Chronic Wasting Disease Prion Strain Emergence and Host Range Expansion
''Successful transmission of an emergent strain of CWD prion, H95+, into mice resulted in infection. Thus, emergent CWD prion strains may have higher zoonotic potential than common strains.''
Chronic Wasting Disease Prion Strain Emergence and Host Range Expansion
Allen Herbst,1 Camilo Duque Velásquez,1 Elizabeth Triscott, Judd M. Aiken, Debbie McKenzie
Author affiliation: University of Alberta, Edmonton, Alberta, Canada DOI: https://doi.org/10.3201/eid2309.161474
Human and mouse prion proteins share a structural motif that regulates resistance to common chronic wasting disease (CWD) prion strains. Successful transmission of an emergent strain of CWD prion, H95+, into mice resulted in infection. Thus, emergent CWD prion strains may have higher zoonotic potential than common strains. Chronic wasting disease (CWD) is a contagious prion disease of cervids that is spreading globally. CWD is enzootic in multiple cervid species, including deer and elk; the major foci of disease are Colorado/Wyoming (USA), Wisconsin/Illinois (USA), and Alberta/Saskatchewan (Canada). CWD is also present in captive cervids in South Korea and wild reindeer and moose in Norway (https://www.nwhc. usgs.gov/images/cwd/cwd_map.jpg). CWD results from the conformational transformation of the host-encoded cellular prion protein (PrPC) into protease-resistant, detergent-insoluble, β-sheet rich, amyloidogenic conformers, termed prions (PrPCWD). Within their conformation, prion strains encipher the information that directs the templated misfolding and aggregation of PrPC molecules into additional prions (1).
Although the sequence homology of PrP among mammals is high, the ability of particular prion strains to cause disease in different species is determined by the conformational compatibility between a given strain and the host PrPC (2). We previously identified 2 strains of CWD prion in white-tailed deer (3), Wisc-1 and H95+ ; these strains exhibit distinct biological properties in deer and transgenic cervidized mice. To ascertain the host range of different strains from cervids, we inoculated CWD prions isolated from experimentally infected deer with different PRNP genotypes (Q95G96 [wild type (wt)], S96/wt, H95/wt, and H95/S96) and from elk (CWD2 strain) into hamsters and mice. All isolates have been successfully transmitted into transgenic mice expressing wt cervid PrP and contain high titers of CWD prions (3).
Mice inoculated with H95+ CWD prions succumbed to clinical disease at 575 ± 47 or 692 ± 9 days, depending on the H95+ isolate (Table). Mice inoculated with Wisc-1 or elk CWD or uninfected deer homogenates were euthanized at day 708 after infection with no signs of prion disease. Clinical signs of H95+ CWD in C57Bl/6 mice included ataxia, lethargy, tail rigidity, and dermatitis. Protease-resistant PrPCWD was present in all mice infected with H95+ prions and was not detected in mice infected with Wisc-1 or CWD2 (online Technical Appendix, https://wwwnc.cdc. gov/EID/article/23/9/16-1474-Techapp1.pdf).
In contrast to mice, hamsters succumbed to clinical disease when inoculated with Wisc-1 CWD prions but were less susceptible to H95+ CWD prions (Table). Clinical signs of CWD in hamsters began with lethargy and, upon arousal, retrocollis; as the disease progressed, lethargy declined with increased dystonic movement including ataxia and tremors. Hyperesthesia was not observed. Subclinical disease (no clinical signs but PrP-res positive by Western blot) was observed in a subset of hamsters (online Technical Appendix).
Successful interspecies prion transmission at the molecular level depends on the compatibility of the invading prion conformers and structural determinants imposed by host PrPC. One structural motif is the loop region between β sheet 2 and α helix 2 of PRPC at aa 170–174 (online Technical Appendix). Host species containing PrPC molecules with a flexible β2-α2 loop (mice and humans) are hypothesized to be incompatible with prions derived from species containing a rigid loop (deer and elk) (4,5). Previous attempts to transmit CWD to mice have failed (6,7). Our data show that prions from a prototypic rigid-loop species (deer) can transmit to a flexible-loop species (mice). The transmission is strain dependent. H95+ overrides the conformational restriction imposed by the mouse PrP flexible loop that Wisc-1 and CWD2 cannot overcome, suggesting that the invading prion strain is a dominant contributor to the species/transmission barrier. How the N terminal amino acid polymorphism (Q95H) affects the conformation of PrP, altering the deer-to-mouse transmission barrier, is unknown. Further structural studies may clarify the effect of N terminal residues on β2-α2 loop rigidity.
