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1. Classical scrapie in small ruminants is caused by at least four different prion strains

Author

Natalia Fernández-Borges, María Zamora-Ceballos, Lorenzo González, Juan Carlos Espinosa, Juan María Torres, Leonor Orge, Patricia Aguilar-Calvo, J.L. Pitarch, Olivier Andreoletti, Romolo Nonno, Alba Marín-Moreno, 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), University of California [San Diego] (UC San Diego), University of California (UC), Animal and Plant Health Agency [Addlestone, UK] (APHA), Instituto Nacional de Investigação Agrária e Veterinária = National Institute for Agrarian and Veterinary Research [Oeiras, Portugal] (INIAV), 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), Istituto Superiore di Sanità (ISS), This work was funded by European Union Projects [FOOD‑CT‑2006‑36353 GoatBSE] to JMT and OA, and 219235 ERA‑NET EMIDA [GOAT‑TSE‑FREE] to JCE, OA and RN, Spanish Ministerio de Economía Industria y Competitividad [AGL2009‑11553‑C02‑02] to JMT, AEI/FEDER UE [AGL2016‑78054‑R] to JMT and JCE, and fellowship BES‑2010‑ 040922 to PAC, and fellowship Instituto Nacional de Investigación y Tecnología Agraria y Agroalimentaria [INIA‑FPI‑SGIT‑2015‑02] to AMM., European Project: 39519,GOATBSE, European Project: 219235,EC:FP7:KBBE,FP7-ERANET-2007-RTD,EMIDA(2008), University of California, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Istituto Superiore di Sanita [Rome], European Commission, Ministerio de Economía y Competitividad (España), CSIC - Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Marín-Moreno, Alba [0000-0002-4023-6398], Aguilar-Calvo, Patricia [0000-0001-5859-0240], Espinosa, Juan Carlos [0000-0002-6719-9902], Zamora-Ceballos, María [0000-0002-4694-2365], Pitarch, José Luis [0000-0003-3016-9125], González, Lorenzo [0000-0003-1513-1399], Orge, Leonor [0000-0002-2673-2758], Andréoletti, Olivier [0000-0002-7369-6016], Nonno, Romolo [0000-0001-7556-1564], Torres, Juan María [0000-0003-0443-9232], Marín-Moreno, Alba, Aguilar-Calvo, Patricia, Espinosa, Juan Carlos, Zamora-Ceballos, María, Pitarch, José Luis, González, Lorenzo, Orge, Leonor, Andréoletti, Olivier, Nonno, Romolo, and Torres, Juan María

Subjects
Adverse event, Prions, 040301 veterinary sciences, Bovine spongiform encephalopathy, Veterinary medicine, animal diseases, Sheep Diseases, Scrapie, Biology, Single strain, 0403 veterinary science, 03 medical and health sciences, SF600-1100, medicine, Animals, Small ruminant, Sheep, Domestic, 030304 developmental biology, 0303 health sciences, Sheep disease, Goat Diseases, Transmissible spongiform encephalopathy, Sheep, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, General Veterinary, Animal, Goats, 04 agricultural and veterinary sciences, Classical scrapie, medicine.disease, Domestic sheep, Virology, nervous system diseases, Europe, Species barrier, Goat, Prion, Goat disease, Research Article
Abstract

