Publications by authors named "Olivier Andréoletti"

142 Publications

Preclinical transmission of prions by blood transfusion is influenced by donor genotype and route of infection.

PLoS Pathog 2021 Feb 18;17(2):e1009276. Epub 2021 Feb 18.

The Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom.

Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease resulting from zoonotic transmission of bovine spongiform encephalopathy (BSE). Documented cases of vCJD transmission by blood transfusion necessitate on-going risk reduction measures to protect blood supplies, such as leucodepletion (removal of white blood cells, WBCs). This study set out to determine the risks of prion transmission by transfusion of labile blood components (red blood cells, platelets, plasma) commonly used in human medicine, and the effectiveness of leucodepletion in preventing infection, using BSE-infected sheep as a model. All components were capable of transmitting prion disease when donors were in the preclinical phase of infection, with the highest rates of infection in recipients of whole blood and buffy coat, and the lowest in recipients of plasma. Leucodepletion of components (<106 WBCs/unit) resulted in significantly lower transmission rates, but did not completely prevent transmission by any component. Donor PRNP genotype at codon 141, which is associated with variation in incubation period, also had a significant effect on transfusion transmission rates. A sensitive protein misfolding cyclic amplification (PMCA) assay, applied to longitudinal series of blood samples, identified infected sheep from 4 months post infection. However, in donor sheep (orally infected), the onset of detection of PrPSc in blood was much more variable, and generally later, compared to recipients (intravenous infection). This shows that the route and method of infection may profoundly affect the period during which an individual is infectious, and the test sensitivity required for reliable preclinical diagnosis, both of which have important implications for disease control. Our results emphasize that blood transfusion can be a highly efficient route of transmission for prion diseases. Given current uncertainties over the prevalence of asymptomatic vCJD carriers, this argues for the maintenance and improvement of current measures to reduce the risk of transmission by blood products.
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http://dx.doi.org/10.1371/journal.ppat.1009276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891701PMC
February 2021

Site-specific analysis of N-glycans from different sheep prion strains.

PLoS Pathog 2021 Feb 18;17(2):e1009232. Epub 2021 Feb 18.

Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy.

Prion diseases are a group of neurodegenerative diseases affecting a wide range of mammalian species, including humans. During the course of the disease, the abnormally folded scrapie prion protein (PrPSc) accumulates in the central nervous system where it causes neurodegeneration. In prion disorders, the diverse spectrum of illnesses exists because of the presence of different isoforms of PrPSc where they occupy distinct conformational states called strains. Strains are biochemically distinguished by a characteristic three-band immunoblot pattern, defined by differences in the occupancy of two glycosylation sites on the prion protein (PrP). Characterization of the exact N-glycan structures attached on either PrPC or PrPSc is lacking. Here we report the characterization and comparison of N-glycans from two different sheep prion strains. PrPSc from both strains was isolated from brain tissue and enzymatically digested with trypsin. By using liquid chromatography coupled to electrospray mass spectrometry, a site-specific analysis was performed. A total of 100 structures were detected on both glycosylation sites. The N-glycan profile was shown to be similar to the one on mouse PrP, however, with additional 40 structures reported. The results presented here show no major differences in glycan composition, suggesting that glycans may not be responsible for the differences in the two analyzed prion strains.
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http://dx.doi.org/10.1371/journal.ppat.1009232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891774PMC
February 2021

Wide distribution of prion infectivity in the peripheral tissues of vCJD and sCJD patients.

Acta Neuropathol 2021 Mar 2;141(3):383-397. Epub 2021 Feb 2.

UMR INRA ENVT 1225, Interactions Hôtes Agents Pathogènes, Ecole Nationale Vétérinaire de Toulouse, 23 Chemin des Capelles, 31076, Toulouse, France.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the commonest human prion disease, occurring most likely as the consequence of spontaneous formation of abnormal prion protein in the central nervous system (CNS). Variant Creutzfeldt-Jakob disease (vCJD) is an acquired prion disease that was first identified in 1996. In marked contrast to vCJD, previous investigations in sCJD revealed either inconsistent levels or an absence of PrP in peripheral tissues. These findings contributed to the consensus that risks of transmitting sCJD as a consequence of non-CNS invasive clinical procedures were low. In this study, we systematically measured prion infectivity levels in CNS and peripheral tissues collected from vCJD and sCJD patients. Unexpectedly, prion infectivity was detected in a wide variety of peripheral tissues in sCJD cases. Although the sCJD infectivity levels varied unpredictably in the tissues sampled and between patients, these findings could impact on our perception of the possible transmission risks associated with sCJD.
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http://dx.doi.org/10.1007/s00401-021-02270-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882550PMC
March 2021

Potential BSE risk posed by the use of ruminant collagen and gelatine in feed for non-ruminant farmed animals.

EFSA J 2020 Oct 28;18(10):e06267. Epub 2020 Oct 28.

