[not sure who is speaking] could you please disconnect Mr. Singeltary

[TSS] you are not going to answer my question?

[not sure whom speaking] NO

snip...see full archive and more of this;


*** Singeltary reply ; Molecular, Biochemical and Genetic Characteristics of BSE in Canada Singeltary reply ;


THURSDAY, JANUARY 7, 2021 

Atypical Nor-98 Scrapie TSE Prion USA State by State Update January 2021


Terry S. Singeltary Sr.
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