Three serial passages of bovine spongiform encephalopathy in sheep do not significantly affect discriminatory test results

Stack, M.J.; González, Lorenzo; Jeffrey, Martin; Martin, Stuart; Macaldowie, C.; Chaplin, Melanie J.; Thorne, Jemma; Sayers, Robin; Davis, L.A.; Bramwell, Jason; Grimmer, Steve; Bellworthy, S. J.

doi:10.1099/vir.0.005983-0

Cited by 26 publications

(30 citation statements)

References 22 publications

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“…Neither of these two isolates was by PMCA thus far statistically significantly different in Pearson correlation tests from the orally transmitted BSE agent. This could be expected since it has been demonstrated that specific diagnostic features characteristic for BSE in sheep remain conserved over at least three serial passages in sheep (21).…”

Section: Discussionmentioning

confidence: 91%

“…Typical for BSE during cross-species transmission are the conservation of some key characteristics that can be measured in mouse straintyping studies or by molecular phenotyping (mouse brain lesion profiles and the typical molecular weight and predominant diglycosylated species on Western blots). These signatures usually remain preserved for several passages in foreign species (21). Based on the typical signatures and epidemiological data, the occurrence of a novel variant of CJD in humans was linked to BSE (22).…”

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confidence: 99%

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

Priem

Langeveld

Keulen

et al. 2014

J Virol

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Bovine spongiform encephalopathy (BSE) can be efficiently transmitted to small ruminants (sheep and goats) with certain prion protein (PrP) genotypes. Polymorphisms in PrP of both the host and donor influence the transmission efficiency of transmissible spongiform encephalopathies (TSEs) in general. These polymorphisms in PrP also modulate the PrP conversion underlying TSE agent replication. Here we demonstrate that single-round protein misfolding cyclic amplification (PMCA) can be used to assess species and polymorphism barriers at the molecular level. We assessed those within and between the ovine and bovine species in vitro using a variety of natural scrapie and experimentally generated cross-species BSE agents. These BSE agents include ovBSE-ARQ isolates (BSE derived from sheep having the ARQ/ARQ PrP genotype), and two unique BSE-derived variants: BSE passaged in VRQ/VRQ sheep and a cow BSE agent isolate generated by back-transmission of ovBSE-ARQ into its original host. PMCA allowed us to quantitatively determine PrP conversion profiles that correlated with known in vivo transmissibility and susceptibility in the two ruminant species in which strain-specific molecular signatures, like its molecular weight after protease digestion, were maintained. Furthermore, both BSE agent isolates from ARQ and VRQ sheep demonstrated a surprising transmission profile in which efficient transmissions to both sheep and bovine variants was combined. Finally, all data support the notion that ARQ-derived sheep BSE points to a significant increase in virulence compared to all other tested scrapie-and BSE-derived variants reflected by the increased conversion efficiencies of previously inefficient convertible PrP variants (including the so-called "resistant" sheep ARR variant). IMPORTANCEPrion diseases such as scrapie in sheep and goats, BSE in cattle, and Creutzfeldt-Jakob disease (CJD) in humans are fatal neurodegenerative diseases caused by prions. BSE is known to be transmissible to a variety of hosts, including sheep and humans. Based on the typical BSE agent strain signatures and epidemiological data, the occurrence of a novel variant of CJD in humans was linked to BSE occurrence in the United Kingdom. Measures, including genetic selection of sheep toward less susceptible PrP genotypes, have been implemented to lower the risk of BSE transmission into sheep, since the disease could potentially spread into a natural reservoir. In this study, we demonstrated using molecular PrP conversion studies that when BSE is first transmitted through sheep, the host range is modified significantly and the PrP converting potency increased, allowing the ovine BSE to transmit more efficiently than cow BSE into supposedly less susceptible hosts. P rion diseases, or transmissible spongiform encephalopathies (TSEs), include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeldt-Jakob disease (CJD) in humans. TSEs in sheep and cattle are naturally occurring infectious and fatal neurological disorde...