15 pág. Centro de Investigación en Sanidad Animal (CISA), The diversity of goat scrapie strains in Europe has recently been studied using bioassays in a wide collection of rodent models, resulting in the classification of classical scrapie into four different categories. However, the sole use of the first passage does not lead to isolate adaptation and identification of the strains involved and might therefore lead to misclassification of some scrapie isolates. Therefore, this work reports the complete transmission study of a wide collection of goat transmissible spongiform encephalopathy (TSE) isolates by intracranial inoculation in two transgenic mouse lines overexpressing either small ruminant (TgGoat-ARQ) or bovine (TgBov) PrPC. To compare scrapie strains in sheep and goats, sheep scrapie isolates from different European countries were also included in the study. Once the species barrier phenomenon was overcome, an accurate classification of the isolates was attained. Thus, the use of just two rodent models allowed us to fully differentiate at least four different classical scrapie strains in small ruminants and to identify isolates containing mixtures of strains. This work reinforces the idea that classical scrapie in small ruminants is a prion disease caused by multiple different prion strains and not by a single strain, as is the case for epidemic classical bovine spongiform encephalopathy (BSE-C). In addition, the clear dissimilarity between the different scrapie strains and BSE-C does not support the idea that classical scrapie is the origin of epidemic BSE-C., This work was funded by European Union Projects [FOOD-CT-2006-36353 [GoatBSE] to JMT and OA and 219235 ERA-NET EMIDA [GOAT-TSE-FREE] to JCE, OA and RN], Spanish Ministerio de Economía Industria y Competitividad [AGL2009-11553-C02-02 to JMT, AGL2016-78054-R (AEI/FEDER, UE) to JMT and JCE and fellowship BES-2010- 040922 to PAC], and Instituto Nacional de Investigación y Tecnología Agraria y Agroalimentaria [fellowship INIA-FPI-SGIT-2015-02 to AMM]. The funders had no role in the study design, data collection and interpretation, or the decision to submit the work for publication

Published
2021

2. Allelic Interference in Prion Replication Is Modulated by the Convertibility of the Interfering PrP C and Other Host-Specific Factors

Author

Naima Aron, Séverine Lugan, Juan María Torres, Jean-Yves Douet, Hervé Cassard, Patricia Aguilar-Calvo, Patricia Lorenzo, Juan Carlos Espinosa, Alvina Huor, Alba Marín-Moreno, Irene Prieto, Ana Villa-Diaz, Olivier Andreoletti, 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), Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This work was funded by EU Projects FOOD-CT-2006-36353 (Goat-BSE) and CT2009-222887 (Priority) and by the Spanish Ministerio de Economía y Competitividad (grant AGL2016-78054-R [AEI/FEDER, UE]) and a fellowship (BES-2010-040922) to P.A.-C. A.M.-M. was supported by a fellowship from the INIA (FPI-SGIT-2015-02)., European Project: 36353,GOATBSE, European Project: 222887,EC:FP7:KBBE,FP7-KBBE-2007-2A,PRIORITY(2009), 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), Ministerio de Economía y Competitividad (España), CSIC - Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Espinosa, Juan Carlos, Andreoletti, Olivier, Marín-Moreno, Alba, Cassard, Hervé, Prieto, Irene, Huor, Alvina, Torres, Juan María, Espinosa, Juan Carlos [0000-0002-6719-9902], Andreoletti, Olivier [0000-0002-7369-6016], Marín-Moreno, Alba [0000-0002-4023-6398], Cassard, Hervé [0000-0001-8651-6179], Prieto, Irene [0000-0001-5900-8419], Huor, Alvina [0000-0002-5598-9958], and Torres, Juan María [0000-0003-0443-9232]

Subjects
Genetically modified mouse, prion replication, 040301 veterinary sciences, Transgene, animal diseases, [SDV]Life Sciences [q-bio], Endogeny, Scrapie, Prion propagation, Biology, Interference (genetic), Microbiology, BSE, 0403 veterinary science, Prion interference, 03 medical and health sciences, prion strain, Virology, prion propagation, Allele, Gene, Peptide sequence, 030304 developmental biology, 0303 health sciences, Prion replication, scrapie, food and beverages, 04 agricultural and veterinary sciences, QR1-502, Prion strain, Cell biology, nervous system diseases, prion interference
Abstract

