Five Cases Atypical scrapie in Australia to date

Five Cases Atypical scrapie in Australia to date

Atypical scrapie in Australia

RW Cook, a * J Bingham, b AS Besier, c CL Bayley, d M Hawes, e PL Shearer, f M Yamada, b J Bergfeld, b DT Williams b and DJ Middleton b

Background

Since its initial detection in Norway in 1998, atypical scrapie (‘atypical/Nor98 scrapie’) has been reported in sheep in the majority of European countries (including in regions free of classical scrapie) and in the Falkland Islands, the USA, Canada, New Zealand and Australia.

Case series

The diagnosis in Australia of atypical scrapie in four Merino and one Merino-cross sheep showing clinical signs of neurological disease was based on the detection of grey matter neuropil vacuolation (spongiform change) in the brain (particularly in the molecular layer of the cerebellar cortex) and associated abnormal prion protein (PrP Sc ) deposition in both grey and white matter. Changes were minimal in the caudal brainstem, the predilection site for lesions of classical scrapie.

Conclusion

The distinctive lesion profile of atypical scrapie in these five sheep highlights the diagnostic importance of routine histological evaluation of the cerebellum for evidence of neuropil vacuolation and associated PrP Sc deposition in adult sheep with suspected neurological disease.

Keywords

atypical scrapie; prion disease; sheep; transmissible spongiform encephalopathy

Abbreviations ANZSDP, Australian and New Zealand Standard Diagnostic Procedure; CNS, central nervous system; DMNV, dorsal motor nucleus of the vagus nerve; H&E, haematoxylin and eosin; IHC, immunohistochemistry; NTSESP, National TSE Surveillance Program; PrP Sc , abnormal prion protein isomer; TSE, transmissible spongiform encephalopathy. Aust Vet J 2016 doi: 10.1111/avj.12529

Scrapie is a transmissible spongiform encephalopathy (TSE) or prion disease of small ruminants that occurs in classical and atypical forms. Classical scrapie is characterised histologically by vacuolation and abnormal prion protein (PrP Sc ) immunolabelling of neuronal cytoplasm and grey matter neuropil within the central nervous system (CNS), with a predilection for the caudal brainstem, mainly at the level of the obex and typically involving the dorsal motor nucleus of the vagus nerve (DMNV).1 The Western immuno- blot pattern (‘molecular signature’) of PrP Sc extracted from brains of classical scrapie cases has three bands comprising unglycosylated, monoglycosylated and diglycosylated PrP Sc residues with molecular masses between 18 and 30 kDa.2

In contrast, atypical scrapie (‘atypical/Nor98 scrapie’)is defined by a characteristic neuroanatomical distribution of neuropil vacuolation and PrP Sc immunolabelling in the brain, and a multiband PrP Sc Western immunoblot pattern with a fast-migrating, lower band of molecular mass <15 2="" 5="" also="" and="" at="" basal="" brain.2="" cerebellar="" cerebral="" change="" cortex="" demonstrates="" deposition="" detected="" ganglia.="" grey="" immu-="" immunohistochemistry="" in="" intracytoplasmic="" is="" kda.="" layer="" mainly="" matter="" molecular="" nerve="" neurons.3="" neuropil="" no="" nolabelling="" nucleus="" of="" or="" p="" particularly="" prp="" sc="" sites="" spinal="" spongiform="" the="" there="" these="" throughout="" tract="" trigeminal="" vacuolation="" white="" within="">
Since its initial detection in Norway in 1998,5 atypical scrapie has been reported in sheep in the majority of European countries (including in regions free of classical scrapie)2,6 and in the Falkland Islands,7 the USA,8 Canada,9 New Zealand10 and Australia.11,12 It usually occurs as single cases within sheep flocks, in an older age range than classical scrapie, and is often found in sheep with prion protein genotypes associated with resistance to classical scrapie.2

Worldwide, most cases of atypical scrapie have been detected during surveillance testing of apparently healthy sheep at slaughter or fallen stock (diseased or dead animals) by rapid immunochemical methods introduced for testing of small ruminants for TSE in the European Union from 2002.4,6 Prevalence estimates of atypical scrapie from these two test populations (slaughter and fallen stock) were remarkably uniform across 14 European countries (average 6.1 and 8.2 cases, respectively, per 10,000 tests), in contrast to the more variable and clustered occurrence of classical scrapie.6

The National TSE Surveillance Program (NTSESP) in Australia includes passive surveillance for classical scrapie by histological screening of brains from sheep (at least 18 months of age) with clini- cal signs of progressive neurological disease.13 In this report, we describe the clinical and pathological findings in five NTSESP cases of atypical scrapie detected in New South Wales (in 1999 and 2016), Western Australia (in 2009)11 and Victoria (in 2011 and 2014).12

Case reports

History and clinical findings
Case 1 (euthanased 2 August 1999, New South Wales: archival
NTSESP material). A 2-year-old Merino ewe in mid-gestation devel-
oped hindlimb ataxia, muscle tremors, weakness and depression,
with progression to recumbency in 2 weeks.

*Corresponding author: 2 Evelyn Villa Drive, Alstonville, New South Wales 2477, Australia; cookr@lis.net.au

a Regional Veterinary Laboratory, NSW Department of Primary Industries, Wollongbar, New South Wales 2480, Australia

b CSIRO, Australian Animal Health Laboratory, Geelong, Victoria, Australia

c Animal Health Laboratories, Department of Agriculture and Food, South Perth, Western Australia, Australia

d Gribbles Veterinary Pathology, Clayton, Victoria, Australia

e Department of Economic Development, AgriBio Centre, Bundoora, Victoria,

Australia
f Elizabeth Macarthur Agricultural Institute, NSW Department of Primary Industries,Menangle, New South Wales, Australia

snip...see ;

http://onlinelibrary.wiley.com/wol1/doi/10.1111/avj.12529/full
<15 2="" 5="" also="" and="" at="" basal="" brain.2="" cerebellar="" cerebral="" change="" cortex="" demonstrates="" deposition="" detected="" ganglia.="" grey="" immu-="" immunohistochemistry="" in="" intracytoplasmic="" is="" kda.="" layer="" mainly="" matter="" molecular="" nerve="" neurons.3="" neuropil="" no="" nolabelling="" nucleus="" of="" or="" p="" particularly="" prp="" sc="" sites="" spinal="" spongiform="" the="" there="" these="" throughout="" tract="" trigeminal="" vacuolation="" white="" within="">

http://onlinelibrary.wiley.com/doi/10.1111/avj.12529/epdf?r3_referer=wol&tracking_action=preview_click&show_checkout=1&purchase_referrer=onlinelibrary.wiley.com&purchase_site_license=LICENSE_DENIED_NO_CUSTOMER


Thursday, October 7, 2010

Australia first documented case of atypical scrapie confirmed

http://nor-98.blogspot.com/2010/10/australia-first-documented-case-of.html

Australia Senate BSE TSE Prion Terry S. Singeltary Sr.

http://www.aph.gov.au/~/media/wopapub/senate/senate/commttee/S12742_pdf.ashx

Saturday, April 23, 2016

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

Juan Maria Torres a, Olivier Andreoletti b, J uan-Carlos Espinosa a. Vincent Beringue c. Patricia Aguilar a,

Natalia Fernandez-Borges a. and Alba Marin-Moreno a

"Centro de Investigacion en Sanidad Animal ( CISA-INIA ). Valdeolmos, Madrid. Spain; b UMR INRA -ENVT 1225 Interactions Holes Agents Pathogenes. ENVT. Toulouse. France: "UR892. Virologie lmmunologie MolécuIaires, Jouy-en-Josas. France

Dietary exposure to bovine spongiform encephalopathy (BSE) contaminated bovine tissues is considered as the origin of variant Creutzfeldt Jakob (vCJD) disease in human. To date, BSE agent is the only recognized zoonotic prion. Despite the variety of Transmissible Spongiform Encephalopathy (TSE) agents that have been circulating for centuries in farmed ruminants there is no apparent epidemiological link between exposure to ruminant products and the occurrence of other form of TSE in human like sporadic Creutzfeldt Jakob Disease (sCJD). However, the zoonotic potential of the diversity of circulating TSE agents has never been systematically assessed. The major issue in experimental assessment of TSEs zoonotic potential lies in the modeling of the ‘species barrier‘, the biological phenomenon that limits TSE agents’ propagation from a species to another. In the last decade, mice genetically engineered to express normal forms of the human prion protein has proved essential in studying human prions pathogenesis and modeling the capacity of TSEs to cross the human species barrier.