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

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

Priem

Langeveld

Keulen

et al. 2014

J Virol

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“…In our previous studies we used a dose of 5 g of cattle BSE brain per (adult) sheep and this resulted in clinical disease at an average incubation period of around 800 days (16). The 5-g dose, or even larger amounts, has become the normal oral dose when clinical disease is required for pathogenesis studies in our own and other labs (3,47,52,59). In the present study, the lower doses (ranging from 0.1 g to 1 g per animal) were chosen such that the sheep in the adult group would not all become clinically affected by BSE.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility of Young Sheep to Oral Infection with Bovine Spongiform Encephalopathy Decreases Significantly after Weaning

Hunter

Houston

Foster

et al. 2012

J Virol

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bBovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) (or prion disease) that is readily transmissible to sheep by experimental infection and has the shortest incubation period in animals with the ARQ/ARQ PRNP genotype (at codons 136, 154, and 171). Because it is possible that sheep in the United Kingdom could have been infected with BSE by being fed contaminated meat and bone meal supplements at the same time as cattle, there is considerable interest in the responses of sheep to BSE inoculation. Epidemiological evidence suggests that very young individuals are more susceptible to TSE infection; however, this has never been properly tested in sheep. In the present study, low doses of BSE were fed to lambs of a range of ages (ϳ24 h, 2 to 3 weeks, 3 months, and 6 months) and adult sheep. The incidence of clinical BSE disease after inoculation was high in unweaned lambs (ϳ24 h and 2 to 3 weeks old) but much lower in older weaned animals The incubation period was also found to be influenced by the genotype at codon 141 of the PRNP gene, as lambs that were LF heterozygotes had a longer mean incubation period than those that were homozygotes of either type. The results suggest that sheep in the United Kingdom would have been at high risk of BSE infection only if neonatal animals had inadvertently ingested contaminated supplementary foodstuffs.T ransmissible spongiform encephalopathies (TSEs) are prion diseases that affect many mammals and are associated with the presence of the protein PrP Sc , a protease-resistant form of a normal host protein, PrP C . PrP Sc is believed to form all or part of the infectious agent (44). The natural sheep TSE is scrapie; however, sheep can also be experimentally infected with bovine spongiform encephalopathy (BSE) by several routes, including intracerebral, oral (17), and intravenous (28). The manifestation of clinical signs of BSE following inoculation depends upon a number of factors, the most important being the PRNP genotype. In the Neuropathogenesis Unit, Edinburgh, United Kingdom (NPU), Cheviot sheep, animals homozygous for the ARQ PRNP gene allele (codons 136, 154, and 171 indicated in order) are most susceptible (23). However, for reasons that are currently unknown, a various number of adult ARQ/ARQ sheep will survive a challenge with BSE (16). Understanding this aspect of resistance is of fundamental importance. One potential influence on disease outcome following infection with any TSE is the age at which the individual is challenged. Because of the etiology of scrapie, which suggests that in sheep the risk for infection is very high during the perinatal period, many sheep challenge studies, including the study described in reference 3, have used young lambs rather than adult sheep as infection models. In addition, epidemiological studies in cattle (15) have suggested that in general, younger individuals are more susceptible to infection with BSE, and studies in human beings have shown that more individuals at relatively young ages have b...

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“…Indeed the biochemical form of prion protein deposited in the brain in vCJD patients was found to be indistinguishable from that in BSE (Collinge et al, 1996), and it appeared that the BSE agent had highly stable features even after passage in other, but not all, host species. This was instrumental for developing tests aimed at discriminating the BSE agent from other TSE agents, in particular in small ruminants (Gretzschel et al, 2005;Stack et al, 2009 (Pirisinu et al, 2010). A subsequent study investigated the properties of PrP Sc from Atypical scrapie in small ruminants as compared to atypical human prions, including GSS cases with different PrP mutations and VPSPr.…”

Section: Biochemical Comparisonmentioning

confidence: 99%

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

2015

EFSA Journal

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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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Three serial passages of bovine spongiform encephalopathy in sheep do not significantly affect discriminatory test results

Cited by 26 publications

References 22 publications

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

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

Susceptibility of Young Sheep to Oral Infection with Bovine Spongiform Encephalopathy Decreases Significantly after Weaning

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

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