Assessing the Transmissibility of CWD to Humans

Summary

Principal Investigator: Qingzhong Kong
Abstract: DESCRIPTION (provided by applicant): Chronic wasting disease (CWD), the prion disease in cervids (deer and elk), is widespread in North America. The cervid population is huge (approximately 22 million) and venison consumption very significant in USA. The fast spreading CWD is hard to contain, and it may pose a serious threat to human health if it is transmissible to humans, even at a low rate. This proposal will use transgenic (Tg) mouse models to answer three critical questions pertinent to the potential dangers posed by CWD to humans: Can CWD be transmitted to humans directly (Aim 1)? Can CWD be transmitted to humans after passage through secondary hosts (cattle or sheep) (Aim 2)? Has CWD transmission to humans already occurred (Aim 3)? The ultimate goals are to define the risks of direct and indirect CWD transmission to humans and to establish a surveillance program to monitor for human subjects infected by CWD prions. Research Design: For Aims 1 and 2, humanized and cervidized Tg mice will be intracerebrally (i.e.) inoculated with brain homogenates either from human subjects with sporadic Creutzfeldt-Jakob disease (CJD) or from CWD-affected animals including: Rocky Mountain elk, mule deer, white-tail deer, cattle, and sheep;sheep scrapie will also be inoculated as a control. The inoculated animals will then be monitored and compared for the transmission rate, incubation time, neurological symptoms, accumulation and distribution of PrP-Sc, and the glycoforms and conformational stability of PrP-Sc before and after passage in the Tg mice. Secondary transmissions will be done to examine for asymptomatic carriers of prion infectivity. Oral transmissions will be performed for CWD isolates that demonstrated infectivity in humanized Tg mice after i.e. inoculation. For Aim 3, cervidized Tg mice will be i.e. inoculated with brain homogenates from CJD subjects who had consumed venison from CWD endemic areas as well as from sporadic CJD subjects not exposed to CWD. The prion infectivity liters in the brain homogenates will be determined for all involved CJD subjects, and the same infectivity dose will be used for inoculation. A statistically significant higher transmission efficiency of prions from "CWD-exposed" CJD subjects than that of the sporadic CJD subjects unexposed to CWD will suggest that the "CWD-exposed" subject likely acquired his CJD from CWD.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc A novel human disease with abnormal prion protein sensitive to protease
    Pierluigi Gambetti
    Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
    Ann Neurol 63:697-708. 2008
  2. pmc Thermodynamic stabilization of the folded domain of prion protein inhibits prion infection in vivo
    Qingzhong Kong
    Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
    Cell Rep 4:248-54. 2013
  3. pmc Abnormal brain iron homeostasis in human and animal prion disorders
    Ajay Singh
    Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America
    PLoS Pathog 5:e1000336. 2009
  4. pmc PrP conformational transitions alter species preference of a PrP-specific antibody
    Wen Quan Zou
    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 4410, USA
    J Biol Chem 285:13874-84. 2010
  5. pmc Instability of the octarepeat region of the human prion protein gene
    Baiya Li
    Department of Physiology and Pathophysiology, Xi an Jiaotong University School of Medicine, Xi an, Shaanxi, China
    PLoS ONE 6:e26635. 2011
  6. pmc Cellular prion protein regulates its own α-cleavage through ADAM8 in skeletal muscle
    Jingjing Liang
    Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
    J Biol Chem 287:16510-20. 2012

Scientific Experts

  • Qingzhong Kong
  • Neena Singh
  • Wen Quan Zou
  • Jingjing Liang
  • Baiya Li
  • Ajay Singh
  • Pierluigi Gambetti
  • Sarah Medina
  • Janna Kiselar
  • Debra Sorensen
  • Witold K Surewicz
  • Stephanie A Booth
  • Wei Wang
  • Sergei Ilchenko
  • Liuting Qing
  • Jianqun Yan
  • Fusong Chen
  • Maradumane L Mohan
  • Alfred Orina Isaac
  • Mark L Cohen
  • Jason Bartz
  • Xiu Luo
  • Marcelo A Barria
  • Ermias D Belay
  • Xiangzhu Xiao
  • Jue Yuan
  • Mark Cohen
  • James A Mastrianni
  • Thomas Wisniewski
  • Karen Marder
  • Zhiqian Dong
  • Lawrence B Schonberger
  • D Gonzalez-Romero
  • Claudio Soto
  • Christine M Hulette
  • Carrie Harris
  • Thomas Montine
  • Mengjie Zheng
  • Rudy Castellani
  • Dennis W Dickson
  • Amer Alshekhlee
  • James R Burke

Detail Information

Publications6

  1. pmc A novel human disease with abnormal prion protein sensitive to protease
    Pierluigi Gambetti
    Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
    Ann Neurol 63:697-708. 2008
    ....
  2. pmc Thermodynamic stabilization of the folded domain of prion protein inhibits prion infection in vivo
    Qingzhong Kong
    Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
    Cell Rep 4:248-54. 2013
    ....
  3. pmc Abnormal brain iron homeostasis in human and animal prion disorders
    Ajay Singh
    Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America
    PLoS Pathog 5:e1000336. 2009
    ..These data implicate redox-iron in prion disease-associated neurotoxicity, a novel observation with significant implications for prion disease pathogenesis...
  4. pmc PrP conformational transitions alter species preference of a PrP-specific antibody
    Wen Quan Zou
    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 4410, USA
    J Biol Chem 285:13874-84. 2010
    ....
  5. pmc Instability of the octarepeat region of the human prion protein gene
    Baiya Li
    Department of Physiology and Pathophysiology, Xi an Jiaotong University School of Medicine, Xi an, Shaanxi, China
    PLoS ONE 6:e26635. 2011
    ....
  6. pmc Cellular prion protein regulates its own α-cleavage through ADAM8 in skeletal muscle
    Jingjing Liang
    Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
    J Biol Chem 287:16510-20. 2012
    ..Moreover, we found that overexpression of PrP(C) led to up-regulation of ADAM8, suggesting that PrP(C) may regulate its own α-cleavage through modulating ADAM8 activity...