Assessment of the zoonotic potential of atypical scrapie prions in humanized mice reveals rare phenotypic convergence but not identity with sporadic CJD prions

Alba Marín-Moreno; Fabienne Reine; Laetitia Herzog; Naima Aron; Florence Jaffrézic; Jean-Luc Vilotte; Human Rezaei; Olivier Andréoletti; Davy Martin; Vincent Béringue

doi:10.1093/infdis/jiae093

Assessment of the zoonotic potential of atypical scrapie prions in humanized mice reveals rare phenotypic convergence but not identity with sporadic CJD prions

J Infect Dis. 2024 Feb 24:jiae093. doi: 10.1093/infdis/jiae093. Online ahead of print.

Affiliations

¹ Université Paris-Saclay, INRAE, UVSQ, VIM, 78350 Jouy-en-Josas, France.
² INRAE, ENVT, IHAP, 31000, Toulouse, France.
³ Université Paris-Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France.

PMID: 38401890
DOI: 10.1093/infdis/jiae093

Abstract

Background: Atypical/Nor98 scrapie (AS) is an idiopathic infectious prion disease affecting sheep and goats. Recent findings suggest that zoonotic prions from bovine spongiform encephalopathy (C-BSE) may co-propagate with atypical/Nor98 prions in AS sheep brains. Investigating the risk AS poses to humans is crucial.

Methods: To assess the risk of sheep/goat-to-human transmission of AS, we serially inoculated brain tissue from field and laboratory isolates into transgenic mice overexpressing human prion protein (Met129 allele). We studied clinical outcomes as well as presence of prions in brains and spleens.

Results: No transmission occurred on the primary passage, with no clinical disease or pathological prion protein in brains and spleens. On subsequent passages, one isolate gradually adapted, manifesting as prions with a phenotype resembling those causing MM1-type sporadic Creutzfeldt-Jakob disease in humans. However, further characterization using in vivo and in vitro techniques confirmed both prion agents as different strains, revealing a case of phenotypic convergence. Importantly, no C-BSE prions emerged in these mice, especially in the spleen, which is more permissive than the brain for C-BSE cross-species transmission.

Conclusions: The results obtained suggest a low the zoonotic for AS. Rare adaptation may allow the emergence of prions phenotypically resembling those spontaneously forming in humans.

Keywords: Atypical scrapie; RT-QuIC; in vitro prion amplification; phenotypic convergence; prion; species barrier; sporadic Creutzfeldt-Jakob diseases.