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Thread: Cervid to human prion transmission

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    Exclamation Cervid to human prion transmission

    Cervid to human prion transmission

    Kong, Qingzhong

    Case Western Reserve University, Cleveland, OH, United States

    Abstract

    Prion disease is transmissible and invariably fatal. Chronic wasting disease (CWD) is the prion disease affecting deer, elk and moose, and it is a widespread and expanding epidemic affecting 22 US States and 2 Canadian provinces so far. CWD poses the most serious zoonotic prion transmission risks in North America because of huge venison consumption (>6 million deer/elk hunted and consumed annually in the USA alone), significant prion infectivity in muscles and other tissues/fluids from CWD-affected cervids, and usually high levels of individual exposure to CWD resulting from consumption of the affected animal among often just family and friends. However, we still do not know whether CWD prions can infect humans in the brain or peripheral tissues or whether clinical/asymptomatic CWD zoonosis has already occurred, and we have no essays to reliably detect CWD infection in humans. We hypothesize that:

    (1) The classic CWD prion strain can infect humans at low levels in the brain and peripheral lymphoid tissues;

    (2) The cervid-to-human transmission barrier is dependent on the cervid prion strain and influenced by the host (human) prion protein (PrP) primary sequence;

    (3) Reliable essays can be established to detect CWD infection in humans;and

    (4) CWD transmission to humans has already occurred. We will test these hypotheses in 4 Aims using transgenic (Tg) mouse models and complementary in vitro approaches.

    Aim 1 will prove that the classical CWD strain may infect humans in brain or peripheral lymphoid tissues at low levels by conducting systemic bioassays in a set of "humanized" Tg mouse lines expressing common human PrP variants using a number of CWD isolates at varying doses and routes. Experimental "human CWD" samples will also be generated for Aim 3.

    Aim 2 will test the hypothesis that the cervid-to-human prion transmission barrier is dependent on prion strain and influenced by the host (human) PrP sequence by examining and comparing the transmission efficiency and phenotypes of several atypical/unusual CWD isolates/strains as well as a few prion strains from other species that have adapted to cervid PrP sequence, utilizing the same panel of humanized Tg mouse lines as in Aim 1.

    Aim 3 will establish reliable essays for detection and surveillance of CWD infection in humans by examining in details the clinical, pathological, biochemical and in vitro seeding properties of existing and future experimental "human CWD" samples generated from Aims 1-2 and compare them with those of common sporadic human Creutzfeldt-Jakob disease (sCJD) prions.

    Aim 4 will attempt to detect clinical CWD-affected human cases by examining a significant number of brain samples from prion-affected human subjects in the USA and Canada who have consumed venison from CWD-endemic areas utilizing the criteria and essays established in Aim 3. The findings from this proposal will greatly advance our understandings on the potential and characteristics of cervid prion transmission in humans, establish reliable essays for CWD zoonosis and potentially discover the first case(s) of CWD infection in humans.

    Public Health Relevance There are significant and increasing human exposure to cervid prions because chronic wasting disease (CWD, a widespread and highly infectious prion disease among deer and elk in North America) continues spreading and consumption of venison remains popular, but our understanding on cervid-to-human prion transmission is still very limited, raising public health concerns. This proposal aims to define the zoonotic risks of cervid prions and set up and apply essays to detect CWD zoonosis using mouse models and in vitro methods. The findings will greatly expand our knowledge on the potentials and characteristics of cervid prion transmission in humans, establish reliable essays for such infections and may discover the first case(s) of CWD infection in humans.

    Funding Agency Agency National Institute of Health (NIH)

    Institute National Institute of Neurological Disorders and Stroke (NINDS)

    Type Research Project (R01)

    Project # 1R01NS088604-01A1

    Application # 9037884

    Study Section Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)

    Program Officer Wong, May

    Project Start 2015-09-30

    Project End 2019-07-31

    Budget Start 2015-09-30

    Budget End 2016-07-31

    Support Year 1

    Fiscal Year 2015

    Total Cost $337,507

    Indirect Cost $118,756

    Institution

    Name Case Western Reserve University

    Department Pathology

    Type Schools of Medicine

    DUNS # 077758407

    City Cleveland

    State OH

    Country United States

    Zip Code 44106

    http://grantome.com/grant/NIH/R01-NS088604-01A1

    ================================================== =========

    We hypothesize that:

    (1) The classic CWD prion strain can infect humans at low levels in the brain and peripheral lymphoid tissues;

    (2) The cervid-to-human transmission barrier is dependent on the cervid prion strain and influenced by the host (human) prion protein (PrP) primary sequence;

    (3) Reliable essays can be established to detect CWD infection in humans;and

    (4) *** CWD transmission to humans has already occurred. *** We will test these hypotheses in 4 Aims using transgenic (Tg) mouse models and complementary in vitro approaches.