EFSA was requested to estimate the cattle bovine spongiform encephalopathy (BSE) risk (C-, L- and H-BSE) posed by ruminant collagen and gelatine produced from raw material fit for human consumption, or from material classified as Category 3 animal by-products (ABP), to be used in feed intended for non-ruminant animals, including aquaculture animals. Three risk pathways (RP) were identified by which cattle could be exposed to ruminant feed cross-contaminated with ruminant collagen or gelatine: 1) recycled former foodstuffs produced in accordance with Regulation (EC) No 853/2004 (RP1), 2) technological or nutritional additives or 3) compound feed, produced either in accordance with Regulation (EC) No 853/2004 (RP2a) or Regulation (EU) No 142/2011 (RP2b). A probabilistic model was developed to estimate the BSE infectivity load measured in cattle oral ID (CoID )/kg, in the gelatine produced from the bones and hide of one infected animal older than 30 months with clinical BSE (worst-case scenario). The amount of BSE infectivity (50th percentile estimate) in a member state (MS) with negligible risk status was 7.6 × 10 CoID /kg, and 3.1 × 10 CoID /kg in a MS with controlled risk status. The assessment considered the potential contamination pathways and the model results (including uncertainties) regarding the current epidemiological situation in the EU and current statutory controls. Given the estimated amount of BSE infectivity to which cattle would be exposed in a single year, and even if all the estimated undetected BSE cases in the EU were used for the production of collagen or gelatine (either using raw materials fit for human consumption or Category 3 ABP raw materials), it was concluded that the probability that no new case of BSE in the cattle population would be generated through any of the three RP is 99-100% (almost certain).
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http://dx.doi.org/10.2903/j.efsa.2020.6267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592076PMC
October 2020

Evaluation of an alternative method for production of biodiesel from processed fats derived from Category 1, 2 and 3 animal by-products (submitted by College Proteins).

EFSA J 2020 Apr 20;18(4):e06089. Epub 2020 Apr 20.

An alternative method for the production of biodiesel from processed fats derived from Category 1, 2 and 3 animal by-products was assessed. The method is based on a pre-cleaning process, acidic esterification/transesterification of tallow using 1.5% methanesulfonic acid w/w; 140°C; 5.5 bar absolute pressure (bara); 4 h, followed by fractional distillation. The application focuses on the capacity of the alternative method to inactivate prions. Given the limitations that biodiesel presents for direct measurement of prion infectivity, the BIOHAZ Panel considered, based on the outcome of previous EFSA Opinions and current expert evaluation, that a reduction of 6 log in detectable PrP signal would be necessary to consider the process at least equivalent to previously approved methods for Category 1 animal by-products. This is in addition to the inactivation achieved by the pressure sterilisation method applied before the application of any biodiesel production method. Experimental data were provided via ad hoc studies commissioned to quantify the reduction in detectable PrP in material spiked with scrapie hamster strain 263K, as measured by western blot, for the first two steps, with distillation assumed to provide at least an additional 3 log reduction, based on published data. Despite the intrinsic methodological caveats of the detection of PrP in laboratory studies, the BIOHAZ Panel considers that the alternative method, including the final fractional distillation, is capable of achieving the required 6 log reduction of the strain 263K PrP signal. Therefore, the method under assessment can be considered at least equivalent to the processing methods previously approved for the production of biodiesel from all categories of animal by-product raw materials. It is recommended to check the feasibility of the proposed HACCP plan by recording the main processing parameters for a certain time period under real industrial conditions.
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http://dx.doi.org/10.2903/j.efsa.2020.6089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448056PMC
April 2020

Host prion protein expression levels impact prion tropism for the spleen.

PLoS Pathog 2020 07 23;16(7):e1008283. Epub 2020 Jul 23.

Université Paris-Saclay, INRAE, UVSQ, VIM Jouy-en-Josas, France.

Prions are pathogens formed from abnormal conformers (PrPSc) of the host-encoded cellular prion protein (PrPC). PrPSc conformation to disease phenotype relationships extensively vary among prion strains. In particular, prions exhibit a strain-dependent tropism for lymphoid tissues. Prions can be composed of several substrain components. There is evidence that these substrains can propagate in distinct tissues (e.g. brain and spleen) of a single individual, providing an experimental paradigm to study the cause of prion tissue selectivity. Previously, we showed that PrPC expression levels feature in prion substrain selection in the brain. Transmission of sheep scrapie isolates (termed LAN) to multiple lines of transgenic mice expressing varying levels of ovine PrPC in their brains resulted in the phenotypic expression of the dominant sheep substrain in mice expressing near physiological PrPC levels, whereas a minor substrain replicated preferentially on high expresser mice. Considering that PrPC expression levels are markedly decreased in the spleen compared to the brain, we interrogate whether spleen PrPC dosage could drive prion selectivity. The outcome of the transmission of a large cohort of LAN isolates in the spleen from high expresser mice correlated with the replication rate dependency on PrPC amount. There was a prominent spleen colonization by the substrain preferentially replicating on low expresser mice and a relative incapacity of the substrain with higher-PrPC level need to propagate in the spleen. Early colonization of the spleen after intraperitoneal inoculation allowed neuropathological expression of the lymphoid substrain. In addition, a pair of substrain variants resulting from the adaptation of human prions to ovine high expresser mice, and exhibiting differing brain versus spleen tropism, showed different tropism on transmission to low expresser mice, with the lymphoid substrain colonizing the brain. Overall, these data suggest that PrPC expression levels are instrumental in prion lymphotropism.
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http://dx.doi.org/10.1371/journal.ppat.1008283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402522PMC
July 2020

Update on chronic wasting disease (CWD) III.

EFSA J 2019 Nov 11;17(11):e05863. Epub 2019 Nov 11.