Transmission of H95+ CWD prions to mice further confirms the value of specifying strain when defining species barriers. Experimental transmission of CWD prion into macaques and transgenic mice expressing human PrP suggests a considerable transmission barrier to CWD prions (although squirrel monkeys are susceptible), and human prion protein is converted inefficiently in vitro (8,9). Successful infection of a flexible-loop species (mice) with H95+ CWD raises concerns for the potential pathogenicity of H95+ prions to other flexible-loop species. Transmission studies with Wisc-1 and H95+ in transgenic humanized and bovinized mice are ongoing.
The increasing prevalence of CWD indicates selection for cervids with resistance alleles, such as S96 and H95. Genetic resistance to a given prion strain selects for the emergence of novel prion strains with altered properties such as H95+ and Nor98 (3,10). The iterative transmission of CWD prions to cervids with protective alleles of PrPC and the consequent emergence of new CWD prion strains highlights the dynamics of the CWD panzootic and the value of characterizing the host range of emergent CWD prion strains.
''Successful transmission of an emergent strain of CWD prion, H95+, into mice resulted in infection. Thus, emergent CWD prion strains may have higher zoonotic potential than common strains.''
*** 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
you can see more evidence here ;
2017 PRION CONFERENCE
First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques: a work in progress
Stefanie Czub1, Walter Schulz-Schaeffer2, Christiane Stahl-Hennig3, Michael Beekes4, Hermann Schaetzl5 and Dirk Motzkus6 1
University of Calgary Faculty of Veterinary Medicine/Canadian Food Inspection Agency; 2Universitatsklinikum des Saarlandes und Medizinische Fakultat der Universitat des Saarlandes; 3 Deutsches Primaten Zentrum/Goettingen; 4 Robert-Koch-Institut Berlin; 5 University of Calgary Faculty of Veterinary Medicine; 6 presently: Boehringer Ingelheim Veterinary Research Center; previously: Deutsches Primaten Zentrum/Goettingen
This is a progress report of a project which started in 2009. 21 cynomolgus macaques were challenged with characterized CWD material from white-tailed deer (WTD) or elk by intracerebral (ic), oral, and skin exposure routes. Additional blood transfusion experiments are supposed to assess the CWD contamination risk of human blood product. Challenge materials originated from symptomatic cervids for ic, skin scarification and partially per oral routes (WTD brain). Challenge material for feeding of muscle derived from preclinical WTD and from preclinical macaques for blood transfusion experiments. We have confirmed that the CWD challenge material contained at least two different CWD agents (brain material) as well as CWD prions in muscle-associated nerves.
Here we present first data on a group of animals either challenged ic with steel wires or per orally and sacrificed with incubation times ranging from 4.5 to 6.9 years at postmortem. Three animals displayed signs of mild clinical disease, including anxiety, apathy, ataxia and/or tremor. In four animals wasting was observed, two of those had confirmed diabetes. All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals. Protein misfolding cyclic amplification (PMCA), real-time quaking-induced conversion (RT-QuiC) and PET-blot assays to further substantiate these findings are on the way, as well as bioassays in bank voles and transgenic mice.
At present, a total of 10 animals are sacrificed and read-outs are ongoing. Preclinical incubation of the remaining macaques covers a range from 6.4 to 7.10 years. Based on the species barrier and an incubation time of > 5 years for BSE in macaques and about 10 years for scrapie in macaques, we expected an onset of clinical disease beyond 6 years post inoculation.