To assess the zoonotic potential of prions circulating in farmed ruminants, we study their transmission ability in transgenic mice expressing human PrPC (HuPrP-Tg). Two lines of mice expressing different forms of the human PrPC (129Met or 129Val) are used to determine the role of the Met129Val dimorphism in susceptibility/resistance to the different agents.

These transmission experiments confirm the ability of BSE prions to propagate in 129M- HuPrP-Tg mice and demonstrate that Met129 homozygotes may be susceptible to BSE in sheep or goat to a greater degree than the BSE agent in cattle and that these agents can convey molecular properties and neuropathological indistinguishable from vCJD. However homozygous 129V mice are resistant to all tested BSE derived prions independently of the originating species suggesting a higher transmission barrier for 129V-PrP variant.

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

why do we not want to do TSE transmission studies on chimpanzees $

5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man. I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough. Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.

snip...

R. BRADLEY

https://web.archive.org/web/20170126051158/http://collections.europarchive.org/tna/20080102222950/http://www.bseinquiry.gov.uk/files/yb/1990/09/23001001.pdf

*** 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

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

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

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

http://scrapie-usa.blogspot.com/2016/04/scrapie-ws-01-prion-diseases-in-animals.html

1978 SCRAPIE IN CONFIDENCE SCJD

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/03/09001001.pdf

<15 2="" 5="" also="" and="" at="" basal="" brain.2="" cerebellar="" cerebral="" change="" cortex="" demonstrates="" deposition="" detected="" ganglia.="" grey="" immu-="" immunohistochemistry="" in="" intracytoplasmic="" is="" kda.="" layer="" mainly="" matter="" molecular="" nerve="" neurons.3="" neuropil="" no="" nolabelling="" nucleus="" of="" or="" p="" particularly="" prp="" sc="" sites="" spinal="" spongiform="" the="" there="" these="" throughout="" tract="" trigeminal="" vacuolation="" white="" within="">
http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/06/01001001.pdf


http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/06/27001001.pdf


<15 2="" 5="" also="" and="" at="" basal="" brain.2="" cerebellar="" cerebral="" change="" cortex="" demonstrates="" deposition="" detected="" ganglia.="" grey="" immu-="" immunohistochemistry="" in="" intracytoplasmic="" is="" kda.="" layer="" mainly="" matter="" molecular="" nerve="" neurons.3="" neuropil="" no="" nolabelling="" nucleus="" of="" or="" p="" particularly="" prp="" sc="" sites="" spinal="" spongiform="" the="" there="" these="" throughout="" tract="" trigeminal="" vacuolation="" white="" within="">http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/06/27002001.pdf


http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/06/27003001.pdf


http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/06/27004001.pdf


http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/08/18001001.pdf
<15 2="" 5="" also="" and="" at="" basal="" brain.2="" cerebellar="" cerebral="" change="" cortex="" demonstrates="" deposition="" detected="" ganglia.="" grey="" immu-="" immunohistochemistry="" in="" intracytoplasmic="" is="" kda.="" layer="" mainly="" matter="" molecular="" nerve="" neurons.3="" neuropil="" no="" nolabelling="" nucleus="" of="" or="" p="" particularly="" prp="" sc="" sites="" spinal="" spongiform="" the="" there="" these="" throughout="" tract="" trigeminal="" vacuolation="" white="" within="">
<15 2="" 5="" also="" and="" at="" basal="" brain.2="" cerebellar="" cerebral="" change="" cortex="" demonstrates="" deposition="" detected="" ganglia.="" grey="" immu-="" immunohistochemistry="" in="" intracytoplasmic="" is="" kda.="" layer="" mainly="" matter="" molecular="" nerve="" neurons.3="" neuropil="" no="" nolabelling="" nucleus="" of="" or="" p="" particularly="" prp="" sc="" sites="" spinal="" spongiform="" the="" there="" these="" throughout="" tract="" trigeminal="" vacuolation="" white="" within="">
http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/10/06001001.pdf
<15 2="" 5="" also="" and="" at="" basal="" brain.2="" cerebellar="" cerebral="" change="" cortex="" demonstrates="" deposition="" detected="" ganglia.="" grey="" immu-="" immunohistochemistry="" in="" intracytoplasmic="" is="" kda.="" layer="" mainly="" matter="" molecular="" nerve="" neurons.3="" neuropil="" no="" nolabelling="" nucleus="" of="" or="" p="" particularly="" prp="" sc="" sites="" spinal="" spongiform="" the="" there="" these="" throughout="" tract="" trigeminal="" vacuolation="" white="" within="">


http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/10/06002001.pdf
<15 2="" 5="" also="" and="" at="" basal="" brain.2="" cerebellar="" cerebral="" change="" cortex="" demonstrates="" deposition="" detected="" ganglia.="" grey="" immu-="" immunohistochemistry="" in="" intracytoplasmic="" is="" kda.="" layer="" mainly="" matter="" molecular="" nerve="" neurons.3="" neuropil="" no="" nolabelling="" nucleus="" of="" or="" p="" particularly="" prp="" sc="" sites="" spinal="" spongiform="" the="" there="" these="" throughout="" tract="" trigeminal="" vacuolation="" white="" within="">

1979

SILENCE ON CJD AND SCRAPIE

1980

SILENCE ON CJD AND SCRAPIE

*** 1981 NOVEMBER

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1981/11/26001001.pdf
<15 2="" 5="" also="" and="" at="" basal="" brain.2="" cerebellar="" cerebral="" change="" cortex="" demonstrates="" deposition="" detected="" ganglia.="" grey="" immu-="" immunohistochemistry="" in="" intracytoplasmic="" is="" kda.="" layer="" mainly="" matter="" molecular="" nerve="" neurons.3="" neuropil="" no="" nolabelling="" nucleus="" of="" or="" p="" particularly="" prp="" sc="" sites="" spinal="" spongiform="" the="" there="" these="" throughout="" tract="" trigeminal="" vacuolation="" white="" within="">

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1981/11/26001001.pdf
<15 2="" 5="" also="" and="" at="" basal="" brain.2="" cerebellar="" cerebral="" change="" cortex="" demonstrates="" deposition="" detected="" ganglia.="" grey="" immu-="" immunohistochemistry="" in="" intracytoplasmic="" is="" kda.="" layer="" mainly="" matter="" molecular="" nerve="" neurons.3="" neuropil="" no="" nolabelling="" nucleus="" of="" or="" p="" particularly="" prp="" sc="" sites="" spinal="" spongiform="" the="" there="" these="" throughout="" tract="" trigeminal="" vacuolation="" white="" within="">
<15 2="" 5="" also="" and="" at="" basal="" brain.2="" cerebellar="" cerebral="" change="" cortex="" demonstrates="" deposition="" detected="" ganglia.="" grey="" immu-="" immunohistochemistry="" in="" intracytoplasmic="" is="" kda.="" layer="" mainly="" matter="" molecular="" nerve="" neurons.3="" neuropil="" no="" nolabelling="" nucleus="" of="" or="" p="" particularly="" prp="" sc="" sites="" spinal="" spongiform="" the="" there="" these="" throughout="" tract="" trigeminal="" vacuolation="" white="" within="">
Thursday, August 04, 2016

*** MEETING ON THE FEASIBILITY OF CARRYING OUT EPIDEMIOLOGICAL STUDIES ON CREUTZFELDT JAKOB DISEASE 1978 THE SCRAPIE FILES IN CONFIDENCE CONFIDENTIAL SCJD

http://scrapie-usa.blogspot.com/2016/08/meeting-on-feasibility-of-carrying-out.html
<15 2="" 5="" also="" and="" at="" basal="" brain.2="" cerebellar="" cerebral="" change="" cortex="" demonstrates="" deposition="" detected="" ganglia.="" grey="" immu-="" immunohistochemistry="" in="" intracytoplasmic="" is="" kda.="" layer="" mainly="" matter="" molecular="" nerve="" neurons.3="" neuropil="" no="" nolabelling="" nucleus="" of="" or="" p="" particularly="" prp="" sc="" sites="" spinal="" spongiform="" the="" there="" these="" throughout="" tract="" trigeminal="" vacuolation="" white="" within="">

Terry S. Singeltary Sr.