The European Commission asked EFSA for a Scientific Opinion: to revise the state of knowledge about the differences between the chronic wasting disease (CWD) strains found in North America (NA) and Europe and within Europe; to review new scientific evidence on the zoonotic potential of CWD and to provide recommendations to address the potential risks and to identify risk factors for the spread of CWD in the European Union. Full characterisation of European isolates is being pursued, whereas most NA CWD isolates have not been characterised in this way. The differing surveillance programmes in these continents result in biases in the types of cases that can be detected. Preliminary data support the contention that the CWD strains identified in Europe and NA are different and suggest the presence of strain diversity in European cervids. Current data do not allow any conclusion on the implications of strain diversity on transmissibility, pathogenesis or prevalence. Available data do not allow any conclusion on the zoonotic potential of NA or European CWD isolates. The risk of CWD to humans through consumption of meat cannot be directly assessed. At individual level, consumers of meat, meat products and offal derived from CWD-infected cervids will be exposed to the CWD agent(s). Measures to reduce human dietary exposure could be applied, but exclusion from the food chain of whole carcasses of infected animals would be required to eliminate exposure. Based on NA experiences, all the risk factors identified for the spread of CWD may be associated with animals accumulating infectivity in both the peripheral tissues and the central nervous system. A subset of risk factors is relevant for infected animals without involvement of peripheral tissues. All the risk factors should be taken into account due to the potential co-localisation of animals presenting with different disease phenotypes.
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http://dx.doi.org/10.2903/j.efsa.2019.5863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008890PMC
November 2019

Prion infection, transmission, and cytopathology modeled in a low-biohazard human cell line.

Life Sci Alliance 2020 08 30;3(8). Epub 2020 Jun 30.

Institute of Neuropathology, University of Zurich, Zurich, Switzerland

Transmission of prion infectivity to susceptible murine cell lines has simplified prion titration assays and has greatly reduced the need for animal experimentation. However, murine cell models suffer from technical and biological constraints. Human cell lines might be more useful, but they are much more biohazardous and are often poorly infectible. Here, we describe the human clonal cell line hovS, which lacks the human gene and expresses instead the ovine VRQ allele. HovS cells were highly susceptible to the PG127 strain of sheep-derived murine prions, reaching up to 90% infected cells in any given culture and were maintained in a continuous infected state for at least 14 passages. Infected hovS cells produced proteinase K-resistant prion protein (PrP), pelletable PrP aggregates, and bona fide infectious prions capable of infecting further generations of naïve hovS cells and mice expressing the VRQ allelic variant of ovine PrP Infection in hovS led to prominent cytopathic vacuolation akin to the spongiform changes observed in individuals suffering from prion diseases. In addition to expanding the toolbox for prion research to human experimental genetics, the hovS cell line provides a human-derived system that does not require human prions. Hence, the manipulation of scrapie-infected hovS cells may present fewer biosafety hazards than that of genuine human prions.
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http://dx.doi.org/10.26508/lsa.202000814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335386PMC
August 2020

SFPQ and Tau: critical factors contributing to rapid progression of Alzheimer's disease.

Acta Neuropathol 2020 09 23;140(3):317-339. Epub 2020 Jun 23.

Department of Neurology, University Medical Center Göttingen and the German Center for Neurodegenerative Diseases (DZNE), Robert-Koch-Straße 40, 37075, Göttingen, Germany.

Dysfunctional RNA-binding proteins (RBPs) have been implicated in several neurodegenerative disorders. Recently, this paradigm of RBPs has been extended to pathophysiology of Alzheimer's disease (AD). Here, we identified disease subtype specific variations in the RNA-binding proteome (RBPome) of sporadic AD (spAD), rapidly progressive AD (rpAD), and sporadic Creutzfeldt Jakob disease (sCJD), as well as control cases using RNA pull-down assay in combination with proteomics. We show that one of these identified proteins, splicing factor proline and glutamine rich (SFPQ), is downregulated in the post-mortem brains of rapidly progressive AD patients, sCJD patients and 3xTg mice brain at terminal stage of the disease. In contrast, the expression of SFPQ was elevated at early stage of the disease in the 3xTg mice, and in vitro after oxidative stress stimuli. Strikingly, in rpAD patients' brains SFPQ showed a significant dislocation from the nucleus and cytoplasmic colocalization with TIA-1. Furthermore, in rpAD brain lesions, SFPQ and p-tau showed extranuclear colocalization. Of note, association between SFPQ and tau-oligomers in rpAD brains suggests a possible role of SFPQ in oligomerization and subsequent misfolding of tau protein. In line with the findings from the human brain, our in vitro study showed that SFPQ is recruited into TIA-1-positive stress granules (SGs) after oxidative stress induction, and colocalizes with tau/p-tau in these granules, providing a possible mechanism of SFPQ dislocation through pathological SGs. Furthermore, the expression of human tau in vitro induced significant downregulation of SFPQ, suggesting a causal role of tau in the downregulation of SFPQ. The findings from the current study indicate that the dysregulation and dislocation of SFPQ, the subsequent DNA-related anomalies and aberrant dynamics of SGs in association with pathological tau represents a critical pathway which contributes to rapid progression of AD.
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http://dx.doi.org/10.1007/s00401-020-02178-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423812PMC
September 2020

Prions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures.

mBio 2020 06 16;11(3). Epub 2020 Jun 16.

