[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]
The emergence of classical BSE from atypical/Nor98 scrapie
Alvina Huor, Juan Carlos Espinosa, Enric Vidal, Hervé Cassard, Jean-Yves Douet, Séverine Lugan, Naima Aron, Alba Marín-Moreno, Patricia Lorenzo, Patricia Aguilar-Calvo, Juan Badiola, Rosa Bolea, Martí Pumarola, Sylvie L. Benestad, Leonore Orge, Alana M. Thackray, Raymond Bujdoso, Juan-Maria Torres, and Olivier Andreoletti
PNAS first published December 16, 2019 / DOI: https://doi.org/10.1073/pnas.1915737116
Edited by Michael B. A. Oldstone, Scripps Research Institute, La Jolla, CA, and approved November 15, 2019 (received for review September 11, 2019)
The origin of transmissible BSE in cattle remains unestablished. Sheep scrapie is a potential source of this known zoonotic. Here we investigated the capacity of sheep scrapie to propagate in bovine PrP transgenic mice. Unexpectedly, transmission of atypical but not classical scrapie in bovine PrP mice resulted in propagation of classical BSE prions. Detection of prion seeding activity by in vitro protein misfolding cyclic amplification demonstrated BSE prions in the original atypical scrapie isolates. BSE prion seeding activity was also detected in ovine PrP mice inoculated with limiting dilutions of atypical scrapie. Our data demonstrate that classical BSE prions can emerge during intra- and interspecies passage of atypical scrapie and provide an unprecedented insight into the evolution of mammalian prions.
Atypical/Nor98 scrapie (AS) is a prion disease of small ruminants. Currently there are no efficient measures to control this form of prion disease, and, importantly, the zoonotic potential and the risk that AS might represent for other farmed animal species remains largely unknown. In this study, we investigated the capacity of AS to propagate in bovine PrP transgenic mice. Unexpectedly, the transmission of AS isolates originating from 5 different European countries to bovine PrP mice resulted in the propagation of the classical BSE (c-BSE) agent. Detection of prion seeding activity in vitro by protein misfolding cyclic amplification (PMCA) demonstrated that low levels of the c-BSE agent were present in the original AS isolates. C-BSE prion seeding activity was also detected in brain tissue of ovine PrP mice inoculated with limiting dilutions (endpoint titration) of ovine AS isolates. These results are consistent with the emergence and replication of c-BSE prions during the in vivo propagation of AS isolates in the natural host. These data also indicate that c-BSE prions, a known zonotic agent in humans, can emerge as a dominant prion strain during passage of AS between different species. These findings provide an unprecedented insight into the evolution of mammalian prion strain properties triggered by intra- and interspecies passage. From a public health perspective, the presence of c-BSE in AS isolates suggest that cattle exposure to small ruminant tissues and products could lead to new occurrences of c-BSE.
prion – atypical scrapie – c-BSE
1 A.H., J.C.E., and E.V. contributed equally to the work.
2 To whom correspondence may be addressed. Email: firstname.lastname@example.org.
Author contributions: E.V. and O.A. designed research; A.H., J.C.E., E.V., H.C., J.-Y.D., S.L., N.A., A.M.-M., P.L., P.A.-C., J.B., R. Bolea, M.P., and O.A. performed research; S.L.B. and L.O. contributed new reagents/analytic tools; A.H., J.C.E., E.V., S.L.B., L.O., A.M.T., R. Bujdoso, J.M.T., and O.A. analyzed data; and A.H., S.L.B., L.O., A.M.T., R. Bujdoso, and O.A. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1915737116/-/DCSupplemental.
Published under the PNAS license.
Keywords: Prions; BSE; Cattle; Scrapie.