Goat K222-PrPC polymorphic variant does not provide resistance to atypical scrapie in transgenic mice

Research article

 

Open Access

 

Goat K222-PrPC polymorphic variant does not provide resistance to atypical scrapie in transgenic mice

 

Patricia Aguilar-Calvo1, 6, Juan-Carlos Espinosa1, Olivier Andréoletti2, Lorenzo González3, Leonor Orge4, Ramón Juste5 and Juan-María Torres1Email author Veterinary Research201647:96 DOI: 10.1186/s13567-016-0380-7

 

© The Author(s) 2016

 

Received: 11 June 2016

 

Accepted: 1 September 2016

 

Published: 22 September 2016

 

Abstract Host prion (PrPC) genotype is a major determinant for the susceptibility to prion diseases. The Q/K222-PrPC polymorphic variant provides goats and mice with high resistance against classical scrapie and bovine spongiform encephalopathy (BSE); yet its effect against atypical scrapie is unknown. Here, transgenic mice expressing the goat wild-type (wt) or the K222-PrPC variant were intracerebrally inoculated with several natural cases of atypical scrapie from sheep and goat and their susceptibility to the prion disease was determined. Goat wt and K222-PrPC transgenic mice were 100% susceptible to all the atypical scrapie isolates, showing similar survival times and almost identical disease phenotypes. The capacity of the K222-PrPC variant to replicate specifically the atypical scrapie strain as efficiently as the goat wt PrPC, but not the classical scrapie or cattle-BSE as previously reported, further suggests the involvement of concrete areas of the host PrPC in the strain-dependent replication of prions.

 

 snip...

 

 Susceptibility to prions and disease phenotypes are likely modulated by conformational properties of prion strains and the PrPC and PrPSc amino acid sequence [13]. Some host PrPC amino acid sequences may have greater “plasticity” or ability to misfold—as proposed for the unique susceptibility of bank voles to a wide variety of prion diseases [14] and to “in vitro” conversion experiments [15]—while others may show the opposite situation, locking PrPC and preventing its conversion by different prion strains. Nonetheless, the plasticity of the host PrPC would not explain why certain amino acid substitutions inhibit the replication of some prion strains but not others. A clear example is the goat K222 variant which provides high resistance against classical scrapie and bovine spongiform encephalopathy (BSE) from cattle—being protective even in heterozygous mice and goats [5, 6, 9]—but it is as efficient as the goat wt PrPC in replicating sheep and goat-BSE [5] and atypical scrapie when intracerebrally inoculated. The resistance of the K222 variant to classical scrapie was associated to the additional positive charge at codon 222 provided by the lysine amino acid, which could interfere with the PrPC:PrPSc interaction, abolishing or lowering the conversion rates of PrPC [16]. Similarly, the perturbations in the PrPC surface charge distribution and structural rearrangements mainly localized at the β2–α2 loop region (residues 169–179 in goat PrPC numbering) are likely to underlie the resistance of the human E/K219 variant against CJD [17].

 

More recently, the existence of critical initial PrPC–PrPSc interaction sites during the templating of PrPC by different prions was proposed [18]. The involvement of specific PrPC areas in the strain-dependent replication of prions could account for the variable role of the K222-PrPC variant in the susceptibility to scrapie. While for classical scrapie polymorphic variants along the PrPC have been associated to modulate the susceptibility to the disease, for atypical scrapie only few have been reported—A/V136, F/L141, R/H154 and Q/R171 [4, 19]— that, interestingly, are all located within β1–α1 and β2–α2 loops. This area could be the critical segment for atypical scrapie interaction with the host PrPC and therefore any amino acid exchange outside this segment would not affect the capacity of replication of the atypical scrapie, as observed in our transmission study in goat wt and K222-PrPC mice. In fact this area seems to be accessible in the abnormally folded aggregate of the atypical scrapie agent as suggested by the observation that the C-terminal part of atypical scrapie PrPSc can be specifically trimmed by PK [20]. In conclusion, although more information is still needed to decipher the mechanisms of prion conversion, our study points to the involvement of specific PrPC areas in the strain-dependent replication of prions. Thus, strategies to fight prion diseases based on genotype breeding programs should be prion strain targeted.

 

 http://veterinaryresearch.biomedcentral.com/articles/10.1186/s13567-016-0380-7

 

 *** Grant Agreement number: 222887 ***

 

*** Project acronym: PRIORITY ***

 

*** Project title: Protecting the food chain from prions: shaping European priorities through basic and applied research Funding ***

 

Scheme: Large-scale integrating project Period covered: from Oct. 1, 2009 to Sept. 30, 2014

 

Name of the scientific representative of the project's co-ordinator1, Title and Organisation: Jesús R. Requena, Ph.D., Associate Professor, Department of medicine, University of Santiago de Compostela, Spàin. Tel: 34-881815464 Fax: 34-881815403 E-mail: jesus.requena@usc.es

 

Project website¡Error! Marcador no definido. address: www.prionpriority.eu

 

PRIORITY, PROJECT FINAL REPORT

 

*** 14) Concluding that atypical scrapie can transmit to Humans and that its strain properties change as it transmits between species ***

 

snip...

 

Block D: Prion epidemiology

 

Studies on atypical scrapie were identified as a key element of this block, given the potential risk associated to this agent. We studied the permeability of Human, bovine and porcine species barriers to atypical scrapie agent transmission. Experiments in transgenic mice expressing bovine, porcine or human PrPC suggest that this TSE agent has the intrinsic ability to propagate across these species barriers including the Human one. Upon species barrier passage the biological properties and phenotype of atypical scrapie seem to be altered. Further experiments are currently ongoing (in the framework of this project but also in other projects) in order to: (i) characterize the properties of the prion that emerged from the propagation of atypical scrapie in tg Hu; (ii) to confirm that the phenomena we observed are also true for atypical scrapie isolates other than the ones we have studied.

 

In parallel, studies in shep have concluded that: 

 

*** Atypical scrapie can be transmitted by both oral and intracerebral route in sheep with various PRP genotypes 

 

*** Low but consistent amount of infectivity accumulates in peripheral tissue (mammary gland, lymph nodes, placenta, skeletal muscles, nerves) of sheep incubating atypical scrapie.

 

*** The combination of data from all our studies leads us to conclude that: 

 

*** Atypical scrapie passage through species barriers can lead to the emergence of various prions including classical BSE (following propagation in porcine PRP transgenic mice). 

 

*** Atypical scrapie can propagate, with a low efficacy, in human PrP expressing mice. This suggests the existence of a zoonotic potential for this TSE agent.

 

snip...

 

We advance our main conclusions and recommendations, in particular as they might affect public policy, including a detailed elaboration of the evidence that led to them. Our main recommendations are:

 

a. The issue of re-introducing ruminant protein into the food-chain The opinion of the members of Priority is that sustaining an absolute feed ban for ruminant protein to ruminants is the essential requirement, especially since the impact of non-classical forms of scrapie in sheep and goats is not fully understood and cannot be fully estimated. Therefore, the consortium strongly recommends prohibiting re-introduction of processed ruminant protein into the food-chain. Arguments in support of this opinion are:

 

• the large (and still uncharacterized) diversity of prion agents that circulate in animal populations;

 

• the uncertainties related to prion epidemiology in animal populations;

 

• the unknown efficacy of industrial processes applied to reduce microbiological risk during processed animal protein (PAP) production on most prion agents; • the intrinsic capacity of prions to cross interspecies transmission barriers; • the lack of sensitive methodology for identifying cross contamination in food.

 

• the evolution of natural food chains in nature (i.e. who eats whom or what) has generated an efficient barrier preventing, to some extent, novel prion epidemies and that this naturally evolved ecology should be respected.

 

The consortium is also hesitant to introduce processed ruminant proteins into fish food considering the paucity of data on prion infections in fishes and sea animals including those of mammalian origin, and the risk of establishing an environmental contamination of the oceans that cannot be controlled.

 

b. Atypical prion agents and surveillance

 

Atypical prion agents (see below) will probably continue to represent the dominant form of prion diseases in the near future, particularly in Europe.

 

*** Atypical L-type BSE has clear zoonotic potential, as demonstrated in experimental models.

 

*** Similarly, there are now some data that seem to indicate that the atypical scrapie agent can cross various species barriers.

 

*** Moreover, the current EU policy for eradicating scrapie (genetic selection in affected flocks) is ineffective for preventing atypical scrapie.

 

*** The recent identification of cell-to-cell propagation and the protein-encoded strain properties of human neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, suggest that they bear the potential to be transmissible even if not with the same efficiency as CJD. More epidemiological data from large cohorts are necessary to reach any conclusion on the impact of their transmissibility on public health. Re-evaluations of safety precautions may become necessary depending on the outcome of these studies. In that context it would appear valuable

 

• to develop knowledge related to the pathogenesis and inter-individual transmission of atypical prion agents in ruminants (both intra- and inter-species)

 

• to improve the sensitivity of detection assays that are applied in the field towards this type of agent

 

• to maintain a robust surveillance of both animal and human populations

 

c. The need for extended research on prions

 

Intensified searching for a molecular determinants of the species barrier is recommended, since this barrier is a key for many important policy areas - risk assessment, proportional policies, the need for screening of human products and food. In this respect, prion strain structural language also remains an important issue for public health for the foreseeable future. Understanding the structural basis for strains and the basis for adaptation of a strain to a new host will require continued fundamental research. Prions maintain a complex two-way relationship with the host cell and fundamental research is needed on mechanisms for their transmission, replication and cause of nervous system dysfunction and death.