UMR INRA ENVT 1225, Interactions Hôte Agent Pathogène, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France

Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently classified according to the methionine/valine polymorphism at codon 129 of the gene and the proteinase K-digested abnormal prion protein (PrP) 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 PrP 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 ( = 29) that displayed either a single or mixed type 1/type 2 PrP were transmitted into human-PrP-expressing mice (tgHu). These bioassays demonstrated that two distinct prion strains (M1 and V2) 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 and V2 strains, including in patients who displayed a "pure" type 1 or type 2 PrP The use of a highly sensitive prion amplification technique that specifically probes the V2 strain revealed the presence of the V2 prion in more than 80% of the investigated isolates, including isolates that propagated as a pure M1 strain in tgHu. These results demonstrate that at least two sCJD prion strains can be present in a single patient. 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 PrP into PrP, 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 of these sCJD strains varied both between patients and between brain areas in a single patient. These findings strongly support the view that the replication of an sCJD prion strain in the brain of a patient can result in the propagation of different prion strain subpopulations. Beyond its conceptual importance for our understanding of prion strain properties and evolution, the sCJD strain mixture phenomenon and its frequency among patients have important implications for the development of therapeutic strategies for prion diseases.
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http://dx.doi.org/10.1128/mBio.00393-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298703PMC
June 2020

Radical Change in Zoonotic Abilities of Atypical BSE Prion Strains as Evidenced by Crossing of Sheep Species Barrier in Transgenic Mice.

Emerg Infect Dis 2020 06;26(6):1130-1139

Classical bovine spongiform encephalopathy (BSE) is the only zoonotic prion disease described to date. Although the zoonotic potential of atypical BSE prions have been partially studied, an extensive analysis is still needed. We conducted a systematic study by inoculating atypical BSE isolates from different countries in Europe into transgenic mice overexpressing human prion protein (PrP): TgMet, TgMet/Val, and TgVal. L-type BSE showed a higher zoonotic potential in TgMet mice than classical BSE, whereas Val-PrP variant was a strong molecular protector against L-type BSE prions, even in heterozygosis. H-type BSE could not be transmitted to any of the mice. We also adapted 1 H- and 1 L-type BSE isolate to sheep-PrP transgenic mice and inoculated them into human-PrP transgenic mice. Atypical BSE prions showed a modification in their zoonotic ability after adaptation to sheep-PrP producing agents able to infect TgMet and TgVal, bearing features that make them indistinguishable of sporadic Creutzfeldt-Jakob disease prions.
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http://dx.doi.org/10.3201/eid2606.181790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7258450PMC
June 2020

The Prion-like protein Shadoo is involved in mouse embryonic and mammary development and differentiation.

Sci Rep 2020 04 21;10(1):6765. Epub 2020 Apr 21.

Université Paris-Saclay, INRAE, AgroParisTech, UMR1313-GABI, 78350, Jouy-en-Josas, France.

Shadoo belongs to the prion protein family, an evolutionary conserved and extensively studied family due to the implication of PrP in Transmissible Spongiform Encephalopathies. However, the biological function of these genes remains poorly understood. While Sprn-knockdown experiments suggested an involvement of Shadoo during mouse embryonic development, Sprn-knockout experiments in 129Pas/C57BL/6J or 129Pas/FVB/NCr mice did not confirm it. In the present study, we analyzed the impact of Sprn gene invalidation in a pure FVB/NJ genetic background, using a zinc finger nuclease approach. The in-depth analysis of the derived knockout transgenic mice revealed a significant increase in embryonic lethality at early post-implantation stages, a growth retardation of young Sprn-knockout pups fed by wild type mice and a lactation defect of Sprn-knockout females. Histological and transcriptional analyses of knockout E7.5 embryos, E14.5 placentas and G7.5 mammary glands revealed specific roles of the Shadoo protein in mouse early embryogenesis, tissue development and differentiation with a potential antagonist action between PrP and Shadoo. This study thus highlights the entanglement between the proteins of the prion family.
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http://dx.doi.org/10.1038/s41598-020-63805-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174383PMC
April 2020

Mixtures of prion substrains in natural scrapie cases revealed by ovinised murine models.

Sci Rep 2020 03 19;10(1):5042. Epub 2020 Mar 19.

Centro de Encefalopatías y Enfermedades Transmisibles Emergentes, Facultad de Veterinaria, Instituto Agroalimentario de Aragón - IA2 (Universidad de Zaragoza - CITA), 50013, Zaragoza, Spain.

Phenotypic variability in prion diseases, such as scrapie, is associated to the existence of prion strains, which are different pathogenic prion protein (PrP) conformations with distinct pathobiological properties. To faithfully study scrapie strain variability in natural sheep isolates, transgenic mice expressing sheep cellular prion protein (PrP) are used. In this study, we used two of such models to bioassay 20 scrapie isolates from the Spain-France-Andorra transboundary territory. Animals were intracerebrally inoculated and survival periods, proteinase K-resistant PrP (PrP) banding patterns, lesion profiles and PrP distribution were studied. Inocula showed a remarkable homogeneity on banding patterns, all of them but one showing 19-kDa PrP. However, a number of isolates caused accumulation of 21-kDa PrP in TgShp XI. A different subgroup of isolates caused long survival periods and presence of 21-kDa PrP in Tg338 mice. It seemed that one major 19-kDa prion isoform and two distinct 21-kDa variants coexisted in source inocula, and that they could be separated by bioassay in each transgenic model. The reason why each model favours a specific component of the mixture is unknown, although PrP expression level may play a role. Our results indicate that coinfection with more than one substrain is more frequent than infection with a single component.
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http://dx.doi.org/10.1038/s41598-020-61977-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081250PMC
March 2020

Goats naturally devoid of PrP are resistant to scrapie.

