Nature of TSE infection and Routes of Transmission

Lead Research Organisation: University of Edinburgh
Department Name: The Roslin Institute

Abstract

We aim to study the biochemical and biophysical nature of different strains of agent and their modes of transfer from animal to animal for the development of specific disease control in combination with efficient health and environmental protection measures. The refinement of diagnostic methods and genetic programmes will be used to eradicate novel TSE agents and provide models for risk reduction in other diseases. We will follow the agent in its route into the host and study the cellular, molecular and genetic mechanisms that enhance or prevent efficient transmission. The objectives of this theme are: To define TSE strains. Understand the TSE infectious agent and diagnosing disease. Define routes of transmission between animals. Understand genetic control of susceptibility/resistance. To define the role of PrP gene regulation in TSE disease. Investigate therapeutic intervention.

Publications

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Barr J (2010) Differential protein expression profiling in BSE disease. in Archives of physiology and biochemistry

 
Description We have identified novel DNA-derived aptamers that bind mammalian prion proteins and that could form part of future diagnostic tests for TSE disease. We have also developed a novel method to allow high-resolution strain differentiation using mass spectrometric analysis of N-terminal peptides.
Previous studies by us and others had shown a significant species barrier to infection of humans with cattle BSE. However following transmission of BSE through sheep, increased susceptibility to infection was observed in transgenic mice homozygous for human 129M PrP. This is despite the observation that both cattle and sheep BSE can equally convert human 129M PrP in vitro. These data suggest that other genetic factors in addition to PrP sequence can influence zoonotic transmission.
We have developed new methods of identifying TSE strains in sheep, particularly useful when studying mixed infections.
Genetic control of susceptibility/resistance may also function through control of PRNP gene expression. We have identified new control sites at the PRNP gene locus which may be important in disease control.
Understanding how natural scrapie spreads between individuals and between flocks is important in the development of control measures. In comparison of classical and atypical scrapie we have accumulated information on two populations now being used in detailed genomic sequencing projects to provide further information on genetic control of atypical scrapie.
We have revealed a new association of ovine PRNP codon 141 with BSE susceptibility and confirmed association of PRNP with goat scrapie in the UK. Our studies of European and American deer have highlighted the variability of the PRNP gene and its association with susceptibility in cervids which are at risk of developing chronic wasting disease (CWD). We have also shown that most carnivorous scavengers exposed to CWD appear to be susceptible based on their PRNP genotypes. Our studies have revealed novel regulation mechanisms of the ovine PRNP gene, which may be associated with scrapie susceptibility.
Exploitation Route These findings have advanced the basic knowledge of prion research and been published in peer review journals.
Sectors Agriculture, Food and Drink

 
Description EU policy on safety of embryos with regard to scrapie in sheep
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
Impact Affects use of sheep embryo transfer in international trade. To prevent scrapie transmission, the advice is to use genetically resistant animals.
 
Description Member of the ACDP
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact The Advisory Committee on Dangerous pathogens advises the UK government on all issues related to dangerous pathogens from situations, in the field, in health care and laboratory practice. I serve on the committee as the expert on the Transmissible Spongiform Encephalopathies
 
Description Member of the British Neuroscience Advisory Board
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Member of the CJD Sample Oversight Committee Group
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact The committee aims to facilitate the development of diagnostics for vCJD through working with developers and providing access to rare samples
 
Description Member of the European Food Safety Authority
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact involved in development of policy on prion diseases
 
Description Member of the International Science Advisory Council of APRI
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact The importance of this committee which I now chair is to provide scientific knowledge and expertise to the growing scientific community of the APRI
 
Description Member of the UK SEAC Advisory Body
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact Spongiform Encephalopathy Advisory Committee advised Government on all accept of the Transmissible Spongiform Encephalopathies throughout the BSE and vCJD epidemics
 
Description WHO TSE Working Group
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact developed policy on prion diseases
 
Description A study of scrapie affected goat herds
Amount £165,073 (GBP)
Funding ID SE1956 
Organisation Department For Environment, Food And Rural Affairs (DEFRA) 
Sector Public
Country United Kingdom
Start 04/2008 
End 05/2011
 
Description Defra R&D
Amount £2,348,412 (GBP)
Funding ID SE1852/1853 
Organisation Department For Environment, Food And Rural Affairs (DEFRA) 
Sector Public
Country United Kingdom
Start 01/2003 
End 12/2014
 