 

Early detection of prion infection, ideally at preclinical stage, also remains crucial for development of effective treatment strategies in humans affected by the disease.

 

Position of the Priority consortium

 

Nearly 30 years ago, the appearance in the UK of Bovine Spongiform Encephalopathy (BSE) quickly brought the previously obscure “prion diseases” to the spotlight. The ensuing health and food crises that spread throughout Europe had devastating consequences. In the UK alone, there were more than 36,000 farms directly affected by BSE and the transmission of BSE prions to humans via the food chain has caused over 200 people in Europe to die from variant Creutzfeldt-Jakob disease (vCJD) (http://www.cjd.ed.ac.uk

 

Origins of prion epidemies

 

Classical BSE now appears to be under control, with 18 EU Member States having achieved the World Organisation for Animal Health (Office International Epizooties) „negligible risk‟ status (May 2014; http://www.oie.int/en/animal-health-in-the-world/official-disease-status/bse/list-of-bse-risk-status/), and the remaining MS assessed as „controlled‟ risk. Of note, research, including EU-funded research, has played a key role in this success: while the origin of the infection was never defined, the principle driver of the epidemic was identified as prions in Meat and Bone Meal (MBM). Tests based on prion protein-specific antibodies were developed, allowing detection of infected animals, and a better understanding of disease pathogenesis and the distribution of infectivity in edible tissues; experimental investigation of transmission barriers between different species allowed a rational estimation of risks, etc. All of this led to the implementation of rational and effective policies, such as the MBM ban to protect the animal feed chain, and the Specified Risk Material (SRM) regulations to protect the human food chain.

 

In spite of this progress, prions are still a threat. Epidemiological re-assessment indicates that the ∼10 year incubation period separating the peaks of the BSE and the vCJD epidemics is probably too short. In addition, results from a large number of human tonsil and appendix analyses in the UK suggest that there may be a high number of asymptomatic individuals who are positive for the disease-associated conformer prion protein PrPSc. While vCJD is the only form of human prion disease that has been consistently demonstrated to have lymphoreticular involvement, there has been no systematic investigation of lymphoid tissue in cases with other prion diseases.

 

The human prion problem

 

The clinical cases of vCJD identified to date have all shared a common PrP genotype (M129M), although one pre-clinical case was confirmed as an M129V heterozygote, and it has been mooted that perhaps only the M129M proportion of the population is susceptible. However, in the UK appendix study, PrP accumulation was described in samples representing every codon 129 genotype, raising the possibility that genotype does not confer resistance but instead modulates incubation period. Apart from the two UK studies, the lymphoid tissues of non-CJD patients have not been examined for the presence of PrPSc, so, these cases may not solely represent pre-clinical vCJD, but also other forms of prion disease.

 

Recent experiments in highly susceptible mouse models indicate the presence of infectivity in blood or blood components at late disease stages in sporadic CJD. The significance of this experimental finding for humans has to be explored in more detail and, at the present time, there is no evidence for the transmission of prions via blood in sporadic CJD. However a likely scenario is that all those with signs of infection or abnormal PrP accumulation in peripheral tissue could have infective blood, posing the risk for transmission via blood products, which has been clearly demonstrated in experimental models, and confirmed in several cases of vCJD in man. Altogether, these data clearly demonstrate the potential risk of a second wave of vCJD, particularly when the number people identified with lymphoid accumulation of PrPSc (16/32,411) gives a prevalence estimate in the UK of 493 per million, much higher than the number of clinical cases seen to date.

 

The animal prion problem

 

An increasing number of reports on cases of “atypical” BSE in cattle throughout the EU and beyond may lead to a new epidemic, particularly since we still do not understand all factors determining the species barrier. Ovine scrapie is another concern, because it could mask ovine BSE, presumably transmissible to humans. Scrapie is endemic and not likely to be eradicated soon, although current control measures are effective at greatly reducing disease incidence. Atypical forms, which may be spontaneous, are not affected by these control measures and these forms of disease will persist in the global animal population. The low prevalence of these disease forms makes effective surveillance very challenging. However, there is a clear risk attendant on ignoring these cases without an understanding of their possible zoonotic potential, particularly when most forms of human disease have no established aetiology. In summary, atypical cases of BSE and scrapie presently clearly outnumber classical cases in cattle and sheep in all member states.

 

We will highlight the state-of-the-art knowledge and point out scientific challenges and the major questions for research. Strategic objectives and priorities in Europe in the future for research that aims to control, eliminate or eradicate the threat posed by prions to our food and health are also indicated.

 

The Priority project has focused on 4 themes, namely the structure, function, conversion and toxicity of prions; detection of prions; mechanisms of prion transmission and spreading and epidemiology of prion diseases. This paper summarizes the opinions/positions reached within these themes at the end of the project.

 

http://cordis.europa.eu/docs/results/222/222887/final1-priority-final-report.pdf

 

Assessment of the PrPc amino-terminal domain in prion species barriers

 

Kristen A. Davenporta, Davin M. Hendersona, Candace K. Mathiasona and Edward A. Hoovera# + Author Affiliations

 

Prion Research Center, Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523a ABSTRACT Chronic wasting disease (CWD) in cervids and bovine spongiform encephalopathy (BSE) in cattle are prion diseases that are caused by the same protein-misfolding mechanism, but appear to pose different risks to humans. We are interested in understanding the differences between the species barriers of CWD and BSE. We used real-time, quaking-induced conversion (RT-QuIC) to model the central molecular event in prion disease, the templated misfolding of the normal prion protein, PrPc, to a pathogenic, amyloid isoform, PrPSc. We examined the role of the PrPc amino-terminal domain (NTD, aa23-90) in cross-species conversion by comparing the conversion efficiency of various prion seeds in either full-length (aa23-231) or truncated (aa90-231) PrPc. We demonstrate that the presence of white-tailed deer and bovine NTDs hindered seeded conversion of PrPc, but human and bank vole NTDs did the opposite. Additionally, full-length human and bank vole PrPc were more likely to be converted to amyloid by CWD prions than were their truncated forms. A chimera with replacement of the human NTD by the bovine NTD resembled human PrPc. The requirement for an NTD, but not for the specific human sequence, suggests that the NTD interacts with other regions of the human PrPc to increase promiscuity. These data contribute to the evidence that, in addition to primary sequence, prion species barriers are controlled by interactions of the substrate NTD with the rest of the substrate PrPc molecule.

 

Importance We demonstrate that the amino-terminal domain of the normal prion protein, PrPc, hinders seeded conversion of bovine and white-tailed deer PrPc to the prion form, but it facilitates conversion of the human and bank vole PrPc to the prion form. Additionally, we demonstrate that the amino-terminal domain of human and bank vole PrPc requires interaction with the rest of the molecule to facilitate conversion by CWD prions. These data suggest that interactions of the amino-terminal domain with the rest of the PrPc molecule play an important role in the susceptibility of humans to CWD prions.

 

snip...

 

We found that human rPrPc can be readily converted to an amyloid state by CWD prions, and that the NTD facilitates this conversion. As there is little evidence for the susceptibility of humans to CWD, the biologic significance of our observation remains to be determined. However, the role of the NTD in this in vitro phenomenon may be important to the in vivo mechanism as well. RT-QuIC, transgenic mouse bioassay, and PMCA measure different outcomes. This manuscript compares the efficiency of initial amyloid formation, while bioassay and PMCA reflect total accumulation of protease-resistant PrPSc, which may explain the difference in the apparent susceptibility of full-length human rPrPc in these models. The molecular underpinnings for species barriers and trans-species prion conversion remain a complex, yet important problem in prion biology. We propose that an interaction between the amino terminal

 

FOOTNOTES

 

↵#Address correspondence to Edward A. Hoover, edward.hoover@colostate.edu Copyright © 2016, American Society for Microbiology. All Rights Reserved.

 

http://jvi.asm.org/content/early/2016/09/15/JVI.01121-16.abstract

 

http://jvi.asm.org/content/early/2016/09/15/JVI.01121-16.full.pdf+html

 

Tuesday, September 27, 2016

 

Classical Scrapie Diagnosis in ARR/ARR Sheep in Brazil

 

Acta Scientiae Veterinariae, 2015. 43(Suppl 1): 69.