Vet Res 2020 Jan 10;51(1). Epub 2020 Jan 10.

Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Sandnes, Norway.

Prion diseases are progressive and fatal, neurodegenerative disorders described in humans and animals. According to the "protein-only" hypothesis, the normal host-encoded prion protein (PrP) is converted into a pathological and infectious form (PrP) in these diseases. Transgenic knockout models have shown that PrP is a prerequisite for the development of prion disease. In Norwegian dairy goats, a mutation (Ter) in the prion protein gene (PRNP) effectively blocks PrP synthesis. We inoculated 12 goats (4 PRNP, 4 PRNP, and 4 PRNP) intracerebrally with goat scrapie prions. The mean incubation time until clinical signs of prion disease was 601 days post-inoculation (dpi) in PRNP goats and 773 dpi in PRNP goats. PrP and vacuolation were similarly distributed in the central nervous system (CNS) of both groups and observed in all brain regions and segments of the spinal cord. Generally, accumulation of PrP was limited in peripheral organs, but all PRNP goats and 1 of 4 PRNP goats were positive in head lymph nodes. The four PRNP goats remained healthy, without clinical signs of prion disease, and were euthanized 1260 dpi. As expected, no accumulation of PrP was observed in the CNS or peripheral tissues of this group, as assessed by immunohistochemistry, enzyme immunoassay, and real-time quaking-induced conversion. Our study shows for the first time that animals devoid of PrP due to a natural mutation do not propagate prions and are resistant to scrapie. Clinical onset of disease is delayed in heterozygous goats expressing about 50% of PrP levels.
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http://dx.doi.org/10.1186/s13567-019-0731-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954626PMC
January 2020

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

J Infect Dis 2020 Jan 9. Epub 2020 Jan 9.

Centro de Investigación en Sanidad Animal (CISA-INIA), Valdeolmos, Madrid, Spain.

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.
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http://dx.doi.org/10.1093/infdis/jiz646DOI Listing
January 2020

Characterization of goat prions demonstrates geographical variation of scrapie strains in Europe and reveals the composite nature of prion strains.

Sci Rep 2020 01 8;10(1):19. Epub 2020 Jan 8.

Wageningen BioVeterinary Research, Lelystad, the Netherlands.

Bovine Spongiform Encephalopathy (BSE) is the only animal prion which has been recognized as a zoonotic agent so far. The identification of BSE in two goats raised the need to reliably identify BSE in small ruminants. However, our understanding of scrapie strain diversity in small ruminants remains ill-defined, thus limiting the accuracy of BSE surveillance and spreading fear that BSE might lurk unrecognized in goats. We investigated prion strain diversity in a large panel of European goats by a novel experimental approach that, instead of assessing the neuropathological profile after serial transmissions in a single animal model, was based on the direct interaction of prion isolates with several recipient rodent models expressing small ruminants or heterologous prion proteins. The findings show that the biological properties of scrapie isolates display different patterns of geographical distribution in Europe and suggest that goat BSE could be reliably discriminated from a wide range of biologically and geographically diverse goat prion isolates. Finally, most field prion isolates showed composite strain features, with discrete strain components or sub-strains being present in different proportions in individual goats or tissues. This has important implications for understanding the nature and evolution of scrapie strains and their transmissibility to other species, including humans.
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http://dx.doi.org/10.1038/s41598-019-57005-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949283PMC
January 2020

Transmissible spongiform encephalopathy in goats: is PrP rapid test sensitivity affected by genotype?

J Vet Diagn Invest 2020 Jan 2;32(1):87-93. Epub 2020 Jan 2.

APHA-Weybridge, Addlestone, Surrey, UK (Simmons, Thorne, Spiropoulos, Hawkins, Cassar).

Transmissible spongiform encephalopathy (TSE) surveillance in goats relies on tests initially approved for cattle, subsequently assessed for sheep, and approval extrapolated for use in "small ruminants." The current EU-approved immunodetection tests employ antibodies against various epitopes of the prion protein PrP, which is encoded by the host gene. The caprine gene is polymorphic, mostly at codons different from the ovine . The EU goat population is much more heterogeneous than the sheep population, with more -related polymorphisms, and with marked breed-related differences. The ability of the current tests to detect disease-specific PrP generated against these different genetic backgrounds is currently assumed, rather than proven. We examined whether common polymorphisms within the goat gene might have any adverse effect on the relative performance of EU-approved rapid tests. The sample panel comprised goats from the UK, Cyprus, France, and Italy, with either experimental or naturally acquired scrapie at both the preclinical and/or unknown and clinical stages of disease. Test sensitivity was significantly lower and more variable when compared using samples from animals that were preclinical or of unknown status. However, all of the rapid tests included in our study were able to correctly identify all samples from animals in the clinical stages of disease, apart from samples from animals polymorphic for serine or aspartic acid at codon 146, in which the performance of the Bio-Rad tests was profoundly affected. Our data show that some polymorphisms may adversely affect one test and not another, as well as underline the dangers of extrapolating from other species.
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http://dx.doi.org/10.1177/1040638719896327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003235PMC
January 2020

The emergence of classical BSE from atypical/Nor98 scrapie.

