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Thread: NIH Lack of Transmission of Chronic Wasting Disease to Cynomolgus Macaques?

  1. #1
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    Default NIH Lack of Transmission of Chronic Wasting Disease to Cynomolgus Macaques?

    IN THIS STUDY, NOT THE TRANSMISSION STUDIES DONE BY STEFANIE.CZUB STEFANIE.CZUB@INSPECTION.GC.CA THAT HAS YET TO BE PUBLISHED IN A PEER REVIEW JOURNAL, BUT WAS IN PART PUBLISHED IN LAST YEARS PRION 2017 CONFERENCE. SEE CWD TRANSMISSION TO MACAQUE IN THE CZUB ET AL STUDY, AFTER THIS NEWER PUBLISHED STUDY BY NIH RACE EL AL USING RT-QUIC IS REAL-TIME QUAKING-INDUCED CONVERSION. IF BOTH STUDIES HOLD UP, I WOULD SAY THAT THE TRANSMISSION WITH CWD INFECTIOUS TISSUE TO MACAQUE, AS OPPOSED TO THIS STUDY WOULD BE MUCH MORE CONCERNING, IMO...TERRY

    THURSDAY, APRIL 26, 2018

    NIH Lack of Transmission of Chronic Wasting Disease to Cynomolgus Macaques

    http://chronic-wasting-disease.blogs...f-chronic.html

    NEW TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY TSE PRION DISEASE (MAD CAMEL DISEASE) IN A NEW SPECIES

    NEW OUTBREAK OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY TSE PRION DISEASE IN A NEW SPECIES

    Subject: Prion Disease in Dromedary Camels, Algeria

    Our identification of this prion disease in a geographically widespread livestock species requires urgent enforcement of surveillance and assessment of the potential risks to human and animal health.

    https://wwwnc.cdc.gov/eid/article/24/6/17-2007_article

    http://camelusprp.blogspot.com/2018/...ry-camels.html

    ***> IMPORTS AND EXPORTS <***

    http://camelusprp.blogspot.com/2018/...prion-mad.html

    2017 USAHA RESOLUTION

    RESOLUTION NUMBER: 1 Combined with 6, 13, 16, and 22 APPROVED

    SUBJECT MATTER: Adequate Funding for Prevention, Diagnosis, and Response for Foreign Animal Disease Outbreaks

    http://www.usaha.org/upload/Resoluti...22_FAD_Sup.pdf

    http://camelusprp.blogspot.com/2018/...tein-gene.html

    where and when does it end???

    ***> PLEASE WATCH THIS VIDEO, AND BE SURE TO SEE AROUND THE 8 MINUTE MARK, VERY, VERY, DISTURBING...terry

    https://www.youtube.com/watch?v=nrzPAMfSp1U

    ***> LISTEN TO THIS CWD BLUES DIDDY ABOUT WISCONSIN CWD TSE PRION...terry

    https://www.youtube.com/watch?v=6DHindrC1x0

    TUESDAY, APRIL 17, 2018

    ***> Chronic wasting disease: Bambi vs. the prion <***

    Research Project: Immunodiagnostics to Detect Prions and Other Important Animal Pathogens

    Location: Produce Safety and Microbiology Research

    http://chronic-wasting-disease.blogs...-vs-prion.html

    FRIDAY, APRIL 20, 2018

    ***> Scrapie Transmits To Pigs By Oral Route

    what about the terribly flawed USA tse prion feed ban?

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

    http://scrapie-usa.blogspot.com/2018...ral-route.html

    TUESDAY, APRIL 24, 2018

    ARS Research atypical Nor98 and Michigan Scrapie, CWD, CJD and mad cow feed

    Research Project: Genetic Impact and Improved Diagnostics for Sheep and Goat Transmissible Spongiform Encephalopathies

    http://nor-98.blogspot.com/2018/04/a...nor98-and.html


    Terry S. Singeltary Sr.