 

http://scrapie-usa.blogspot.com/2016/09/classical-scrapie-diagnosis-in-arrarr.html

 

 Wednesday, September 28, 2016

 

Norway sides with OIE, decides to expose millions of consumers to the ATYPICAL BSE SRM TSE Prion aka mad cow type disease

 

http://bse-atypical.blogspot.com/2016/09/norway-sides-with-oie-decides-to-expose.html

 

Friday, September 23, 2016

 

North Iceland reporting more cases of Scrapie (Rida)

 

http://scrapie-usa.blogspot.com/2016/09/north-iceland-reporting-more-cases-of.html

 

 Monday, September 19, 2016

 

Identification of the first case of atypical scrapie in Japan

 

http://nor-98.blogspot.com/2016/09/identification-of-first-case-of.html

 

Monday, September 19, 2016

 

Evidence of scrapie transmission to sheep via goat milk

 

http://scrapie-usa.blogspot.com/2016/09/evidence-of-scrapie-transmission-to.html

 

Tuesday, September 06, 2016

 

A comparison of classical and H-type bovine spongiform encephalopathy associated with E211K prion protein polymorphism in wild type and EK211 cattle following intracranial inoculation

 

http://bse-atypical.blogspot.com/2016/09/a-comparison-of-classical-and-h-type.html

 

‘’We demonstrate that the presence of white-tailed deer and bovine NTDs hindered seeded conversion of PrPc, but human and bank vole NTDs did the opposite. Additionally, full-length human and bank vole PrPc were more likely to be converted to amyloid by CWD prions than were their truncated forms. ‘’

 

***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.***

 

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

 

Monday, May 02, 2016

 

*** Zoonotic Potential of CWD Prions: An Update Prion 2016 Tokyo ***

 

 http://chronic-wasting-disease.blogspot.com/2016/05/zoonotic-potential-of-cwd-prions-update.html

 

SCRAPIE AND CWD ZOONOSIS

 

PRION 2016 CONFERENCE 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

 

http://scrapie-usa.blogspot.com/2016/04/scrapie-ws-01-prion-diseases-in-animals.html

 

http://chronic-wasting-disease.blogspot.com/

 

Saturday, September 24, 2016

 

Assessment of the PrPc amino-terminal domain in prion species barriers

 

http://chronic-wasting-disease.blogspot.com/2016/09/assessment-of-prpc-amino-terminal.html

 

*** 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...

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/mb/m09/tab05.pdf

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/mb/m09a/tab01.pdf

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1987/06/10004001.pdf

 

In Confidence - Perceptions of unconventional slow virus diseases of animals in the USA - APRIL-MAY 1989 - G A H Wells

 

3. Prof. A. Robertson gave a brief account of BSE. The US approach was to accord it a very low profile indeed. Dr. A Thiermann showed the picture in the ''Independent'' with cattle being incinerated and thought this was a fanatical incident to be avoided in the US at all costs. ...

 

http://web.archive.org/web/20060307063531/http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf

 

”The occurrence of CWD must be viewed against the contest of the locations in which it occurred. It was an incidental and unwelcome complication of the respective wildlife research programmes. Despite it’s subsequent recognition as a new disease of cervids, therefore justifying direct investigation, no specific research funding was forthcoming. The USDA veiwed it as a wildlife problem and consequently not their province!” ...page 26.

 

http://collections.europarchive.org/tna/20080102193705/http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf

 

Scrapie-like disorder in a Nyala (Tragelaphus angasi)

 

IN CONFIDENCE

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1986/11/00001001.pdf

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1986/06/23001001.pdf

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1986/07/08001001.pdf

 

Spongiform encephalopathy has so far only been recorded in the sheep and goat, man, mink, and several deer including the mule deer, black tailed deer and the elk (most, if not all, of the deer incidents occurred in wild life parts in Wyoming and Colorado). Clinical cases in deer all occurred from 3 1/2 to 5 years old and usually 60-80% losses occurred over a 4 year period...

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1986/07/24001001.pdf

 

The clinical and neuropathological findings in F22 are consistent with the spongiform encephalopathies of animals and man. The agents causing spongiform encephalopathy in various species cannot be unequivocally distinguished and some isolates of human agent cause neurologic disease in goats indistinguishable from scrapie. The spongiform encephalopathies are invariably fatal once clinical signs of disease are evident and as very high fatality rates (79% of 67 animals) are recorded in Mule deer it is important that an awareness of the disease is maintained at Marwell.

 

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1986/07/21001001.pdf

 

Thursday, August 04, 2016

 

MEETING ON THE FEASIBILITY OF CARRYING OUT EPIDEMIOLOGICAL STUDIES ON CREUTZFELDT JAKOB DISEASE 1978 THE SCRAPIE FILES IN CONFIDENCE CONFIDENTIAL SCJD

 

http://scrapie-usa.blogspot.com/2016/08/meeting-on-feasibility-of-carrying-out.html

 

snip...

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/06/27002001.pdf

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/06/27003001.pdf

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/06/27004001.pdf

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/08/18001001.pdf

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/10/06001001.pdf

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1978/10/06002001.pdf

 

1979

 

SILENCE ON CJD AND SCRAPIE

 

1980

 

SILENCE ON CJD AND SCRAPIE

 

*** 1981 NOVEMBER

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1981/11/26001001.pdf

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1981/11/26001001.pdf

 

snip...see full text ;

 

Thursday, August 04, 2016

 

MEETING ON THE FEASIBILITY OF CARRYING OUT EPIDEMIOLOGICAL STUDIES ON CREUTZFELDT JAKOB DISEASE 1978 THE SCRAPIE FILES IN CONFIDENCE CONFIDENTIAL SCJD

 

http://scrapie-usa.blogspot.com/2016/08/meeting-on-feasibility-of-carrying-out.html

 

Scrapie Field Trial Experiments Mission, Texas, The Moore Air Force Base Scrapie Experiment 1964

 

How Did CWD Get Way Down In Medina County, Texas?

 

Confucius ponders...

 

Could the Scrapie experiments back around 1964 at Moore Air Force near Mission, Texas, could this area have been ground zero for CWD TSE Prion (besides the CWD cases that have waltzed across the Texas, New Mexico border near WSMR Trans Pecos region since around 2001)?

 

Epidemiology of Scrapie in the United States 1977

 

snip...

 

Scrapie Field Trial Experiments Mission, Texas

 

A Scrapie Field Trial was developed at Mission, Texas, to provide additional information for the eradication program on the epidemiology of natural scrapie. The Mission Field Trial Station is located on 450 acres of pastureland, part of the former Moore Air Force Base, near Mission, Texas. It was designed to bring previously exposed, and later also unexposed, sheep or goats to the Station and maintain and breed them under close observation for extended periods to determine which animals would develop scrapie and define more closely the natural spread and other epidemiological aspects of the disease.

 

The 547 previously exposed sheep brought to the Mission Station beginning in 1964 were of the Cheviot, Hampshire, Montadale, or Suffolk breeds. They were purchased as field outbreaks occurred, and represented 21 bloodlines in which scrapie had been diagnosed. Upon arrival at the Station, the sheep were maintained on pasture, with supplemental feeding as necessary. The station was divided into 2 areas: (1) a series of pastures and-pens occupied by male animals only, and (2) a series of pastures and pens occupied by females and young progeny of both sexes. ...

 

snip...see full text ;

 

http://web.archive.org/web/20030513212324/http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf

 

P.97: Scrapie transmits to white-tailed deer by the oral route and has a molecular profile similar to chronic wasting disease and distinct from the scrapie inoculum

 

Justin Greenlee1, S Jo Moore1, Jodi Smith1, M Heather West Greenlee2, and Robert Kunkle1

 

1National Animal Disease Center; Ames, IA USA;

 

2Iowa State University; Ames, IA USA

 

The purpose of this work was to determine susceptibility of white-tailed deer (WTD) to the agent of sheep scrapie and to compare the resultant PrPSc to that of the original inoculum and chronic wasting disease (CWD). We inoculated WTD by a natural route of exposure (concurrent oral and intranasal (IN); n D 5) with a US scrapie isolate. All scrapie-inoculated deer had evidence of PrPSc accumulation. PrPSc was detected in lymphoid tissues at preclinical time points, and deer necropsied after 28 months post-inoculation had clinical signs, spongiform encephalopathy, and widespread distribution of PrPSc in neural and lymphoid tissues. Western blotting (WB) revealed PrPSc with 2 distinct molecular profiles. WB on cerebral cortex had a profile similar to the original scrapie inoculum, whereas WB of brainstem, cerebellum, or lymph nodes revealed PrPSc with a higher profile resembling CWD. Homogenates with the 2 distinct profiles from WTD with clinical scrapie were further passaged to mice expressing cervid prion protein and intranasally to sheep and WTD. In cervidized mice, the 2 inocula have distinct incubation times. Sheep inoculated intranasally with WTD derived scrapie developed disease, but only after inoculation with the inoculum that had a scrapie-like profile. The WTD study is ongoing, but deer in both inoculation groups are positive for PrPSc by rectal mucosal biopsy. In summary, this work demonstrates that WTD are susceptible to the agent of scrapie, 2 distinct molecular profiles of PrPSc are present in the tissues of affected deer, and inoculum of either profile readily passes to deer.