Proc Natl Acad Sci U S A 2019 Dec 16. Epub 2019 Dec 16.

UMR Institut National de la Recherche Agronomique (INRA)/École Nationale Vétérinaire de Toulouse (ENVT) 1225, Interactions Hôtes Agents Pathogènes, 31076 Toulouse, France;

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.
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http://dx.doi.org/10.1073/pnas.1915737116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936354PMC
December 2019

Four types of scrapie in goats differentiated from each other and bovine spongiform encephalopathy by biochemical methods.

Vet Res 2019 Nov 25;50(1):97. Epub 2019 Nov 25.

Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanita (ISS), 299-00161, Rome, Italy.

Scrapie in goats has been known since 1942, the archetype of prion diseases in which only prion protein (PrP) in misfolded state (PrP) acts as infectious agent with fatal consequence. Emergence of bovine spongiform encephalopathy (BSE) with its zoonotic behaviour and detection in goats enhanced fears that its source was located in small ruminants. However, in goats knowledge on prion strain typing is limited. A European-wide study is presented concerning the biochemical phenotypes of the protease resistant fraction of PrP (PrP) in over thirty brain isolates from transmissible spongiform encephalopathy (TSE) affected goats collected in seven countries. Three different scrapie forms were found: classical scrapie (CS), Nor98/atypical scrapie and one case of CH1641 scrapie. In addition, CS was found in two variants-CS-1 and CS-2 (mainly Italy)-which differed in proteolytic resistance of the PrP N-terminus. Suitable PrP markers for discriminating CH1641 from BSE (C-type) appeared to be glycoprofile pattern, presence of two triplets instead of one, and structural (in)stability of its core amino acid region. None of the samples exhibited BSE like features. BSE and these four scrapie types, of which CS-2 is new, can be recognized in goats with combinations of a set of nine biochemical parameters.
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http://dx.doi.org/10.1186/s13567-019-0718-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878695PMC
November 2019

Prion strain-dependent tropism is maintained between spleen and granuloma and relies on lymphofollicular structures.

Sci Rep 2019 10 10;9(1):14656. Epub 2019 Oct 10.

VIM, INRA, Université Paris-Saclay, 78350, Jouy-en-Josas, France.

In peripherally acquired prion diseases, prions move through several tissues of the infected host, notably in the lymphoid tissue, long before the occurrence of neuroinvasion. Accumulation can even be restricted to the lymphoid tissue without neuroinvasion and clinical disease. Several experimental observations indicated that the presence of differentiated follicular dendritic cells (FDCs) in the lymphoid structures and the strain type are critical determinants of prion extraneural replication. In this context, the report that granulomatous structures apparently devoid of FDCs could support prion replication raised the question of the requirements for prion lymphotropism. The report also raised the possibility that nonlymphoid tissue-tropic prions could actually target these inflammatory structures. To investigate these issues, we examined the capacity of closely related prions, albeit with opposite lymphotropism (or FDC dependency), for establishment in experimentally-induced granuloma in ovine PrP transgenic mice. We found a positive correlation between the prion capacity to accumulate in the lymphoid tissue and granuloma, regardless of the prion detection method used. Surprisingly, we also revealed that the accumulation of prions in granulomas involved lymphoid-like structures associated with the granulomas and containing cells that stain positive for PrP, Mfge-8 but not CD45 that strongly suggest FDCs. These results suggest that the FDC requirement for prion replication in lymphoid/inflammatory tissues may be strain-dependent.
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http://dx.doi.org/10.1038/s41598-019-51084-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787085PMC
October 2019

RNA editing alterations define manifestation of prion diseases.

Proc Natl Acad Sci U S A 2019 09 6;116(39):19727-19735. Epub 2019 Sep 6.

Neurodegenerative Diseases Research Group, Department of Pharmacy, School of Health Sciences, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece;

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 tg340-129MM 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.
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http://dx.doi.org/10.1073/pnas.1803521116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765247PMC
September 2019

Incomplete inactivation of atypical scrapie following recommended autoclave decontamination procedures.

Transbound Emerg Dis 2019 Sep 17;66(5):1993-2001. Epub 2019 Jun 17.

Animal and Plant Health Agency (APHA), Weybridge, Surrey, UK.

Prions are highly resistant to the decontamination procedures normally used to inactivate conventional pathogens. This is a challenging problem not only in the medical and veterinary fields for minimizing the risk of transmission from potentially infective sources but also for ensuring the safe disposal or subsequent use of animal by-products. Specific pressure autoclaving protocols were developed for this purpose, but different strains of prions have been reported to have differing resistance patterns to established prion decontamination procedures, and as additional TSE strains are identified it is necessary to determine the effectiveness of such procedures. In this study we assessed the efficacy of sterilization using the EU recommended autoclave procedure for prions (133°C, 3 Bar for 20 min) on the atypical or Nor98 (AS/Nor98) scrapie strain of sheep and goats. Using a highly sensitive murine mouse model (tg338) that overexpresses ovine PrP , we determined that this method of decontamination reduced the infectivity titre by 10 . Infectivity was nonetheless still detected after applying the recommended autoclaving protocol. This shows that AS/Nor98 can survive the designated legislative decontamination conditions, albeit with a significant decrease in titre. The infectivity of a classical scrapie isolate subjected to the same decontamination conditions was reduced by 10 suggesting that the AS/Nor98 isolate is less sensitive to decontamination than the classical scrapie source.
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http://dx.doi.org/10.1111/tbed.13247DOI Listing
September 2019

Animal prion diseases: the risks to human health.

