Cassard et al. 2014, Evidence for zoonotic potential of ovine scrapie prions (Nature Communications 5:5821)

Key facts

• Fifteen authors are listed, first author Cassard H and last author Andreoletti O, across five affiliations: UMR INRA ENVT 1225 IHAP at the veterinary school in Toulouse, CISA-INIA at Valdeolmos near Madrid, the Norwegian Veterinary Institute in Oslo, INRA ISP at the Tours centre in Nouzilly, and UR892 Virologie et Immunologie Moleculaires at Jouy-en-Josas.
• The abstract states that a panel of sheep scrapie prions propagated in several humanised mouse models at an efficiency comparable to cattle BSE, and that serial passage of different isolates gave prions phenotypically identical to those of sporadic CJD.
• The paper is Nature Communications 5:5821, doi 10.1038/ncomms6821, PMID 25510416, electronic publication 16 December 2014; Europe PMC marks it as not open access with subscription required and lists 109 citing records, while OpenAlex classes it as bronze open access and counts 153 citations.
• OpenAlex lists two funders: European Commission award 222887, the FP7 project on protecting the food chain from prions, and Interreg.
• The published PDF is organised into results sections on scrapie isolates propagating in human PrP mice, a second human PrP mouse line, similar phenotypes of scrapie and sporadic CJD in those mice, human prions propagating without an apparent barrier, scrapie adaptation in bovine PrP mice, and the relative efficacy of scrapie and BSE in human PrP mice; the methods list TSE isolates, paraffin embedded tissue blot and histoblot, PrPres western blot, anti-PrP monoclonal antibodies, mouse bioassays and the transgenic lines.
• A 2015 Scientific Reports paper from the CEA group, co-authored by the Toulouse and Oslo authors of this paper, describes the result as clear evidence of at least a zoonotic potential while setting out its limits: the events were at a low rate, appeared after a second passage in a model that overexpresses human prion protein, ran without clinical signs for up to 750 days, and showed only a marginal increase on second passage.
• The same 2015 paper notes that a successful second passage may reflect strain adaptation in the mouse rather than the zoonotic potential of the original sheep isolate, and that the short life of a mouse limits what a negative first passage can show.
• EFSA was asked by the European Commission to review the article; its experts praised the study and concluded that it supports but does not change the 2011 joint ECDC and EFSA opinion, that there is no scientific proof that classical scrapie passes to people under real-life conditions, and that the scrapie related public health risk from sheep derived food cannot be assessed.
• EFSA also recorded knowledge gaps, in particular on the variability of scrapie strains, their geographic distribution and how that bears on crossing to other species.
• A 2019 Scientific Reports study from CISA-INIA with the CEA group used Hu-Tg340 mice, which express human prion protein at about four times the level in human brain, and reported that none of the Hu-Tg340 mice given the French ARQ/ARQ sheep scrapie isolate PS21 tested positive, which it describes as consistent with the 2014 work; the isolate itself is credited to this paper.
• A 2021 Veterinary Research paper from the same Spanish and French circle states that classical scrapie in small ruminants is caused by at least four different prion strains, that single isolates can hold mixtures, and that while some isolates propagated in human PrP mice with sporadic CJD like features, the zoonotic potential of scrapie is still not fully deciphered.
• A 2024 Journal of Infectious Diseases study of atypical scrapie in human PrP Met129 mice found nothing on first passage and, after gradual adaptation of one isolate on later passages, prions resembling MM1 sporadic CJD that further tests showed to be a different strain, which the authors call phenotypic convergence and read as a low zoonotic potential for atypical scrapie; it was published online on 24 February 2024 with funding from the Fundacion Ramon Areces, Defra, the FRM and the ANSM.
• A 2023 European Journal of Epidemiology age period cohort analysis of 2,475 French sporadic CJD deaths from 1992 to 2016 found mortality rising across birth cohorts, with the 1962 cohort at about 1.65 times the risk of the 1937 cohort, and cites this paper together with the 2015 macaque study as highlighting the possibility of a causal link between sheep scrapie exposure and some sporadic CJD, stated as a possibility rather than a finding.

Timeline

1. 2014Published electronically in Nature Communications as article 5821 of volume 5.
2. 2015The CEA led macaque study is published and cites this paper as evidence of a zoonotic potential, with its limits set out.
3. 2015EFSA publishes its review, requested by the European Commission, and finds no evidence of transmission under real-life conditions.
4. 2018IRTA-CReSA announces project AGL2017-88353-P, which takes this paper as its starting point for testing a small ruminant origin of sporadic CJD.
5. 2019A CISA-INIA and CEA study reports no positive Hu-Tg340 mice for the French scrapie isolate PS21 that came from this paper.
6. 2023A French age period cohort study of sporadic CJD mortality cites the paper when discussing a possible environmental origin.
7. 2024A study of atypical scrapie in human PrP mice reports phenotypic convergence with MM1 sporadic CJD but not strain identity.