 

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

 

Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

 

Title: Scrapie transmits to white-tailed deer by the oral route and has a molecular profile similar to chronic wasting disease

 

Authors

 

item Greenlee, Justin item Moore, S - item Smith, Jodi - item Kunkle, Robert item West Greenlee, M -

 

Submitted to: American College of Veterinary Pathologists Meeting Publication Type: Abstract Only Publication Acceptance Date: August 12, 2015 Publication Date: N/A Technical Abstract: The purpose of this work was to determine susceptibility of white-tailed deer (WTD) to the agent of sheep scrapie and to compare the resultant PrPSc to that of the original inoculum and chronic wasting disease (CWD). We inoculated WTD by a natural route of exposure (concurrent oral and intranasal (IN); n=5) with a US scrapie isolate. All scrapie-inoculated deer had evidence of PrPSc accumulation. PrPSc was detected in lymphoid tissues at preclinical time points, and deer necropsied after 28 months post-inoculation had clinical signs, spongiform encephalopathy, and widespread distribution of PrPSc in neural and lymphoid tissues. Western blotting (WB) revealed PrPSc with 2 distinct molecular profiles. WB on cerebral cortex had a profile similar to the original scrapie inoculum, whereas WB of brainstem, cerebellum, or lymph nodes revealed PrPSc with a higher profile resembling CWD. Homogenates with the 2 distinct profiles from WTD with clinical scrapie were further passaged to mice expressing cervid prion protein and intranasally to sheep and WTD. In cervidized mice, the two inocula have distinct incubation times. Sheep inoculated intranasally with WTD derived scrapie developed disease, but only after inoculation with the inoculum that had a scrapie-like profile. The WTD study is ongoing, but deer in both inoculation groups are positive for PrPSc by rectal mucosal biopsy. In summary, this work demonstrates that WTD are susceptible to the agent of scrapie, two distinct molecular profiles of PrPSc are present in the tissues of affected deer, and inoculum of either profile readily passes to deer.

 

http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=317901

 

http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=260467

 

White-tailed Deer are Susceptible to Scrapie by Natural Route of Infection

 

Jodi D. Smith, Justin J. Greenlee, and Robert A. Kunkle; Virus and Prion Research Unit, National Animal Disease Center, USDA-ARS

 

Interspecies transmission studies afford the opportunity to better understand the potential host range and origins of prion diseases. Previous experiments demonstrated that white-tailed deer are susceptible to sheep-derived scrapie by intracranial inoculation. The purpose of this study was to determine susceptibility of white-tailed deer to scrapie after a natural route of exposure. Deer (n=5) were inoculated by concurrent oral (30 ml) and intranasal (1 ml) instillation of a 10% (wt/vol) brain homogenate derived from a sheep clinically affected with scrapie. Non-inoculated deer were maintained as negative controls. All deer were observed daily for clinical signs. Deer were euthanized and necropsied when neurologic disease was evident, and tissues were examined for abnormal prion protein (PrPSc) by immunohistochemistry (IHC) and western blot (WB). One animal was euthanized 15 months post-inoculation (MPI) due to an injury. At that time, examination of obex and lymphoid tissues by IHC was positive, but WB of obex and colliculus were negative. Remaining deer developed clinical signs of wasting and mental depression and were necropsied from 28 to 33 MPI. Tissues from these deer were positive for scrapie by IHC and WB. Tissues with PrPSc immunoreactivity included brain, tonsil, retropharyngeal and mesenteric lymph nodes, hemal node, Peyer’s patches, and spleen. This work demonstrates for the first time that white-tailed deer are susceptible to sheep scrapie by potential natural routes of inoculation. In-depth analysis of tissues will be done to determine similarities between scrapie in deer after intracranial and oral/intranasal inoculation and chronic wasting disease resulting from similar routes of inoculation.

 

see full text ;

 

http://www.usaha.org/Portals/6/Reports/2010/report-cwal-2010.pdf

 

PO-039: A comparison of scrapie and chronic wasting disease in white-tailed deer

 

Justin Greenlee, Jodi Smith, Eric Nicholson US Dept. Agriculture; Agricultural Research Service, National Animal Disease Center; Ames, IA USA

 

http://www.landesbioscience.com/journals/prion/03-Prion6-2-Transmission-and-strains.pdf

 

White-tailed deer are susceptible to the agent of sheep scrapie by intracerebral inoculation

 

snip...

 

It is unlikely that CWD will be eradicated from free-ranging cervids, and the disease is likely to continue to spread geographically [10]. However, the potential that white-tailed deer may be susceptible to sheep scrapie by a natural route presents an additional confounding factor to halting the spread of CWD. This leads to the additional speculations that

 

1) infected deer could serve as a reservoir to infect sheep with scrapie offering challenges to scrapie eradication efforts and

 

2) CWD spread need not remain geographically confined to current endemic areas, but could occur anywhere that sheep with scrapie and susceptible cervids cohabitate.

 

This work demonstrates for the first time that white-tailed deer are susceptible to sheep scrapie by intracerebral inoculation with a high attack rate and that the disease that results has similarities to CWD. These experiments will be repeated with a more natural route of inoculation to determine the likelihood of the potential transmission of sheep scrapie to white-tailed deer. If scrapie were to occur in white-tailed deer, results of this study indicate that it would be detected as a TSE, but may be difficult to differentiate from CWD without in-depth biochemical analysis.

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3199251/?tool=pubmed

 

http://chronic-wasting-disease.blogspot.com/2011/10/white-tailed-deer-are-susceptible-to.html

 

2012

 

PO-039: A comparison of scrapie and chronic wasting disease in white-tailed deer

 

Justin Greenlee, Jodi Smith, Eric Nicholson US Dept. Agriculture; Agricultural Research Service, National Animal Disease Center; Ames, IA USA

 

snip...

 

The results of this study suggest that there are many similarities in the manifestation of CWD and scrapie in WTD after IC inoculation including early and widespread presence of PrPSc in lymphoid tissues, clinical signs of depression and weight loss progressing to wasting, and an incubation time of 21-23 months. Moreover, western blots (WB) done on brain material from the obex region have a molecular profile similar to CWD and distinct from tissues of the cerebrum or the scrapie inoculum. However, results of microscopic and IHC examination indicate that there are differences between the lesions expected in CWD and those that occur in deer with scrapie: amyloid plaques were not noted in any sections of brain examined from these deer and the pattern of immunoreactivity by IHC was diffuse rather than plaque-like.

 

*** After a natural route of exposure, 100% of WTD were susceptible to scrapie.

 

Deer developed clinical signs of wasting and mental depression and were necropsied from 28 to 33 months PI. Tissues from these deer were positive for PrPSc by IHC and WB. Similar to IC inoculated deer, samples from these deer exhibited two different molecular profiles: samples from obex resembled CWD whereas those from cerebrum were similar to the original scrapie inoculum. On further examination by WB using a panel of antibodies, the tissues from deer with scrapie exhibit properties differing from tissues either from sheep with scrapie or WTD with CWD. Samples from WTD with CWD or sheep with scrapie are strongly immunoreactive when probed with mAb P4, however, samples from WTD with scrapie are only weakly immunoreactive. In contrast, when probed with mAb’s 6H4 or SAF 84, samples from sheep with scrapie and WTD with CWD are weakly immunoreactive and samples from WTD with scrapie are strongly positive. This work demonstrates that WTD are highly susceptible to sheep scrapie, but on first passage, scrapie in WTD is differentiable from CWD.