Brain Pathol 2019 03 22;29(2):248-262. Epub 2019 Jan 22.

UMR INRA ENVT 1225-IHAP, École Nationale Vétérinaire de Toulouse, Toulouse, France.

Transmissible spongiform encephalopathies (TSEs) or prion diseases of animals notably include scrapie in small ruminants, chronic wasting disease (CWD) in cervids and classical bovine spongiform encephalopathy (C-BSE). As the transmission barrier phenomenon naturally limits the propagation of prions from one species to another, and the lack of epidemiological evidence for an association with human prion diseases, the zoonotic potential of these diseases was for a long time considered negligible. However, in 1996, C-BSE was recognized as the cause of a new human prion disease, variant Creutzfeldt-Jakob disease (vCJD), which triggered an unprecedented public health crisis in Europe. Large-scale epidemio-surveillance programs for scrapie and C-BSE that were implemented in the EU after the BSE crisis revealed that the distribution and prevalence of prion diseases in the ruminant population had previously been underestimated. They also led to the recognition of new forms of TSEs (named atypical) in cattle and small ruminants and to the recent identification of CWD in Europe. At this stage, the characterization of the strain diversity and zoonotic abilities associated with animal prion diseases remains largely incomplete. However, transmission experiments in nonhuman primates and transgenic mice expressing human PrP clearly indicate that classical scrapie, and certain forms of atypical BSE (L-BSE) or CWD may have the potential to infect humans. The remaining uncertainties about the origins and relationships between animal prion diseases emphasize the importance of the measures implemented to limit human exposure to these potentially zoonotic agents, and of continued surveillance for both animal and human prion diseases.
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http://dx.doi.org/10.1111/bpa.12696DOI Listing
March 2019

Epigenetic Control of the Notch and Eph Signaling Pathways by the Prion Protein: Implications for Prion Diseases.

Mol Neurobiol 2019 Mar 11;56(3):2159-2173. Epub 2018 Jul 11.

INSERM UMR 1124, 75006, Paris, France.

Among the ever-growing number of self-replicating proteins involved in neurodegenerative diseases, the prion protein PrP remains the most infamous for its central role in transmissible spongiform encephalopathies (TSEs). In these diseases, pathogenic prions propagate through a seeding mechanism, where normal PrP molecules are converted into abnormally folded scrapie isoforms termed PrP. Since its discovery over 30 years ago, much advance has contributed to define the host-encoded cellular prion protein PrP as a critical relay of prion-induced neuronal cell demise. A current consensual view is that the conversion of PrP into PrP in neuronal cells diverts the former from its normal function with subsequent molecular alterations affecting synaptic plasticity. Here, we report that prion infection is associated with reduced expression of key effectors of the Notch pathway in vitro and in vivo, recapitulating changes fostered by the absence of PrP. We further show that both prion infection and PrP depletion promote drastic alterations in the expression of a defined set of Eph receptors and their ephrin ligands, which represent important players in synaptic function. Our data indicate that defects in the Notch and Eph axes can be mitigated in response to histone deacetylase inhibition in PrP-depleted as well as prion-infected cells. We thus conclude that infectious prions cause a loss-of-function phenotype with respect to Notch and Eph signaling and that these alterations are sustained by epigenetic mechanisms.
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http://dx.doi.org/10.1007/s12035-018-1193-7DOI Listing
March 2019

Mammalian prion propagation in PrP transgenic Drosophila.

Brain 2018 09;141(9):2700-2710

University of Cambridge, Department of Veterinary Medicine, Madingley Road, Cambridge, CB3 OES, UK.

Mammalian prions propagate by template-directed misfolding and aggregation of normal cellular prion related protein PrPC as it converts into disease-associated conformers collectively referred to as PrPSc. Mammalian species may be permissive for prion disease because these hosts have co-evolved specific co-factors that assist PrPC conformational change and prion propagation. We have tested this hypothesis by examining whether faithful prion propagation occurs in the normally PrPC-null invertebrate host Drosophila melanogaster. Ovine PrP transgenic Drosophila exposed at the larval stage to ovine scrapie showed a progressive accumulation of transmissible prions in adult flies. Strikingly, the biological properties of distinct ovine prion strains were maintained during their propagation in Drosophila. Our observations show that the co-factors necessary for strain-specific prion propagation are not unique to mammalian species. Our studies establish Drosophila as a novel host for the study of transmissible mammalian prions.
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http://dx.doi.org/10.1093/brain/awy183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113635PMC
September 2018

Detection of PrPres in peripheral tissue in pigs with clinical disease induced by intracerebral challenge with sheep-passaged bovine spongiform encephalopathy agent.

PLoS One 2018 5;13(7):e0199914. Epub 2018 Jul 5.

Centro de Encefalopatías y Enfermedades Transmisibles Emergentes (CEETE), Veterinary Faculty, Universidad de Zaragoza, Zaragoza, Spain.

