Enhanced Virulence of Sheep-Passaged Bovine Spongiform Encephalopathy Agent Is Revealed by Decreased Polymorphism Barriers in Prion Protein Conversion Studies

Priem, J.; Langeveld, J.P.M.; Keulen, L.J.M. van; Zijderveld, F.G. van; Andréoletti, Olivier; Bossers, Alex

doi:10.1128/jvi.02446-13

“…Yet the expression levels of the PrP C alleles in heterozygous animals are considered equal (34,35), which means that during PrP Sc formation in ARR/VRQ scrapie-infected animals, there occurs a selective incorporation of the VRQ-PrP allotype. In vitro assays confirm the relatively high, but not absolute, resistance to conversion of ARR-PrP when this allotype is subjected to scrapie or BSE prions (12,15,26,36). This special property of the ARRPrP allotype is confirmed under in vivo intracerebral (i.c.)…”

mentioning

confidence: 54%

“…With BSE infection, ARR/ARR and VRQ/VRQ sheep have long incubation times to clinical disease following intracerebral challenge at, respectively, Ͼ1,400 days and Ͼ1,000 days, compared to that in the wild-type ARQ/ARQ sheep (around 600 days) (N. Hunter and F. Houston, personal communication). With classical scrapie infection with the agent derived from VRQ-rich sheep flocks, ARR/ARR sheep are nearly fully resistant to challenge, whereas VRQ/VRQ sheep with scrapie have very short incubation times (180 to 720 days), and the wild-type (ARQ/ARQ) sheep have intermediate incubation times (14,27,36,37,40,(49)(50)(51). Interestingly with atypical/ Nor98 scrapie, a prion disease that is nonspreading and may be of spontaneous origin, VRQ/VRQ animals appear highly insensitive based on genotype frequency, while ARR/ARR sheep can be affected but are less frequently so than ARQ/ARQ sheep with this scrapie type (Table 2) (52).…”

Section: Discussionmentioning

confidence: 99%

Prion Type-Dependent Deposition of PRNP Allelic Products in Heterozygous Sheep

Langeveld

¹

,

Jacobs

²

,

Hunter

³

et al. 2016

J Virol

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Susceptibility or resistance to prion infection in humans and animals depends on single prion protein (PrP) amino acid substitutions in the host, but the agent's modulating role has not been well investigated. Compared to disease incubation times in wild-type homozygous ARQ/ARQ (where each triplet represents the amino acids at codons 136, 154, and 171, respectively) sheep, scrapie susceptibility is reduced to near resistance in ARR/ARR animals while it is strongly enhanced in VRQ/VRQ carriers. Heterozygous ARR/VRQ animals exhibit delayed incubation periods. In bovine spongiform encephalopathy (BSE) infection, the polymorphism effect is quite different although the ARR allotype remains the least susceptible. In this study, T ransmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal neurological diseases occurring in some mammalian species, including humans. The TSE agent or prion is characterized by the pivotal role of the host prion protein (PrP) that in disease appears aggregated and structurally abnormal and is named PrP Sc , where "Sc" refers to scrapie in small ruminants, which was recognized in the 18th century in Spanish Merino sheep (1). In healthy situations PrP is a cellular membrane protein (PrP C ) and fully susceptible to proteases, while its PrP Sc isoform is partially resistant to digestion with proteinase K (PK), usually leading to an N-terminally shortened protein called PrP res that still retains the associated infectivity (2-4).From many studies it is obvious that TSEs occur in distinct phenotypic forms that are recognized as TSE or prion disease types, such as classical scrapie in sheep and goat, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy (BSE) in cattle (5-15). In the experimental situation, these types can be considered strains when they are subpassaged to homogeneity in rodent bioassays (16)(17)(18)(19)(20). Susceptibility (and resistance) to animal and human prion diseases, either under infectious or spontaneous conditions, is dependent on single amino acid substitutions in the host's PrP sequence. In most species such substitutions are naturally occurring polymorphisms (7,10,(21)(22)(23)(24).In sheep two PrP polymorphisms in the PrP sequence, V 136 and R 171 (where V is valine and R is arginine, according to the singleletter code used by the IUPAC-IUB Joint Commission on Biochemical Nomenclature), provide, respectively, high and very low susceptibilities to natural scrapie compared to the homozygous

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“…The newly generated PrP Sc produced in homologous conversion assays shares the same biochemical, biological and structural properties as the parental isolate (Castilla et al, 2008a;Green et al, 2008;Thorne et al, 2012;Vidal et al, 2013a;Levavasseur et al, 2014;Priem et al, 2014), although exceptions have been reported . This reproduction of strain adaptation and molecular patterns indicate again that the strain determinants are largely encoded in the structure and folding of PrP Sc (Castilla et al, 2008a).…”

Section: Pmca Was Developed In 2001 As a Technique For The In Vitro Amentioning

confidence: 99%

“…As seen in vivo the strain and source of PrP Sc , in particular the PRNP genotype of seed and substrate, has a clear influence on the amplification pattern obtained by PMCA (Bucalossi et al, 2011;Thorne et al, 2012;Krejciova et al, 2014;Priem et al, 2014). In this regard it is of interest that a switch of the conversion profile has been shown by the amplification of an ARR scrapie isolate in different sheep genotypes, which resulted in a conversion profile that resembled mostly that of ARQ scrapie (Bucalossi et al, 2011;Priem et al, 2014).…”