 

http://www.landesbioscience.com/journals/prion/03-Prion6-2-Transmission-and-strains.pdf

 

2011

 

*** After a natural route of exposure, 100% of white-tailed deer were susceptible to scrapie.

 

http://www.usaha.org/Portals/6/Reports/2011/report-cwal-2011.pdf

 

White-tailed Deer are Susceptible to Scrapie by Natural Route of Infection

 

Jodi D. Smith, Justin J. Greenlee, and Robert A. Kunkle; Virus and Prion Research Unit, National Animal Disease Center, USDA-ARS

 

Interspecies transmission studies afford the opportunity to better understand the potential host range and origins of prion diseases. Previous experiments demonstrated that white-tailed deer are susceptible to sheep-derived scrapie by intracranial inoculation. The purpose of this study was to determine susceptibility of white-tailed deer to scrapie after a natural route of exposure. Deer (n=5) were inoculated by concurrent oral (30 ml) and intranasal (1 ml) instillation of a 10% (wt/vol) brain homogenate derived from a sheep clinically affected with scrapie. Non-inoculated deer were maintained as negative controls. All deer were observed daily for clinical signs. Deer were euthanized and necropsied when neurologic disease was evident, and tissues were examined for abnormal prion protein (PrPSc) by immunohistochemistry (IHC) and western blot (WB). One animal was euthanized 15 months post-inoculation (MPI) due to an injury. At that time, examination of obex and lymphoid tissues by IHC was positive, but WB of obex and colliculus were negative. Remaining deer developed clinical signs of wasting and mental depression and were necropsied from 28 to 33 MPI. Tissues from these deer were positive for scrapie by IHC and WB. Tissues with PrPSc immunoreactivity included brain, tonsil, retropharyngeal and mesenteric lymph nodes, hemal node, Peyer’s patches, and spleen. This work demonstrates for the first time that white-tailed deer are susceptible to sheep scrapie by potential natural routes of inoculation. In-depth analysis of tissues will be done to determine similarities between scrapie in deer after intracranial and oral/intranasal inoculation and chronic wasting disease resulting from similar routes of inoculation.

 

see full text ;

 

http://www.usaha.org/Portals/6/Reports/2010/report-cwal-2010.pdf

 

Friday, April 22, 2016

 

*** Texas Scrapie Confirmed in a Hartley County Sheep where CWD was detected in a Mule Deer

 

http://scrapie-usa.blogspot.com/2016/04/texas-scrapie-confirmed-in-hartley.html

 

Friday, February 26, 2016

 

TEXAS Hartley County Mule Deer Tests Positive for Chronic Wasting Disease CWD TSE Prion

 

http://chronic-wasting-disease.blogspot.com/2016/02/texas-hartley-county-mule-deer-tests.html

 

Tuesday, June 07, 2016

 

Comparison of two US sheep scrapie isolates supports identification as separate strains

 

Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

 

http://scrapie-usa.blogspot.com/2016/06/comparison-of-two-us-sheep-scrapie.html

 

‘’We demonstrate that the presence of white-tailed deer and bovine NTDs hindered seeded conversion of PrPc, but human and bank vole NTDs did the opposite. Additionally, full-length human and bank vole PrPc were more likely to be converted to amyloid by CWD prions than were their truncated forms. ‘’

 

***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.***

 

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

 

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

 

Emmanuel E. Comoy , Jacqueline Mikol , Sophie Luccantoni-Freire , Evelyne Correia , Nathalie Lescoutra-Etchegaray , Valérie Durand , Capucine Dehen , Olivier Andreoletti , Cristina Casalone , Juergen A. Richt , Justin J. Greenlee , Thierry Baron , Sylvie L. Benestad , Paul Brown & Jean-Philippe Deslys

 

Abstract

 

Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10-year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie.

 

snip...

 

In addition to previous studies on scrapie transmission to primate1,8,9 and the recently published study on transgenic humanized mice13, our results constitute new evidence for recommending that the potential risk of scrapie for human health should not be dismissed. Indeed, human PrP transgenic mice and primates are the most relevant models for investigating the human transmission barrier. To what extent such models are informative for measuring the zoonotic potential of an animal TSE under field exposure conditions is unknown. During the past decades, many protective measures have been successfully implemented to protect cattle from the spread of c-BSE, and some of these measures have been extended to sheep and goats to protect from scrapie according to the principle of precaution. Since cases of c-BSE have greatly reduced in number, those protective measures are currently being challenged and relaxed in the absence of other known zoonotic animal prion disease. We recommend that risk managers should be aware of the long term potential risk to human health of at least certain scrapie isolates, notably for lymphotropic strains like the classical scrapie strain used in the current study. Relatively high amounts of infectivity in peripheral lymphoid organs in animals infected with these strains could lead to contamination of food products produced for human consumption. Efforts should also be maintained to further assess the zoonotic potential of other animal prion strains in long-term studies, notably lymphotropic strains with high prevalence like CWD, which is spreading across North America, and atypical/Nor98 scrapie (Nor98)50 that was first detected in the past two decades and now represents approximately half of all reported cases of prion diseases in small ruminants worldwide, including territories previously considered as scrapie free. 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.

 

***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.***

 

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

 

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

 

2015

 

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

 

CWD TSE PRION HUMAN ZOONOSIS POTENTIAL, has it already happened, and being masked as sporadic CJD? and what about iatrogenic, or the pass if forward, friendly fire mode of transmission of cwd to humans, same thing, sporadic cjd ?

 

*** WDA 2016 NEW YORK ***

 

We found that CWD adapts to a new host more readily than BSE and that human PrP was unexpectedly prone to misfolding by CWD prions. In addition, we investigated the role of specific regions of the bovine, deer and human PrP protein in resistance to conversion by prions from another species. We have concluded that the human protein has a region that confers unusual susceptibility to conversion by CWD prions.

 

Student Presentations Session 2

 

The species barriers and public health threat of CWD and BSE prions

 

Ms. Kristen Davenport1, Dr. Davin Henderson1, Dr. Candace Mathiason1, Dr. Edward Hoover1 1Colorado State University

 

Chronic wasting disease (CWD) is spreading rapidly through cervid populations in the USA. Bovine spongiform encephalopathy (BSE, mad cow disease) arose in the 1980s because cattle were fed recycled animal protein. These and other prion diseases are caused by abnormal folding of the normal prion protein (PrP) into a disease causing form (PrPd), which is pathogenic to nervous system cells and can cause subsequent PrP to misfold. CWD spreads among cervids very efficiently, but it has not yet infected humans. On the other hand, BSE was spread only when cattle consumed infected bovine or ovine tissue, but did infect humans and other species. The objective of this research is to understand the role of PrP structure in cross-species infection by CWD and BSE. To study the propensity of each species’ PrP to be induced to misfold by the presence of PrPd from verious species, we have used an in vitro system that permits detection of PrPd in real-time. We measured the conversion efficiency of various combinations of PrPd seeds and PrP substrate combinations. We observed the cross-species behavior of CWD and BSE, in addition to feline-adapted CWD and BSE. We found that CWD adapts to a new host more readily than BSE and that human PrP was unexpectedly prone to misfolding by CWD prions. In addition, we investigated the role of specific regions of the bovine, deer and human PrP protein in resistance to conversion by prions from another species. We have concluded that the human protein has a region that confers unusual susceptibility to conversion by CWD prions. CWD is unique among prion diseases in its rapid spread in natural populations. BSE prions are essentially unaltered upon passage to a new species, while CWD adapts to the new species. This adaptation has consequences for surveillance of humans exposed to CWD.

 

Wildlife Disease Risk Communication Research Contributes to Wildlife Trust Administration Exploring perceptions about chronic wasting disease risks among wildlife and agriculture professionals and stakeholders

 

Ms. Alyssa Wetterau1, Dr. Krysten Schuler1, Dr. Elizabeth Bunting1, Dr. Hussni Mohammed1 1Cornell University

 

Chronic wasting disease (CWD) is a fatal disease of North American Cervidae. New York State (NYS, USA) successfully managed an outbreak of CWD in 2005 in both captive and wild white-tailed deer (Odocoileus virginianus) with no reoccurrence of the disease as of 2015. To attain maximum compliance and efficacy of management actions for prevention of CWD entry, understanding the varied risk perceptions will allow for targeted, proactive communication efforts to address divergences between expert-derived risk assessments and stakeholder risk perceptions. We examined perceived risks associated with CWD introduction and exposure among agricultural and wildlife agency professionals within and outside of NYS, as well as stakeholder groups (e.g., hunters and captive cervid owners). We measured perceived risk using a risk assessment questionnaire online via Qualtrics survey software and evaluated similarities within, as well as differences in, perception among participant groups. New York State biologists employed by the Department of Environmental Conservation and independent non-NYS wildlife and agricultural professionals thought CWD risks associated with captive cervids were high; captive cervid owners thought risks for wild and captive cervids were low. Agriculture and wildlife professional groups agreed on general risk perceptions. We ranked 15 individual risk hazards into high and low medium categories based on all responses. Differences between groups were most evident in hypothetical disease pathways. Any pathway involving inter-state import of live cervids received high ranking for all groups except captive cervid owners. Comparatively low risk perceptions by captive cervid operators may stem from misinformation, lack of understanding of testing programs, and indemnity payments for animal depopulation. Communication and education directed at areas of disagreement may facilitate effective disease prevention and management.