    ================================================== ==========

    Key Molecular Mechanisms of TSEs

    Zabel, Mark D.

    Colorado State University-Fort Collins, Fort Collins, CO, United States Abstract Prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases affecting humans, cervids, bovids, and ovids. The absolute requirement of PrPC expression to generate prion diseases and the lack of instructional nucleic acid define prions as unique infectious agents. Prions exhibit species-specific tropism, inferring that unique prion strains exist that preferentially infct certain host species and confront transmission barriers to heterologous host species. However, transmission barriers are not absolute. Scientific consensus agrees that the sheep TSE scrapie probably breached the transmission barrier to cattle causing bovine spongiform encephalopathy that subsequently breached the human transmission barrier and likely caused several hundred deaths by a new-variant form of the human TSE Creutzfeldt-Jakob disease in the UK and Europe. The impact to human health, emotion and economies can still be felt in areas like farming, blood and organ donations and the threat of a latent TSE epidemic. This precedent raises the real possibility of other TSEs, like chronic wasting disease of cervids, overcoming similar human transmission barriers. A groundbreaking discovery made last year revealed that mice infected with heterologous prion strains facing significant transmission barriers replicated prions far more readily in spleens than brains6. Furthermore, these splenic prions exhibited weakened transmission barriers and expanded host ranges compared to neurogenic prions. These data question conventional wisdom of avoiding neural tissue to avoid prion xenotransmission, when more promiscuous prions may lurk in extraneural tissues. Data derived from work previously funded by NIH demonstrate that Complement receptors CD21/35 bind prions and high density PrPC and differentially impact prion disease depending on the prion isolate or strain used. Recent advances in live animal and whole organ imaging have led us to generate preliminary data to support novel, innovative approaches to assessing prion capture and transport. We plan to test our unifying hypothesis for this proposal that CD21/35 control the processes of peripheral prion capture, transport, strain selection and xenotransmission in the following specific aims. 1. Assess the role of CD21/35 in splenic prion strain selection and host range expansion. 2. Determine whether CD21/35 and C1q differentially bind distinct prion strains 3. Monitor the effects of CD21/35 on prion trafficking in real time and space 4. Assess the role of CD21/35 in incunabular prion trafficking

    Public Health Relevance Transmissible spongiform encephalopathies, or prion diseases, are devastating illnesses that greatly impact public health, agriculture and wildlife in North America and around the world. The impact to human health, emotion and economies can still be felt in areas like farming, blood and organ donations and the threat of a latent TSE epidemic. This precedent raises the real possibility of other TSEs, like chronic wasting disease (CWD) of cervids, overcoming similar human transmission barriers. Early this year Canada reported its first case of BSE in over a decade audits first case of CWD in farmed elk in three years, underscoring the need for continued vigilance and research. Identifying mechanisms of transmission and zoonoses remains an extremely important and intense area of research that will benefit human and other animal populations.

    Funding Agency Agency National Institute of Health (NIH)

    Institute National Institute of Allergy and Infectious Diseases (NIAID)

    Type High Priority, Short Term Project Award (R56)

    Project # 1R56AI122273-01A1

    Application # 9211114

    Study Section Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)