Section: Pmca Was Developed In 2001 As a Technique For The In Vitro Amentioning

confidence: 99%

“…In this regard it is of interest that a switch of the conversion profile has been shown by the amplification of an ARR scrapie isolate in different sheep genotypes, which resulted in a conversion profile that resembled mostly that of ARQ scrapie (Bucalossi et al, 2011;Priem et al, 2014). The newly generated PrP Sc was infectious for several species (Castilla et al, 2005b(Castilla et al, , 2008aGreen et al, 2008;Saa et al, 2012;Di Bari et al, 2013).…”

Section: Pmca Was Developed In 2001 As a Technique For The In Vitro Amentioning

confidence: 99%

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Scientific Opinion on a request for a review of a scientific publication concerning the zoonotic potential of ovine scrapie prions

2015

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The factors that modulate the transmissibility of Transmissible Spongiform Encephalopathies (TSE) and the approaches for the study of their zoonotic potential are reviewed. The paper 'Evidence for zoonotic potential of ovine scrapie prions' by Cassard et al. (2014) is scientifically appraised, focussing on the experimental design, the results and the conclusions. The paper provides evidence in a laboratory experiment that some Classical scrapie isolates can propagate in humanised transgenic mice and produce prions that on second passage are similar to those causing one form of sporadic Creutzfeldt-Jakob disease (sCJD). It is concluded that the results from the study raise the possibility that scrapie prions have the potential to be zoonotic, but do not provide evidence that transmission can or does take place under field conditions. The conclusions of the 2011 ECDC-EFSA 'Joint Scientific Opinion on any possible epidemiological or molecular association between TSEs in animals and humans' are reviewed in the light of the new scientific evidence available since its publication. This supports and strengthens the conclusions of that opinion with regard to the potential for some animal TSE to be zoonotic, but does not provide evidence of a causal link between Classical or Atypical scrapie and human TSE. Current evidence does not establish this link, and no consistent risk factors have been identified for sCJD. The possibility of scrapie-related public health risks from the consumption of ovine products cannot be assessed. Recommendations are formulated on further studies and data that are needed to investigate the zoonotic potential of animal TSE and to estimate the amount of infectivity from TSE-infected products sourced from small ruminants and entering the food chain in the European Union. © European Food Safety Authority, 2015Keywords: Atypical scrapie, Classical scrapie, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, zoonosis Amendment: An amendment has been made to the following sentence on p. 31: 'In this regard the emergence of sCJD is not so surprising, and has been described after inoculation of tgHu mice with cattle BSE and human vCJD (Asante et al., 2002;Beringue et al., 2008b)'. This was carried out to clarify that one of the references reported emergence of sporadic CJD after experimental inoculation of humanised transgenic mice with vCJD, which was not correctly stated in the published opinion. An amendment has been made on p. 28, to add the word 'OR' between two search terms within the literature search string reported. Reproduction is authorised provided the source is acknowledged. Requestor: European CommissionThe EFSA Journal is a publication of the European Food Safety Authority, an agency of the European Union. SummaryFollowing a request from the European Commission (EC), the EFSA Panel on Biological Hazards (BIOHAZ Panel) was asked to deliver a scientific opinion on the review of a scientific publication concerning the zoonotic potential of ovine scrapie prions.T...

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The factors that modulate the transmissibility of Transmissible Spongiform Encephalopathies (TSE) and the approaches for the study of their zoonotic potential are reviewed. The paper 'Evidence for zoonotic potential of ovine scrapie prions' by Cassard et al. (2014) is scientifically appraised, focussing on the experimental design, the results and the conclusions. The paper provides evidence in a laboratory experiment that some Classical scrapie isolates can propagate in humanised transgenic mice and produce prions that on second passage are similar to those causing one form of sporadic Creutzfeldt-Jakob disease (sCJD). It is concluded that the results from the study raise the possibility that scrapie prions have the potential to be zoonotic, but do not provide evidence that transmission can or does take place under field conditions. The conclusions of the 2011 ECDC-EFSA 'Joint Scientific Opinion on any possible epidemiological or molecular association between TSEs in animals and humans' are reviewed in the light of the new scientific evidence available since its publication. This supports and strengthens the conclusions of that opinion with regard to the potential for some animal TSE to be zoonotic, but does not provide evidence of a causal link between Classical or Atypical scrapie and human TSE. Current evidence does not establish this link, and no consistent risk factors have been identified for sCJD. The possibility of scrapie-related public health risks from the consumption of ovine products cannot be assessed. Recommendations are formulated on further studies and data that are needed to investigate the zoonotic potential of animal TSE and to estimate the amount of infectivity from TSE-infected products sourced from small ruminants and entering the food chain in the European Union.

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Enhanced Virulence of Sheep-Passaged Bovine Spongiform Encephalopathy Agent Is Revealed by Decreased Polymorphism Barriers in Prion Protein Conversion Studies

Cited by 18 publications

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Prion Type-Dependent Deposition of PRNP Allelic Products in Heterozygous Sheep

Prion Type-Dependent Deposition of PRNP Allelic Products in Heterozygous Sheep

Scientific Opinion on a request for a review of a scientific publication concerning the zoonotic potential of ovine scrapie prions

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