17 Pág., Early studies in transgenic mouse lines have shown that the coexpression of endogenous murine prion protein (PrPC) and transgenic PrPC from another species either inhibits or allows the propagation of prions, depending on the infecting prion strain and interacting protein species. The way whereby this phenomenon, so-called "interference," is modulated remains to be determined. In this study, different transgenic mouse lines were crossbred to produce mice coexpressing bovine and porcine PrPC, bovine and murine PrPC, or murine and porcine PrPC These animals and their respective hemizygous controls were inoculated with several prion strains from different sources (cattle, mice, and pigs) to examine the effects of the simultaneous presence of PrPC from two different species. Our results indicate interference with the infection process, manifested as extended survival times and reduced attack rates. The interference with the infectious process was reduced or absent when the potentiality interfering PrPC species was efficiently converted by the inoculated agent. However, the propagation of the endogenous murine PrPSc was favored, allowing us to speculate that host-specific factors may disturb the interference caused by the coexpression of an exogenous second PrPC IMPORTANCE Prion propagation can be interfered with by the expression of a second prion protein in the host. In the present study, we investigated prion propagation in a host expressing two different prion protein genes. Our findings indicate that the ability of the second prion protein to interfere with prion propagation is related to the transmissibility of the prion in the host expressing only the interfering prion protein. The interference detected occurs in a prion strain-dependent manner. Interestingly, a bias favoring the propagation of the murine PrP allele has been observed. These results open the door to future studies in order to determine the role of host factors other than the PrP amino acid sequence in the interference in prion propagation., This work was funded by EU Projects FOOD-CT-2006-36353 (Goat-BSE) and CT2009-222887 (Priority) and by the Spanish Ministerio de Economía y Competitividad (grant AGL2016-78054-R [AEI/FEDER, UE]) and a fellowship (BES-2010-040922) to P.A.-C. A.M.-M. was supported by a fellowship from the INIA (FPI-SGIT-2015-02).

Published
2021

3. Porcine Prion Protein as a Paradigm of Limited Susceptibility to Prion Strain Propagation

Author

Juan Carlos Espinosa, Juan María Torres, Olivier Andreoletti, Patricia Aguilar-Calvo, Alba Marín-Moreno, Sylvie L. Benestad, 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), Norwegian Veterinary Institute [Oslo], Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This work was supported by the Spanish Ministerio de Economía y Competitividad (grants AGL2012-37988-C04-04 and AGL2016-78054-R [Agencia Estatal de Investigación/Fondo Europeo de Desarrollo Regional, Unión Europea] to J. C. E. and J. M. T., fellowship BES-2010–040922 to P. A. C., and fellowship INIA-FPI-SGIT-2015-02 to A. M. M.), the UK Food Standards Agency (project FS231051 ['Permeability of the Human Species Barriers to TSE Circulating Agents']), and the Fonds Europeens de Developpement Regional Programme Operationnel de Cooperation Territoriale Espagne France Andorre REDPRION (project EFA148/16 [REDPRION] to O. A.)., Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), European Commission, Food Standards Agency (UK), Espinosa, Juan Carlos, Marín-Moreno, Alba (0000-0002-4023-6398), Benestad, Sylvie L (0000-0002-3011-0484), Andreoletti, Olivier (0000-0002-7369-6016), and Torres, Juan María (0000-0003-0443-9232)

Subjects
0301 basic medicine, Genetically modified mouse, pig, Bovine spongiform encephalopathy, animal diseases, [SDV]Life Sciences [q-bio], Prion strain, Scrapie, Biology, BSE, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Immunology and Allergy, Bioassay, Prion protein, classic scrapie, PrP, prion conversion, atypical/Nor98 scrapie, prion strains, swine, medicine.disease, Virology, nervous system diseases, High resistance, 030104 developmental biology, Infectious Diseases, Protein Misfolding Cyclic Amplification, 030217 neurology & neurosurgery
Abstract