Description Defra R&D
Amount £1,206,000 (GBP)
Funding ID SE1436 
Organisation Department For Environment, Food And Rural Affairs (DEFRA) 
Sector Public
Country United Kingdom
Start 03/2003 
End 12/2012
 
Description Defra R&D contract
Amount £430,414 (GBP)
Funding ID SE1447 
Organisation Department For Environment, Food And Rural Affairs (DEFRA) 
Sector Public
Country United Kingdom
Start 01/2013 
End 09/2016
 
Description Proposal for improvement of goat BSE discriminative diagnosis.
Amount £143,949 (GBP)
Funding ID EU79-0558(93-3740) 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 04/2008 
End 11/2012
 
Description Proposal for improvement of goat BSE discriminative diagnosis.(II)
Amount £435,414 (GBP)
Organisation Department For Environment, Food And Rural Affairs (DEFRA) 
Sector Public
Country United Kingdom
Start 04/2008 
End 11/2012
 
Description Genetic association with scrapie and BSE in sheep and goats 
Organisation Veterinary Laboratories Agency
Country United Kingdom 
Sector Public 
PI Contribution Genetic analysis of sheep and goat samples. Study design and interpretation of data. Manuscript preparation
Collaborator Contribution Sample provision, pathology expertise and manuscript preparation.
Impact González, L., Martin, S., Hawkins, S.A.C. , Goldmann, W., Jeffrey, M., Sisó, S. (2010) Pathogenesis of natural goat scrapie: modulation by host PRNP genotype and effect of co-existent conditions. Vet Res. 41:48 Konold, T., Bone, G.E., Phelan, L.J., Simmons, M.M., González, L., Sisó, S., Goldmann, W., Cawthraw, S., Hawkins, S. A.C. (2010) Monitoring of clinical signs in goats with transmissible spongiform encephalopathies. BMC Vet Res 6:13 González, L., Martin, S., Sisó, S., Konold, T., Ortiz-Peláez, A., Phelan, L., Goldmann, W., Stewart, P., Saunders, G., Windl, O., Jeffrey, M., Hawkins, S.A.C., Dawson, M. and Hope, J. (2009) High prevalence of scrapie in a dairy goat herd:tissue distribution of disease-associated PrP and effect of PRNP genotype and age. Vet Res. 40:65
Start Year 2008
 
Description QuIC analysis of low PrPSc mouse models 
Organisation National Institute of Allergy and Infectious Diseases (NIAID)
Department Rocky Mountain Laboratories
Country United States 
Sector Public 
PI Contribution Provision of brain tissue from an unique mouse model of TSE disease
Collaborator Contribution Performed QuIC analysis of material from our mouse model
Impact Vascellari S, Orrù CD, Hughson AG, King D, Barron RM, Wilham JM, Baron GS, Race B, Pani A and Caughey B (2012). Prion seeding activities of mouse scrapie strains with divergent PrPSc protease sensitivities and amyloid plaque content using RT-QuIC and eQuIC. PLoS One 7:e48969
 
Description Seeding protein aggregation in mice 
Organisation Colorado State University
Country United States 
Sector Academic/University 
PI Contribution Analysis of amyloid plaque seeding in mouse brain
Collaborator Contribution Provision of mice and tissue from animals overexpressing 101L PrP
Impact Piccardo P, King D, Telling G, Manson JC and Barron RM (2013). Dissociation of prion protein amyloid seeding from transmission of a spongiform encephalopathy. J Virol. 87:12349-12356 doi: 10.1128/JVI.00673-13
 
Description Zoonotic transmission of prions 
Organisation Experimental Zooprophylactic Institute of Piedmont
Country Italy 
Sector Charity/Non Profit 
PI Contribution Performed prion transmission studies into human PrP and bovine PrP transgenic mice using bovine brain infected with BASE
Collaborator Contribution Provided the BASE brain tissue
Impact Wilson R, Hart P, Piccardo P, Hunter N, Casalone C, Baron T, and Barron RM (2012). Bovine PrP expression levels in transgenic mice influence transmission characteristics of atypical BSE. Journal of General Virology 93:1132-1140 Wilson R, Plinston C, Hunter N, Casalone C, Corona C, Tagliavini F, Suardi S, Ruggerone M, Moda F, Graziano S, Sbriccoli M, Cardone F, Pocchiari M, Ingrosso L, Baron T, Richt J, Andreoletti O, Simmons M, Lockey R, Manson JC, and Barron RM (2012). Chronic wasting disease and atypical forms of BSE and scrapie are not transmissible to mice expressing wild-type levels of human PrP. Journal of General Virology 93:1624-1629
Start Year 2007
 
