Contributors: Interactions hôtes-agents pathogènes Toulouse (IHAP); Ecole Nationale Vétérinaire de Toulouse (ENVT); Institut National Polytechnique (Toulouse) (Toulouse INP); Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP); Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE); Centro de Investigacion en Sanidad Animal (INIA-CISA); Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria = National Institute for Agricultural and Food Research and Technology (INIA); Toulouse NeuroImaging Center (ToNIC); Université Toulouse III - Paul Sabatier (UT3); Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI); Université Toulouse - Jean Jaurès (UT2J); Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3); Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J); Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3); Université de Toulouse (UT); Virologie et Immunologie Moléculaires (VIM (UR 0892)); Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE); The University of Edinburgh; This work was funded by the European Regional Development Fund POCTEFA TRANSPRION (EFA282/13) and REDPRION (EFA148/16), by the UK Food Standards Agency exploring permeability of the species (M03043 and FS231051), by the European Union through FP7 222887 "Priority," the Alliance Biosecure Foundation (FABS201403), and the Spanish Ministerio de Economia y Competitividad (AGL2016-78054-R AEI/FEDER, UE ). A.M.-M. was supported by a fellowship from the INIA (FPI-SGIT-2015-02).; European Project: EFA282/13; European Project: EFA148/16; European Project: 222887,EC:FP7:KBBE,FP7-KBBE-2007-2A,PRIORITY(2009)
نبذة مختصرة : International audience ; Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently classified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K-digested abnormal prion protein (PrPres) isoform identified by Western blotting (type 1 or type 2). Converging evidence led to the view that MM/MV1, VV/MV2, and VV1 and MM2 sCJD cases are caused by distinct prion strains. However, in a significant proportion of sCJD patients, both type 1 and type 2 PrPres were reported to accumulate in the brain, which raised questions about the diversity of sCJD prion strains and the coexistence of two prion strains in the same patient. In this study, a panel of sCJD brain isolates (n = 29) that displayed either a single or mixed type 1/type 2 PrPres were transmitted into human-PrP-expressing mice (tgHu). These bioassays demonstrated that two distinct prion strains (M1(CJD) and V2(CJD)) were associated with the development of sCJD in MM1/MV1 and VV2/MV2 patients. However, in about 35% of the investigated VV and MV cases, transmission results were consistent with the presence of both M1(CJD) and V2(CJD) strains, including in patients who displayed a "pure" type 1 or type 2 PrPres. The use of a highly sensitive prion in vitro amplification technique that specifically probes the V2(CJD) strain revealed the presence of the V2(CJD) prion in more than 80% of the investigated isolates, including isolates that propagated as a pure M1(CJD) strain in tgHu. These results demonstrate that at least two sCJD prion strains can be present in a single patient.IMPORTANCE: sCJD occurrence is currently assumed to result from spontaneous and stochastic formation of a misfolded PrP nucleus in the brains of affected patients. This original nucleus then recruits and converts nascent PrPC into PrPSc, leading to the propagation of prions in the patient's brain. Our study demonstrates the coexistence of two prion strains in the brains of a majority of the 23 sCJD patients investigated. The relative proportion ...
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