10 Pág. Centro de Investigación en Sanidad Animal (CISA), Although experimental transmission of bovine spongiform encephalopathy (BSE) to pigs and transgenic mice expressing pig cellular prion protein (PrPC) (porcine PrP [PoPrP]-Tg001) has been described, no natural cases of prion diseases in pig were reported. This study analyzed pig-PrPC susceptibility to different prion strains using PoPrP-Tg001 mice either as animal bioassay or as substrate for protein misfolding cyclic amplification (PMCA). A panel of isolates representatives of different prion strains was selected, including classic and atypical/Nor98 scrapie, atypical-BSE, rodent scrapie, human Creutzfeldt-Jakob-disease and classic BSE from different species. Bioassay proved that PoPrP-Tg001-mice were susceptible only to the classic BSE agent, and PMCA results indicate that only classic BSE can convert pig-PrPC into scrapie-type PrP (PrPSc), independently of the species origin. Therefore, conformational flexibility constraints associated with pig-PrP would limit the number of permissible PrPSc conformations compatible with pig-PrPC, thus suggesting that pig-PrPC may constitute a paradigm of low conformational flexibility that could confer high resistance to the diversity of prion strains., This work was supported by the Spanish Ministerio de Economía y Competitividad (grants AGL2012- 37988-C04-04 and AGL2016-78054-R [Agencia Estatal de Investigación/Fondo Europeo de Desarrollo Regional, Unión Europea] to J. C. E. and J. M. T., fellowship BES-2010–040922 to P. A. C., and fellowship INIA-FPI-SGIT-2015-02 to A. M. M.), the UK Food Standards Agency (project FS231051 [“Permeability of the Human Species Barriers to TSE Circulating Agents”]), and the Fonds Europeens de Developpement Regional Programme Operationnel de Cooperation Territoriale Espagne France Andorre REDPRION (project EFA148/16 [REDPRION] to O. A.)

Published
2021

4. The emergence of classical BSE from atypical/Nor98 scrapie

Author

Juan María Torres, Juan José Badiola, Martí Pumarola, Enric Vidal, Naima Aron, Alba Marín-Moreno, Olivier Andreoletti, Juan Carlos Espinosa, Alvina Huor, Séverine Lugan, Patricia Aguilar-Calvo, Hervé Cassard, Leonore Orge, Raymond Bujdoso, Sylvie L. Benestad, Jean-Yves Douet, Patricia Lorenzo, Rosa Bolea, Alana M. Thackray, Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, 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), Centre de Recerca en Sanitat Animal [UAB, Spain] (CReSA), Universitat Autònoma de Barcelona (UAB)-Institute of Agrifood Research and Technology (IRTA), University of Zaragoza - Universidad de Zaragoza [Zaragoza], Centro de Encefalopatías y Enfermedades Transmisibles Emergentes, Unit of Murine and Comparative Pathology, Universitat Autònoma de Barcelona (UAB), Norwegian Veterinary Institute [Oslo], Laboratory of Pathology, National Institute for Agrarian and Veterinary Research, University of Cambridge [UK] (CAM), Department of Veterinary Medicine, University of Cambridge, Cambridge, UK, This work was funded by Fonds Europeens de Developpement Regional Programme Operationnel de Cooperation Territoriale Espagne France Andorre TRANSPRION (EFA282/13) and REDPRION (EFA148/16), the UK Food Standards Agency Exploring permeability of the species barrier (M03043 and FS231051), the European Union through FP7 222887 'Priority, ' the Spanish Ministerio de Economia y Competitividad (AGL2016-78054-R [AEI/FEDER, UE]), and Fundacio La Marato de TV3 (201821-31). A.M.-M. was supported by a fellowship from the INIA (FPI-SGIT-2015-02), and P.A.-C. was supported by a fellowship from the Spanish Ministerio de Economia y Competitividad (BES-2010-040922)., European Project: 222887,EC:FP7:KBBE,FP7-KBBE-2007-2A,PRIORITY(2009), Producció Animal, Sanitat Animal, Espinosa, Juan Carlos [0000-0002-6719-9902], Vidal, Enric [0000-0002-4965-3286], Douet, Jean-Yves [0000-0002-0426-4957], Marín-Moreno, Alba [0000-0002-4023-6398], Torres, Juan-Maria [0000-0003-0443-9232], Andreoletti, Olivier [0000-0002-7369-6016], Apollo - University of Cambridge Repository, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT), and Universitat Autònoma de Barcelona (UAB)-Institut de Recerca i Tecnologia Agroalimentàries = Institute of Agrifood Research and Technology (IRTA)