 

http://www.wda2016.org/uploads/5/8/6/1/58613359/wda_2016_conference_proceedings_low_res.pdf

 

http://csu-cvmbs.colostate.edu/Documents/research-day-2016.pdf

 

* No evaluation of determination of CWD risk is required for alternative livestock or captive wildlife shipped directly to slaughter or to a biosecure facility approved by the Division and the Dept. of Agriculture.

 

http://www.sos.state.co.us/CCR/GenerateRulePdf.do?ruleVersionId=6644&fileName=2%20CCR%20406-0

 

*** We found that CWD adapts to a new host more readily than BSE and that human PrP was unexpectedly prone to misfolding by CWD prions. In addition, we investigated the role of specific regions of the bovine, deer and human PrP protein in resistance to conversion by prions from another species. We have concluded that the human protein has a region that confers unusual susceptibility to conversion by CWD prions. CWD is unique among prion diseases in its rapid spread in natural populations. BSE prions are essentially unaltered upon passage to a new species, while CWD adapts to the new species. This adaptation has consequences for surveillance of humans exposed to CWD. ***

 

PRION 2016 TOKYO

 

Zoonotic Potential of CWD Prions: An Update

 

Ignazio Cali1, Liuting Qing1, Jue Yuan1, Shenghai Huang2, Diane Kofskey1,3, Nicholas Maurer1, Debbie McKenzie4, Jiri Safar1,3,5, Wenquan Zou1,3,5,6, Pierluigi Gambetti1, Qingzhong Kong1,5,6

 

1Department of Pathology, 3National Prion Disease Pathology Surveillance Center, 5Department of Neurology, 6National Center for Regenerative Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.

 

4Department of Biological Sciences and Center for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada,

 

2Encore Health Resources, 1331 Lamar St, Houston, TX 77010

 

Chronic wasting disease (CWD) is a widespread and highly transmissible prion disease in free-ranging and captive cervid species in North America. The zoonotic potential of CWD prions is a serious public health concern, but the susceptibility of human CNS and peripheral organs to CWD prions remains largely unresolved. We reported earlier that peripheral and CNS infections were detected in transgenic mice expressing human PrP129M or PrP129V. Here we will present an update on this project, including evidence for strain dependence and influence of cervid PrP polymorphisms on CWD zoonosis as well as the characteristics of experimental human CWD prions.

 

PRION 2016 TOKYO

 

In Conjunction with Asia Pacific Prion Symposium 2016

 

PRION 2016 Tokyo

 

Prion 2016

 

 http://prion2016.org/dl/newsletter_03.pdf

 

Tuesday, December 16, 2014

 

Evidence for zoonotic potential of ovine scrapie prions

 

Hervé Cassard,1, n1 Juan-Maria Torres,2, n1 Caroline Lacroux,1, Jean-Yves Douet,1, Sylvie L. Benestad,3, Frédéric Lantier,4, Séverine Lugan,1, Isabelle Lantier,4, Pierrette Costes,1, Naima Aron,1, Fabienne Reine,5, Laetitia Herzog,5, Juan-Carlos Espinosa,2, Vincent Beringue5, & Olivier Andréoletti1, Affiliations Contributions Corresponding author Journal name: Nature Communications Volume: 5, Article number: 5821 DOI: doi:10.1038/ncomms6821 Received 07 August 2014 Accepted 10 November 2014 Published 16 December 2014 Article tools Citation Reprints Rights & permissions Article metrics

 

Abstract

 

Although Bovine Spongiform Encephalopathy (BSE) is the cause of variant Creutzfeldt Jakob disease (vCJD) in humans, the zoonotic potential of scrapie prions remains unknown. Mice genetically engineered to overexpress the human ​prion protein (tgHu) have emerged as highly relevant models for gauging the capacity of prions to transmit to humans. These models can propagate human prions without any apparent transmission barrier and have been used used to confirm the zoonotic ability of BSE. Here we show that a panel of sheep scrapie prions transmit to several tgHu mice models with an efficiency comparable to that of cattle BSE. The serial transmission of different scrapie isolates in these mice led to the propagation of prions that are phenotypically identical to those causing sporadic CJD (sCJD) in humans. These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.

 

Subject terms: Biological sciences• Medical research At a glance

 

http://www.nature.com/ncomms/2014/141216/ncomms6821/full/ncomms6821.html

 

*** 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

 

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

 

Juan Maria Torres a, Olivier Andreoletti b, J uan-Carlos Espinosa a. Vincent Beringue c. Patricia Aguilar a,

 

Natalia Fernandez-Borges a. and Alba Marin-Moreno a

 

"Centro de Investigacion en Sanidad Animal ( CISA-INIA ). Valdeolmos, Madrid. Spain; b UMR INRA -ENVT 1225 Interactions Holes Agents Pathogenes. ENVT. Toulouse. France: "UR892. Virologie lmmunologie MolécuIaires, Jouy-en-Josas. France

 

Dietary exposure to bovine spongiform encephalopathy (BSE) contaminated bovine tissues is considered as the origin of variant Creutzfeldt Jakob (vCJD) disease in human. To date, BSE agent is the only recognized zoonotic prion. Despite the variety of Transmissible Spongiform Encephalopathy (TSE) agents that have been circulating for centuries in farmed ruminants there is no apparent epidemiological link between exposure to ruminant products and the occurrence of other form of TSE in human like sporadic Creutzfeldt Jakob Disease (sCJD). However, the zoonotic potential of the diversity of circulating TSE agents has never been systematically assessed. The major issue in experimental assessment of TSEs zoonotic potential lies in the modeling of the ‘species barrier‘, the biological phenomenon that limits TSE agents’ propagation from a species to another. In the last decade, mice genetically engineered to express normal forms of the human prion protein has proved essential in studying human prions pathogenesis and modeling the capacity of TSEs to cross the human species barrier.

 

To assess the zoonotic potential of prions circulating in farmed ruminants, we study their transmission ability in transgenic mice expressing human PrPC (HuPrP-Tg). Two lines of mice expressing different forms of the human PrPC (129Met or 129Val) are used to determine the role of the Met129Val dimorphism in susceptibility/resistance to the different agents.

 

These transmission experiments confirm the ability of BSE prions to propagate in 129M- HuPrP-Tg mice and demonstrate that Met129 homozygotes may be susceptible to BSE in sheep or goat to a greater degree than the BSE agent in cattle and that these agents can convey molecular properties and neuropathological indistinguishable from vCJD. However homozygous 129V mice are resistant to all tested BSE derived prions independently of the originating species suggesting a higher transmission barrier for 129V-PrP variant.

 

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/na101/home/literatum/publisher/tandf/journals/content/kprn20/2016/kprn20.v010.sup01/19336896.2016.1163048/20160418/19336896.2016.1163048.fp.png_v03

 

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

 

Saturday, September 24, 2016

 

Assessment of the PrPc amino-terminal domain in prion species barriers

 

http://chronic-wasting-disease.blogspot.com/2016/09/assessment-of-prpc-amino-terminal.html

 

Tuesday, July 12, 2016

 

*** Chronic Wasting Disease CWD, Scrapie, Bovine Spongiform Encephalopathy BSE, TSE, Prion Zoonosis Science History see history of NIH may destroy human brain collection

 

http://transmissiblespongiformencephalopathy.blogspot.com/2016/07/chronic-wasting-disease-cwd-scrapie.html

 

Saturday, December 12, 2015

 

CREUTZFELDT JAKOB DISEASE CJD TSE PRION REPORT DECEMBER 14, 2015

 

http://creutzfeldt-jakob-disease.blogspot.com/2015/12/creutzfeldt-jakob-disease-cjd-tse-prion.html

 

Monday, August 22, 2016

 

CREUTZFELDT JAKOB DISEASE USA 2015 SPORADIC CJD TOTAL FIGURES REACHES HIGHEST ANNUAL COUNT TO DATE AT 239 CONFIRMED CASES

 

http://creutzfeldt-jakob-disease.blogspot.com/2016/08/creutzfeldt-jakob-disease-usa-2015.html

 

Saturday, July 16, 2016

 

Importation of Sheep, Goats, and Certain Other Ruminants [Docket No. APHIS-2009-0095]RIN 0579-AD10

 

WITH great disgust and concern, I report to you that the OIE, USDA, APHIS, are working to further legalize the trading of Transmissible Spongiform Encephalopathy TSE Pion disease around the globe.

 

THIS is absolutely insane. it’s USDA INC.

 

http://scrapie-usa.blogspot.com/2016/07/importation-of-sheep-goats-and-certain.html

 

 

Terry S. Singeltary Sr.