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    NIH Lack of Transmission of Chronic Wasting Disease to Cynomolgus Macaques

    Discussion

    Several human prion diseases including sCJD, vCJD, and BSE have been previously transmitted to Cynomolgus macaques (CM) (9, 27, 29, 30), suggesting that CM might be a good surrogate primate species to predict human susceptibility to CWD. Earlier we reported that 7 of 14 CM inoculated with CWD by IC or oral routes were negative for prion disease after observation for 4.0 to 8.8 years (22). The present paper reports the final data on the remaining 7 CM who were not euthanized prior to the previous publication in 2014. These animals were observed for 10.9 to 13.4 years and were euthanized for a variety of clinical issues or electively at the termination of the experiment. No CM was found to be positive for CWD based on evaluation of brain and spinal cord for spongiosis and gliosis, as well as testing for PrPSc deposition by IHC and by immunoblot. In addition, tissues from these CM as well as the CM reported in 2014 were tested for PrP amyloid seeding activity using the highly sensitive RT QuIC test. Results of the RT-QuIC assay for all 14 of these CM were negative, and CWD inoculated CM could not be distinguished from 7 negative control CM who were not exposed to CWD. Thus, in this study, no clinical, pathological or biochemical evidence suggested that CWD was transmitted from cervids to CM.

    The long observation time and advanced age of some of the animals in this experiment posed potential problems for the analysis and diagnosis of prion disease in this cohort of CM. In fact, analysis of brain and spinal cord for PrPSc by IHC showed evidence for some unusual PrP deposits suggestive of the disease-associated form of PrP, PrPSc. However, these deposits were quite rare, and most were seen in both uninoculated and CWD-inoculated CM. The deposits stained with 3 different anti-PrP monoclonal antibodies, suggesting that they were indeed PrP, but their detection in uninoculated CM strongly implied that they were not PrPSc (Fig. 4). Detection of PrP staining unique to two orally inoculated CM was a concern (Fig. 5). However, in these two monkeys and all the other monkeys with PrP staining there was no evidence for gliosis or vacuolation in the region of the PrP deposits (Fig. 4G and H and Fig. 5C and D) as is often found in prion disease brain tissue. In addition, the sensitive RT-QuIC test for PrP amyloid seeding activity was negative with these samples, as was standard immunoblotting done for detection of PK-resistant PrP. Thus, there was no supporting evidence for CWD infection of these two CM from either clinical observations or biochemical tests.

    Additional experiments attempting transmission of CWD to CM have been done by another group in Canada and Germany. Although their results have not yet been published, oral presentations and abstracts have stated that they may have seen positive transmission of CWD to some CM. IHC staining of PrP in spinal cord of CWD-inoculated CM was the main disease specific feature reported (31). However, in our present study, we saw similar PrP staining by IHC in spinal cord of both uninoculated and CWD-inoculated CM (Fig. 7). Therefore, we did not regard our data on this observation to be evidence for CWD infection of CM.

    Prion disease transmission to SM and CM has been previously studied by several groups using both human and animal-derived prion agents. Comparing these known patterns of transmission may be helpful toward understanding which monkey model would be more predictive of prion disease transmission to humans. Human prion diseases including sCJD and vCJD, as well as the closely related disease, BSE, were previously shown to readily infect both CM and SM (28, 30, 32, 33). Similar experiments using sheep or rodent-adapted scrapie agents gave slightly different results. SM were highly susceptible to scrapie with rather short incubation periods (1-3 years) (34, 35), and CM were susceptible to scrapie in only 2 of 3 reports, both following much longer incubation periods (28, 34, 36). In transmission studies of CWD to SM and CM, results differed in these two species. SM were susceptible to CWD (22), while CM were not, as shown here and reported by another group as an experiment in progress (28). It is not clear why CM and SM models give such different results with different prion agents. However, known human prion disease susceptibility appears to correlate more closely with the susceptibility pattern of CM as opposed to SM.