Subjects
0301 basic medicine, Genetically modified mouse, atypical scrapie, 040301 veterinary sciences, animal diseases, Prion strain, Scrapie, Biology, 0403 veterinary science, prion, 03 medical and health sciences, [SPI]Engineering Sciences [physics], In vivo, Animal species, Gene, 2. Zero hunger, Multidisciplinary, Malalties priòniques en els animals, food and beverages, 04 agricultural and veterinary sciences, Biological Sciences, Virology, In vitro, 3. Good health, nervous system diseases, 030104 developmental biology, c-BSE, Protein Misfolding Cyclic Amplification
Abstract

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. info:eu-repo/semantics/acceptedVersion

Published
2019

5. RNA editing alterations define manifestation of prion diseases

Author

Orr Shormoni, Inga Zerr, Katrin Thüne, Eirini Kanata, Juan Carlos Espinosa, Franc Llorens, Matthias Schmitz, Olivier Andreoletti, Athanasios Dimitriadis, Vincenzo Capece, Nikolaos Bekas, Stefan Bonn, Dimitra Dafou, Alba Marín-Moreno, Juan María Torres, Isidre Ferrer, Konstantinos Xanthopoulos, Theodoros Sklaviadis, Aristotle University of Thessaloniki, Neurodegenerative Diseases Research Group, Department of Pharmacy, School of Health Sciences, Aristotle University of Thessaloniki-Aristotle University of Thessaloniki-School of Health Sciences, Aristotle University of Thessaloniki-Aristotle University of Thessaloniki, Institute of Health Carlos III, Network Center for Biomedical Research of Neurodegenerative Diseases, University Medical Center Göttingen (UMG), Department of Genetics, Development and Molecular Biology, School of Biology, Faculty of Sciences, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Laboratory of Pharmacology, Department of Pharmaceutical Sciences, School of Health Sciences, 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), Institute Developmental Biochemistry, Microarray and Deep-Sequencing Core Facility, University Medical Center Göttingen (UMG)-University Medical Center Göttingen (UMG), Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Department of Pathology and Experimental Therapeutics, Universitat de Barcelona (UB), This study was supported by the Research Funding program ARISTEIA II (Grant RNA edit 3739), cofinanced by the European Union (European Social Fund-ESF) and Greek national funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (to T.S.), the Alliance BioSecure Foundation project 'RNA editing in CJD' (T.S. and I.Z.), Federal Ministry of Education and Research grants within the German Network for Degenerative Dementia (to I.Z.), the Red Nacional de Priones AGL2015-71764-REDT-MINECO (to F.L., I.Z., J.M.T., and I.F.), the Spanish Ministry of Health-Instituto Carlos III/Fondo Social Europeo CP16/00041 (to F.L.), by the IKYDA Greek-German collaboration Project 57260006 (to F.L., I.Z., D.D., and T.S.), and and in part by Grant AGL2016-78054-R (AEI/FEDER, UE).

Subjects
RNA editing, genetics [Transcriptome], Disease, genetics [Gene Expression Regulation], Creutzfeldt-Jakob Syndrome, Transcriptome, Mice, [SPI]Engineering Sciences [physics], 0302 clinical medicine, Pathogen, 0303 health sciences, Multidisciplinary, Brain, genetics [Creutzfeldt-Jakob Syndrome], Biological Sciences, 3. Good health, medicine.anatomical_structure, PNAS Plus, Disease Progression, ER-stress, Neuropathogenesis, ddc:500, metabolism [Prion Diseases], Genotype, Prions, physiology [RNA Editing], RNA-sequencing, sporadic Creutzfeldt-Jakob disease, Context (language use), Biology, Prion Proteins, 03 medical and health sciences, Lysosome, genetics [Prion Diseases], medicine, Animals, Humans, 030304 developmental biology, Gene Expression Profiling, sporadic Creutzfeldt–Jakob disease, genetics [RNA Editing], prion diseases, Disease Models, Animal, Gene Expression Regulation, metabolism [Brain], Immunology, metabolism [Prions], Unfolded protein response, genetics [Prion Proteins], 030217 neurology & neurosurgery, methods [Gene Expression Profiling], Neuroscience
Abstract