Bovine spongiform encephalopathy (BSE) can be efficiently transmitted to pigs via intracerebral inoculation. A clear link has been established between the consumption of products of bovine origin contaminated with the BSE agent and the development of variant Creutzfeldt-Jakob disease in humans. Small ruminants can also naturally develop BSE, and sheep-adapted BSE (Sh-BSE) propagates more efficiently than cattle BSE in pigs and in mouse models expressing porcine prion protein. In addition, Sh-BSE shows greater efficiency of transmission to human models than original cow BSE. While infectivity and/or abnormal PrP accumulation have been reported in the central nervous system in BSE-infected pigs, the ability of the agent to replicate in peripheral tissues has not been fully investigated. We previously characterized the presence of prions in a panel of tissues collected at the clinical stage of disease from pigs experimentally infected with Sh-BSE. Western blot revealed low levels of PrPres accumulation in lymphoid tissues, nerves, and skeletal muscles from 4 of the 5 animals analysed. Using protein misfolding cyclic amplification (PMCA), which we found to be 6 log fold more sensitive than direct WB for the detection of pig BSE, we confirmed the presence of the Sh-BSE agent in lymphoid organs, nerves, ileum, and striated muscles from all 5 inoculated pigs. Surprisingly, PrPres positivity was also detected in white blood cells from one pig using this method. The presence of infectivity in lymphoid tissues, striated muscles, and peripheral nerves was confirmed by bioassay in bovine PrP transgenic mice. These results demonstrate the ability of BSE-derived agents to replicate efficiently in various peripheral tissues in pigs. Although no prion transmission has been reported in pigs following oral BSE challenge, our data support the continuation of the Feed Ban measure implemented to prevent entry of the BSE agent into the feed chain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199914PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033439PMC
January 2019

The use of PrP transgenic to replace and reduce vertebrate hosts in the bioassay of mammalian prion infectivity.

F1000Res 2018 15;7:595. Epub 2018 May 15.

Department of Veterinary Medicine, University of Cambridge, Cambridge, CB3 OES, UK.

Prion diseases are fatal neurodegenerative conditions of humans and vertebrate species. The transmissible prion agent is a novel infectious particle composed principally of PrP , an abnormal isomer of the normal host protein PrP . The only reliable method to detect mammalian prion infectivity is by bioassay, invariably in a vertebrate host. The current prion bioassays typically involve intracerebral or peripheral inoculation of test material into the experimental host and subsequent euthanasia when clinical signs of terminal prion disease become evident. It may be months or years before the onset of clinical disease becomes evident and a pre-determined clinical end-point is reached. Consequently, bioassay of prion infectivity in vertebrate species is cumbersome, time consuming, expensive, and increasingly open to ethical debate because these animals are subjected to terminal neurodegenerative disease. Prions are a significant risk to public health through the potential for zoonotic transmission of animal prion diseases. Attention has focussed on the measurement of prion infectivity in different tissues and blood from prion-infected individuals in order to determine the distribution of infectious prions in diseased hosts. New animal models are required in order to replace or reduce, where possible, the dependency on the use of vertebrate species, including the 'gold standard' mouse prion bioassay, to assess prion infectivity levels. Here we highlight the development of a  -based prion bioassay, a highly sensitive and rapid invertebrate animal system that can efficiently detect mammalian prions. This novel invertebrate model system will be of considerable interest to biologists who perform prion bioassays as it will promote reduction and replacement in the number of sentient animals currently used for this purpose. This article is a composite of previous methods that provides an overview of the methodology of the model and discusses the experimental data to promote its viability for use instead of more sentient hosts.
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http://dx.doi.org/10.12688/f1000research.14753.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998032PMC
May 2018

Correction to: Cellular mechanisms responsible for cell-to-cell spreading of prions.

Cell Mol Life Sci 2018 07;75(14):2575

Insitut NeuroMyoGène, CNRS UMR5310, INSERM U1217, Faculté de Médecine Rockefeller, Université Claude Bernard Lyon I, 8 Avenue Rockefeller, 69373, Lyon Cedex 08, France.

In the original publication, part of acknowledgement text was missing. The complete acknowledgement section should read as follows.
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http://dx.doi.org/10.1007/s00018-018-2853-5DOI Listing
July 2018

The zoonotic potential of animal prion diseases.

Handb Clin Neurol 2018 ;153:447-462

École Nationale Vétérinaire de Toulouse, Toulouse, France.

Bovine spongiform encephalopathy (BSE) is the only animal prion disease that has been demonstrated to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans. The link between BSE and vCJD was established by careful surveillance, epidemiologic investigations, and experimental studies using in vivo and in vitro models of cross-species transmission. Similar approaches have been used to assess the zoonotic potential of other animal prion diseases, including atypical forms identified through active surveillance. There is no epidemiologic evidence that classical or atypical scrapie, atypical forms of BSE, or chronic wasting disease (CWD) is associated with human prion disease, but the limitations of the epidemiologic data should be taken into account when interpreting these results. Transmission experiments in nonhuman primates and human PrP transgenic mice suggest that classic scrapie, L-type atypical BSE (L-BSE), and CWD may have zoonotic potential, which for L-BSE appears to be equal to or greater than that of classic BSE. The results of in vitro conversion assays to analyze the human transmission barrier correlate well with the in vivo data. However, it is still difficult to predict the likelihood that an animal prion disease will transmit to humans under conditions of field exposure from the results of in vivo or in vitro experiments. This emphasizes the importance of continuing systematic surveillance for both human and animal prion diseases in identifying zoonotic transmission of diseases other than classic BSE.
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http://dx.doi.org/10.1016/B978-0-444-63945-5.00025-8DOI Listing
September 2018