    Based on paleontological and DNA data, evolutionary divergence between SM and CM is believed to have occurred 40-50 million years ago (37, 38), so differences in disease susceptibility should not come as a surprise. However, PrP, which is a key protein influencing the species barrier to prion transmission, has only 5 amino acid residue differences between SM and CM (not counting the extra octapeptide repeat seen in some SM) (21, 39). Any of the five differing residues might explain the differences in CWD susceptibility between SM and CM (14, 40-42). Compared to human PrP, CM and SM have nearly equal numbers of amino acid residue differences (21, 39). Due to the strong influence of single amino acid substitutions within PrP, it remains difficult to predict which of the two primate models better predicts susceptibility of humans to CWD based on amino acid sequence alone. Nevertheless, there is no data suggesting that humans are similar to SM in susceptibility to CWD. In fact, SM are considered by some researchers to be similar to bank voles in their broad susceptibility profile to diverse prion agents.

    Experiments using transgenic mice expressing non-mouse PrP have previously indicated that PrP itself appears to be the most important factor in determining the barrier to cross-species prion infection (14, 40-42). Therefore, transgenic mice expressing human PrP might be an important tool to assess susceptibility of humans to CWD. CWD transmission studies using such mice have been attempted by several laboratories (15-19). In none of these studies has transmission and infection been clearly demonstrated. However, there are many types of mice expressing human PrP at different levels and with different codon 129 genotypes, and the best combination for successful CWD transmission might not yet have been tested. It is unlikely that background non-Prnp mouse genes would block CWD infection of transgenic mice because transgenic mice expressing cervid PrP are in fact susceptible to CWD (19, 43, 44).

    The existence of different strains of CWD infectivity has been demonstrated previously (45-48), and such strains might be a confounding variable in assessment of susceptibility of humans or related animal models to CWD. Possibly human susceptibility to CWD might be restricted to a subset of CWD strains. Therefore, a variety of different CWD sources should be tested in animal models pertinent to human susceptibility to reduce the chance of overlooking a strain capable of human infection.

    Setting aside the above concerns about CWD strains and the validity of CM as a surrogate primate for human susceptibility, the current paper found no evidence for the transmission of CWD to CM using a broad range of data including clinical, pathological and biochemical observations. Despite the observation of several suspicious types of PrP staining by IHC, this evidence was not definitive due to presence of similar lesions in uninoculated and CWD-inoculated CM as well as a lack of gliosis or vacuolation. Similarly, biochemical tests using RT-QuIC and immunoblotting were also unable to distinguish uninoculated from CWD301 inoculated CM, thus also supporting the conclusion that no transmission had occurred.

    302 Materials and Methods...snip

    448 Acknowledgements
    449 We thank Suzette Priola, Cathryn Haigh, and James Carroll for critical review of the manuscript;
    450 Nancy Kurtz and Dan Long for assistance with histology preparation; Andrew MacLean and
    451 Dana Scott for hemosiderin pigment interpretation; Jamie Lovaglio, Dana Scott, Greg Saturday,
    452 Jennifer Hayes and Tracy Cope for additional normal CM tissues; Don Gardner and RMVB staff
    453 for assistance with CM inoculations, animal husbandry and health care; Luisa Gregori from the
    454 FDA, Division of Emerging and Transfusion-Transmitted Diseases for vCJD infected CM brain
    455 material; Stefanie Czub and John Gray for helpful discussions regarding the project; Anita Mora
    456 for graphic art assistance; and Mike Miller, Terry Kreeger, Jean Jewell and Lynn Creekmore for
    457 CWD-agent positive and negative cervid tissues. This research was supported by the Intramural
    458 Research Program of the NIH, National Institute of Allergy and Infectious Diseases.

    SNIP...END...TSS

  3. #3
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    i thought some of you might find interest in this presentation...

    https://www.cste2.org/Webinars/files...ides_FINAL.pdf


    kind regards, terry

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