Significance Prion diseases are fatal neurodegenerative disorders characterized by rapidly progressive dementia. Sporadic Creutzfeldt–Jakob disease (sCJD) is the most prevalent. We report that, specific gene-expression alterations utilizing a reliable in vivo mouse model (tg340-PRNP129MM) with sCJD MM1 subtype, correlate with human disease manifestations in the brain cortex related to disease progression. RNA-editing functions mediated by the APOBEC and ADAR deaminases possibly affecting protein expression necessary for normal brain function, are altered in disease stages. Our data provide powerful evidence, derived from a humanized sCJD mouse model and human autopsy material, discerning the critical role of gene expression and RNA-editing signatures, introducing disease-associated targets that can be extrapolated in other neurodegenerative disorders with common clinical and molecular features., Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein into an infectious cellular pathogen. Clinically characterized by rapidly progressive dementia and accounting for 85% of human prion disease cases, sporadic Creutzfeldt–Jakob disease (sCJD) is the prevalent human prion disease. Although sCJD neuropathological hallmarks are well-known, associated molecular alterations are elusive due to rapid progression and absence of preclinical stages. To investigate transcriptome alterations during disease progression, we utilized tg340-PRNP129MM mice infected with postmortem material from sCJD patients of the most susceptible genotype (MM1 subtype), a sCJD model that faithfully recapitulates the molecular and pathological alterations of the human disease. Here we report that transcriptomic analyses from brain cortex in the context of disease progression, reveal epitranscriptomic alterations (specifically altered RNA edited pathway profiles, eg., ER stress, lysosome) that are characteristic and possibly protective mainly for preclinical and clinical disease stages. Our results implicate regulatory epitranscriptomic mechanisms in prion disease neuropathogenesis, whereby RNA-editing targets in a humanized sCJD mouse model were confirmed in pathological human autopsy material.

Published
2019

6. Effect of Q(211) and K-222 PRNP polymorphic variants in the susceptibility of goats to oral infection with goat bovine spongiform encephalopathy

Author

Wilfred Goldmann, Muhammad Nadeem, Jan P. M. Langeveld, Alex Bossers, Olivier Andreoletti, Kerstin Tauscher, Christine Fast, Patricia Aguilar-Calvo, Martin H. Groschup, Juan María Torres, Juan Carlos Espinosa, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria = National Institute for Agricultural and Food Research and Technology (INIA), Friedrich-Loeffler-Institut (FLI), University of Veterinary Medicine Hannover, Department of Animal Nutrition, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Central Veterinary Institute, Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-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), Spanish Ministry of Science and Innovation [AGL2009-11553-C02-02, AGL2012-37988-C04-04, BES-2010-040922], Dutch Ministry of Economic Affairs [WOT-01-002-001.01] Higher Education Commission of Pakistan, Deutscher Akademischer Austauschdienst, Germany, Biotechnology and Biological Sciences Research Council, European Project: 219235,EC:FP7:KBBE,FP7-ERANET-2007-RTD,EMIDA(2008), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Genetically modified mouse, goats, Genotype, Prions, Bovine spongiform encephalopathy, animal diseases, [SDV]Life Sciences [q-bio], Mice, Transgenic, Scrapie, Biology, transgenic mice, PRNP, Incubation period, BSE, Mice, Galveston Orientation and Amnesia Test, Species Specificity, parasitic diseases, medicine, Animals, Immunology and Allergy, Genetic Predisposition to Disease, Host Pathogen Interaction & Diagnostics, Infectivity, Goat Diseases, Bacteriologie, Bacteriology, Bacteriology, Host Pathogen Interaction & Diagnostics, medicine.disease, susceptibility/resistance, Virology, Host Pathogen Interactie & Diagnostiek, PRNP polymorphisms, 3. Good health, nervous system diseases, Encephalopathy, Bovine Spongiform, Infectious Diseases, Bacteriologie, Host Pathogen Interactie & Diagnostiek, Cattle
Abstract