Description Zoonotic trasnmission of prions 
Organisation French Agency for Food Safety (AFSSA)
Country France 
Sector Public 
PI Contribution Performed transmission experiments to human PrP and bovine PrP transgenic mice using H-BSE infected brain tissue
Collaborator Contribution Provided the H-BSE infected brain tissue
Impact Wilson R, Hart P, Piccardo P, Hunter N, Casalone C, Baron T, and Barron RM (2012). Bovine PrP expression levels in transgenic mice influence transmission characteristics of atypical BSE. Journal of General Virology 93:1132-1140 Wilson R, Plinston C, Hunter N, Casalone C, Corona C, Tagliavini F, Suardi S, Ruggerone M, Moda F, Graziano S, Sbriccoli M, Cardone F, Pocchiari M, Ingrosso L, Baron T, Richt J, Andreoletti O, Simmons M, Lockey R, Manson JC, and Barron RM (2012). Chronic wasting disease and atypical forms of BSE and scrapie are not transmissible to mice expressing wild-type levels of human PrP. Journal of General Virology 93:1624-1629
Start Year 2007
 
Description Zoonotic trasnmission of prions 
Organisation U.S. Department of Agriculture USDA
Department National Animal Disease Center
Country United States 
Sector Public 
PI Contribution Performed transmission studies in human PrP and bovine PrP transgenic mice using Chronic Wasting Disease infected brain tissue
Collaborator Contribution Provided the Chronic Wasting Disease infected brain tissue
Impact Wilson R, Plinston C, Hunter N, Casalone C, Corona C, Tagliavini F, Suardi S, Ruggerone M, Moda F, Graziano S, Sbriccoli M, Cardone F, Pocchiari M, Ingrosso L, Baron T, Richt J, Andreoletti O, Simmons M, Lockey R, Manson JC, and Barron RM (2012). Chronic wasting disease and atypical forms of BSE and scrapie are not transmissible to mice expressing wild-type levels of human PrP. Journal of General Virology 93:1624-1629
Start Year 2007
 
Description BNA Streetfair 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact British Neuroscience Association Streetfair, held at the Barbican Centre in London alongside the annual BNA symposium. Activity to communicate work we do on TSE disease, protein misfolding and neurodegeneration to the public
Year(s) Of Engagement Activity 2013
 
Description Big Bang, Schools science competition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact I was a judge moderator for Big Bang, a schools competition for science projects.
Year(s) Of Engagement Activity 2012,2013
 
Description EFSA Goat TSE committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Expert committee member to advise on the use of selective breeding for TSE resistance in Cyprus
Year(s) Of Engagement Activity 2009
 
Description Highland Show, Ingliston. Scotland's biggest agricultural show 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Presenting posters of research and games to interest youngsters. Answering resulting questions.
Year(s) Of Engagement Activity 2013
 
Description Informa Biopharmaceutical Raw Materials Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Talk about risks of TSE infection in biological produces and processes
Year(s) Of Engagement Activity 2012
 
Description Presentation to SEAC on risks of sheep BSE to humans 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Presentation to the Spongiform Encephalopathy Advisory Committee regarding recent research results on transmission of ovine BSE.
Year(s) Of Engagement Activity 2009
 
Description Press Interview on Americal BASE case for Science News (online article) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Press interview with Science News on recent identification of a case of atypical BSE in the USA
Year(s) Of Engagement Activity 2012
 
Description Prion 2016 chair and invited speaker 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact invited talk to international meeting
Year(s) Of Engagement Activity 2016
 
Description Roslin Institute Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Each year we run an activity designed to engage the public and introduce them to the work we do on TSE diseases, protein misfolding and neurodegeneration
Year(s) Of Engagement Activity 2012,2013,2014,2015,2016
 
Description Roslin Institute public open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Science games for children. Questions from well informed children and more questions from their parents.
Year(s) Of Engagement Activity 2014,2015
 
Description University of Glasgow Dental School Evening Symposium; vCJD- frequently asked questions for dental practitioners. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Public Lecture to Dental Practitioners on the risks of prion disease
Year(s) Of Engagement Activity 2010
 
Description oral presentation at Prion Conference 2011 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Discussion of my research with international colleagues. New collaborations
Year(s) Of Engagement Activity 2011