PRION 2017 DECIPHERING NEURODEGENERATIVE DISORDERS
Subject: PRION 2017 CONFERENCE DECIPHERING NEURODEGENERATIVE DISORDERS VIDEO
PRION 2017 CONFERENCE DECIPHERING NEURODEGENERATIVE DISORDERS
*** PRION 2017 CONFERENCE VIDEO
SATURDAY, JULY 29, 2017
Risk Advisory Opinion: Potential Human Health Risks from Chronic Wasting Disease CFIA, PHAC, HC (HPFB and FNIHB), INAC, Parks Canada, ECCC and AAFC
TUESDAY, JUNE 13, 2017
PRION 2017 CONFERENCE ABSTRACT First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques: a work in progress
TUESDAY, JULY 04, 2017
*** PRION 2017 CONFERENCE ABSTRACTS ON CHRONIC WASTING DISEASE CWD TSE PRION ***
TUESDAY, JUNE 13, 2017
PRION 2017 CONFERENCE ABSTRACT Chronic Wasting Disease in European moose is associated with PrPSc features different from North American CWD
URINE
SUNDAY, JULY 16, 2017
*** Temporal patterns of chronic wasting disease prion excretion in three cervid species ***
WEDNESDAY, JULY 26, 2017
Chronic wasting disease continues to spread Disease of cervids causing local population declines
SUNDAY, AUGUST 06, 2017
*** USA Chronic Wasting Disease CWD TSE Prion Emergency Response Plan Singeltary et al ***
WEDNESDAY, AUGUST 16, 2017
Norway Nordfjella 2 out of apprx 150 animals shot now suspect for Chronic Wasting Disease CWD Skrantesjuke
THURSDAY, AUGUST 17, 2017
JAVMA NEWS Atypical BSE found in Alabama cow September 01, 2017
WEDNESDAY, JULY 26, 2017
Chronic wasting disease continues to spread Disease of cervids causing local population declines
THURSDAY, AUGUST 03, 2017
Wisconsin CWD Showing Up in Northern Wisconsin Deer Farms
Wednesday, February 10, 2016
*** Wisconsin Two deer that escaped farm had chronic wasting disease CWD ***
SATURDAY, AUGUST 12, 2017
Pennsylvania 27 deer from Bedford County farm test positive for chronic wasting disease
WEDNESDAY, AUGUST 16, 2017
OHIO Chronic Wasting Disease CWD TSE Prion UPDATE?
Iowa Supreme Court rules law allows quarantine of CWD deer, not land
This is very, very concerning imo.
IF this ruling is upheld as such ;
''The Iowa Supreme Court upheld the district court ruling — saying the law gives the DNR only the authority to quarantine the deer — not the land. The ruling says if the Iowa Legislature wants to expand the quarantine powers as suggested by the DNR, then it is free to do so.''
IF a 'precedent' is set as such, by the Legislature not intervening to expand quarantine powers to the DNR for CWD TSE Prion, and the precedent is set as such that the cervid industry and land there from, once contaminated with the CWD TSE Prion, are free to repopulate, sell the land, etc, imo, this will blow the lid off any containment efforts of this damn disease CWD TSE Prion. The Iowa Supreme Court did not just pass the cwd buck down the road, the Supreme Court of Iowa just threw the whole state of Iowa under the bus at 100 MPH. i remember the litigation that took place and the fuss over all those 'healthy' looking deer standing out in the pasture, i remember the photo postings and thread on the web on the deer farmers board, of all those healthy looking deer. the big rally behind the owners on the web, how they were going to come and cut the fences, folks liking the comments, 100 deer farmers were going to show up and stop the officials from coming in to test the deer. yep, it was on the www. all those healthy deer, while the litigation was going on, well, they were incubating the cwd tse prion, loading up the land even more, and in the end, 79.8% of those healthy looking deer had CWD TSE Prion. what about the exposure to the other species that come across that land, and then off to some other land? this makes no sense to me, if this is set in stone and the Legislation does not stop it, and stop if fast, any containment of the cwd tse prion will be futile, imo...terry
FRIDAY, JUNE 16, 2017
Iowa Supreme Court rules law allows quarantine of CWD deer, not land
MONDAY, AUGUST 14, 2017
Texas Chronic Wasting Disease CWD TSE Prion History
THURSDAY, AUGUST 17, 2017
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States revisited 2017
wasted days and wasted nights...Freddy Fender
Terry S. Singeltary Sr.
Bacliff, Texas USA
Galveston Bay, on the bottom
posted by Terry S. Singeltary Sr. at
12:31 PM
0 Comments:
Post a Comment
Subscribe to Post Comments [Atom]
<< Home