Background. The prion protein-encoding gene (PRNP) is one of the major determinants for scrapie occurrence in sheep and goats. However, its effect on bovine spongiform encephalopathy (BSE) transmission to goats is not clear. Methods. Goats harboring wild-type, R/Q211 or Q/K222 PRNP genotypes were orally inoculated with a goat-BSE isolate to assess their relative susceptibility to BSE infection. Goats were killed at different time points during the incubation period and after the onset of clinical signs, and their brains as well as several peripheral tissues were analyzed for the accumulation of pathological prion protein (PrPSc) and prion infectivity by mouse bioassay. Results. R/Q211 goats displayed delayed clinical signs compared with wild-type goats. Deposits of PrPSc were detected only in brain, whereas infectivity was present in peripheral tissues too. In contrast, none of the Q/K222 goats showed any evidence of clinical prion disease. No PrPSc accumulation was observed in their brains or peripheral tissues, but very low infectivity was detected in some tissues very long after inoculation (44-45 months). Conclusions. These results demonstrate that transmission of goat BSE is genotype dependent, and they highlight the pivotal protective effect of the K222 PRNP variant in the oral susceptibility of goats to BSE. © 2015 The Author.

Published
2015

7. Elements modulating the prion species barrier and its passage consequences

Author

Alejandro Brun, Aroa Relaño-Ginés, Joaquín Castilla, Patricia Aguilar-Calvo, Elia Alamillo, Olivier Andreoletti, S. A. C. Hawkins, Juan María Torres, María-Eugenia Herva, Mónica Morales, Juan Carlos Espinosa, Susana Molina, Beatriz Parra, Ana Villa-Diaz, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria = National Institute for Agricultural and Food Research and Technology (INIA), Ikerbasque - Basque Foundation for Science, Animal Health and Veterinary Laboratories Agency (AHVLA), Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Spanish Ministerio de Ciencia e Innovacion [RTA2012-00004, AGL2005-03066], European Union [CT-2001-01309, CT-2004-023183, CT2004-506579, CT2009-222887], and Torres, Juan-Maria

Subjects
Mouse, Swine, animal diseases, [SDV]Life Sciences [q-bio], lcsh:Medicine, Biochemistry, Mice, 0302 clinical medicine, Protein sequencing, Infectious Diseases of the Nervous System, lcsh:Science, Peptide sequence, 0303 health sciences, Multidisciplinary, Transmissible spongiform encephalopathy, Strain (chemistry), Animal Models, Cell biology, Encephalopathy, Bovine Spongiform, Veterinary Diseases, Medicine, Infectious diseases, Genetic Engineering, Research Article, Biotechnology, Genetically modified mouse, Prion diseases, Infectious Disease Control, Prions, Bovine spongiform encephalopathy, Transgene, Mice, Transgenic, Biology, 03 medical and health sciences, Model Organisms, mental disorders, medicine, Animals, 030304 developmental biology, Veterinary Prion Diseases, Sheep, Host (biology), lcsh:R, Proteins, medicine.disease, Virology, Creutzfeldt-Jakob disease, nervous system diseases, Disease Models, Animal, lcsh:Q, Cattle, Veterinary Science, Infectious Disease Modeling, 030217 neurology & neurosurgery, Transgenics
Abstract