    Program Officer Beisel, Christopher E

    Project Start 2016-02-16

    Project End 2017-01-31

    Budget Start 2016-02-16

    Budget End 2017-01-31

    Support Year 1

    Fiscal Year 2016

    Total Cost

    Indirect Cost Institution Name Colorado State University-Fort Collins

    Department Microbiology/Immun/Virology

    Type Schools of Veterinary Medicine

    DUNS # 785979618 City Fort Collins

    State CO

    Country United States

    Zip Code 80523

    http://grantome.com/grant/NIH/R56-AI122273-01A1

    PMCA Detection of CWD Infection in Cervid and Non-Cervid Species

    Hoover, Edward Arthur

    Colorado State University-Fort Collins, Fort Collins, CO, United States Abstract Chronic wasting disease (CWD) of deer and elk is an emerging highly transmissible prion disease now recognized in 18 States, 2 Canadian provinces, and Korea. We have shown that Infected deer harbor and shed high levels of infectious prions in saliva, blood, urine, and feces, and in the tissues generating those body fluids and excreta, thereby leading to facile transmission by direct contact and environmental contamination. We have also shown that CWD can infect some non-cervid species, thus the potential risk CWD represents to domestic animal species and to humans remains unknown. Whether prions borne in blood, saliva, nasal fluids, milk, or excreta are generated or modified in the proximate peripheral tissue sites, may differ in subtle ways from those generated in brain, or may be adapted for mucosal infection remain open questions. The increasing parallels in the pathogenesis between prion diseases and human neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases, add relevance to CWD as a transmissible protein misfolding disease. The overall goal of this work is to elucidate the process of CWD prion transmission from mucosal secretory and excretory tissue sites by addressing these questions: (a) What are the kinetics and magnitude of CWD prion shedding post-exposure? (b) Are excreted prions biochemically distinct, or not, from those in the CNS? (c) Are peripheral epithelial or CNS tissues, or both, the source of excreted prions? and (d) Are excreted prions adapted for horizontal transmission via natural/trans-mucosal routes? The specific aims of this proposal are: (1) To determine the onset and consistency of CWD prion shedding in deer and cervidized mice; (2); To compare the biochemical and biophysical properties of excretory vs. CNS prions; (3) To determine the capacity of peripheral tissues to support replication of CWD prions; (4) To determine the protease- sensitive infectious fraction of excreted vs. CNS prions; and (5) To compare the mucosal infectivity of excretory vs. CNS prions. Understanding the mechanisms that enable efficient prion dissemination and shedding will help elucidate how horizontally transmissible prions evolve and succeed, and is the basis of this proposal. Understanding how infectious misfolded proteins (prions) are generated, trafficked, shed, and transmitted will aid in preventing, treating, and managing the risks associated with these agents and the diseases they cause.

    Public Health Relevance Chronic wasting disease (CWD) of deer and elk is an emergent highly transmissible prion disease now recognized throughout the USA as well as in Canada and Korea. We have shown that infected deer harbor and shed high levels of infectious prions in saliva, blood, urine, and feces thereby leading to transmission by direct contact and environmental contamination. In that our studies have also shown that CWD can infect some non-cervid species, the potential risk CWD may represents to domestic animal species and humans remains unknown. The increasing parallels in the development of major human neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases, and prion diseases add relevance to CWD as a model of a transmissible protein misfolding disease. Understanding how infectious misfolded proteins (prions) are generated and transmitted will aid in interrupting, treating, and managing the risks associated with these agents and the diseases they cause.

    Funding Agency Agency National Institute of Health (NIH)

    Institute National Institute of Neurological Disorders and Stroke (NINDS)

    Type Research Project (R01)

    Project # 4R01NS061902-07

    Application # 9010980

    Study Section Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)

    Program Officer Wong, May Project Start 2009-09-30

    Project End 2018-02-28

    Budget Start 2016-03-01

    Budget End 2017-02-28

    Support Year 7

    Fiscal Year 2016

    Total Cost $409,868

    Indirect Cost $134,234 Institution Name Colorado State University-Fort Collins

    Department Microbiology/Immun/Virology

    Type Schools of Veterinary Medicine

    DUNS # 785979618 City Fort Collins

    State CO

    Country United States

    Zip Code 80523

    http://grantome.com/grant/NIH/R01-NS061902-07

    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

    Prion 2016

    Purchase options Price * Issue Purchase USD 198.00

    http://www.tandfonline.com/toc/kprn20/10/sup1

    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/hom...048.fp.png_v03

    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

    http://scrapie-usa.blogspot.com/2016...n-animals.html

    LOOKING FOR CWD IN HUMANS AS nvCJD or as an ATYPICAL CJD, LOOKING IN ALL THE WRONG PLACES $$$

    *** These results would seem to suggest that CWD does indeed have zoonotic potential, at least as judged by the compatibility of CWD prions and their human PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests that if zoonotic CWD occurred, it would most likely effect those of the PRNP codon 129-MM genotype and that the PrPres type would be similar to that found in the most common subtype of sCJD (MM1).***

    https://www.landesbioscience.com/jou...ache=112223249


    snip...see full text ;


    Wednesday, May 11, 2016

    CERVID TO HUMAN PRION TRANSMISSION

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


    kind regards, terry

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    Wednesday, May 11, 2016

    PENNSYLVANIA TWELVE MORE CASES OF CWD FOUND: STATE GEARS UP FOR ADDITIONAL CONTROL MEASURES

    http://chronic-wasting-disease.blogs...es-of-cwd.html


    kind regards, terry

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