International audience; The specific characteristics of Transmissible Spongiform Encephalopathy (TSE) strains may be altered during passage across a species barrier. In this study we investigated the biochemical and biological characteristics of Bovine Spongiform Encephalopathy (BSE) after transmission in both natural host species (cattle, sheep, pigs and mice) and in transgenic mice overexpressing the corresponding cellular prion protein (PrPC) in comparison with other non-BSE related prions from the same species. After these passages, most features of the BSE agent remained unchanged. BSE-derived agents only showed slight modifications in the biochemical properties of the accumulated PrPSc, which were demonstrated to be reversible upon re-inoculation into transgenic mice expressing bovine-PrPC. Transmission experiments in transgenic mice expressing bovine, porcine or human-PrP revealed that all BSE-derived agents were transmitted with no or a weak transmission barrier. In contrast, a high species barrier was observed for the non-BSE related prions that harboured an identical PrP amino acid sequence, supporting the theory that the prion transmission barrier is modulated by strain properties (presumably conformation-dependent) rather than by PrP amino acid sequence differences between host and donor. As identical results were observed with prions propagated either in natural hosts or in transgenic mouse models, we postulate that the species barrier and its passage consequences are uniquely governed by the host PrPC sequence and not influenced by other host genetic factors. The results presented herein reinforce the idea that the BSE agent is highly promiscuous, infecting other species, maintaining its properties in the new species, and even increasing its capabilities to jump to other species including humans. These data are essential for the development of an accurate risk assessment for BSE.

Published
2014

8. Sheep-passaged bovine spongiform encephalopathy agent exhibits altered pathobiological properties in bovine-PrP transgenic mice

Author

Joaquín Castilla, Elia Alamillo, Maria Eugenia Herva, Juan Carlos Espinosa, Olivier Andreoletti, Fayna Díaz San-Segundo, Séverine Lugan, Jan P. M. Langeveld, Juan María Torres, Mónica Morales, Francisco J. Salguero, Caroline Lacroux, Inconnu, Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
PrPSc Proteins, animal diseases, [SDV]Life Sciences [q-bio], Scrapie, 0403 veterinary science, Pathogenesis, Mice, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, 0303 health sciences, Virulence, transmission, Brain, food and beverages, 04 agricultural and veterinary sciences, Immunohistochemistry, Encephalopathy, Bovine Spongiform, Titer, immunoreactivity, CVI - Division Virology, Genetically modified mouse, prion-protein conformation, Prions, 040301 veterinary sciences, Bovine spongiform encephalopathy, Blotting, Western, Molecular Sequence Data, Immunology, Mice, Transgenic, Biology, Microbiology, Incubation period, 03 medical and health sciences, strain, CVI - Divisie Virologie, Species Specificity, Virology, mental disorders, medicine, Animals, features, Amino Acid Sequence, creutzfeldt-jakob-disease, 030304 developmental biology, Sheep, scrapie, medicine.disease, infection, nervous system diseases, Disease Models, Animal, variant, bse agent, Insect Science, Pathogenesis and Immunity, Cattle
Abstract

Sheep can be experimentally infected with bovine spongiform encephalopathy (BSE), and the ensuing disease is similar to scrapie in terms of pathogenesis and clinical signs. BSE infection in sheep is an animal and human health concern. In this study, the transmission in BoPrP-Tg110 mice of prions from BSE-infected sheep was examined and compared to the transmission of original cattle BSE in cattle and sheep scrapie prions. Our results indicate no transmission barrier for sheep BSE prions to infect BoPrP-Tg110 mice, but the course of the disease is accelerated compared to the effects of the original BSE isolate. The shortened incubation period of sheep BSE in the model was conserved in subsequent passage in BoPrP-Tg110 mice, indicating that it is not related to infectious titer differences. Biochemical signature, lesion profile, and PrP Sc deposition pattern of both cattle and sheep BSE were similar. In contrast, all three sheep scrapie isolates tested showed an evident transmission barrier and further adaptation in subsequent passage. Taken together, those data indicate that BSE agent can be altered by crossing a species barrier, raising concerns about the virulence of this new prion towards other species, including humans. The BoPrP-Tg110 mouse bioassay should be considered as a valuable tool for discriminating scrapie and BSE in sheep.

Published
2007

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