Comparative titration of experimental ovine BSE infectivity in sheep and mice

González, Lorenzo; Chianini, Francesca; Martin, Stuart; Sisó, Sílvia; Gibbard, Louise; Reid, H.W.; Jeffrey, Martin

doi:10.1099/vir.0.82426-0

Cited by 19 publications

(25 citation statements)

References 15 publications

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“…Finally, the conversion of the sheep ARR PrP C was also significantly increased ( Fig. 3B and 5), which seems in agreement with efficient intracerebral and intraperitoneal infections of ARR/ ARR sheep with the ovBSE agent (60). Furthermore, similar observations can be made from transmissions depicted in Fig.…”

Section: Discussionsupporting

confidence: 77%

“…Our data clearly add that the ARQ-derived ovine BSE transmits to other hosts (in our case, cattle) with efficiencies similar to that of within-species transmissions. This increased efficiency seems comparable to the measured effect that sheep-derived BSE agent titers were comparable as determined in two different hosts, ARQ sheep and RIII mice (60). Finally, the conversion of the sheep ARR PrP C was also significantly increased ( Fig.…”

Section: Discussionsupporting

confidence: 63%

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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: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 63%

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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“…The infectivity titer of the cattle BSE brainstem pool used in our transmissions was 10 3.3 ID 50 U/g in RIII mice (R. Lockey and M. Simmons, personal communication). Those reported by Gonzalez et al (22) for sheep-passaged BSE were 10 5 ID 50 U/g in RIII mice, suggesting that higher titers may indeed be attained in sheep brain. However, reported infectivity titers for BSE in cattle have been variable (6,20,22).…”

Section: Discussionmentioning

confidence: 67%

“…The observed difference in incubation times between inoculum 1 and inoculum 2 therefore is not unexpected. Previous studies by Gonzalez et al (22) have shown relatively high infectivity titers of sheep-passaged BSE in RIII mice, which were equivalent to those obtained in Romney sheep. The infectivity titer of the cattle BSE brainstem pool used in our transmissions was 10 3.3 ID 50 U/g in RIII mice (R. Lockey and M. Simmons, personal communication).…”

Section: Discussionmentioning

confidence: 70%

Increased Susceptibility of Human-PrP Transgenic Mice to Bovine Spongiform Encephalopathy Infection following Passage in Sheep

Plinston

Hart

Chong

et al. 2011

J Virol

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The risk of the transmission of ruminant transmissible spongiform encephalopathy (TSE) to humans was thought to be low due to the lack of association between sheep scrapie and the incidence of human TSE. However, a single TSE agent strain has been shown to cause both bovine spongiform encephalopathy (BSE) and human vCJD, indicating that some ruminant TSEs are transmissible to humans. While the transmission of cattle BSE to humans in transgenic mouse models has been inefficient, indicating the presence of a significant transmission barrier between cattle and humans, BSE has been transmitted to a number of other species. Here, we aimed to further investigate the human transmission barrier following the passage of BSE in a sheep. Following inoculation with cattle BSE, gene-targeted transgenic mice expressing human PrP showed no clinical or pathological signs of TSE disease. However, following inoculation with an isolate of BSE that had been passaged through a sheep, TSE-associated vacuolation and proteinase K-resistant PrP deposition were observed in mice homozygous for the codon 129-methionine PRNP gene. This observation may be due to higher titers of the BSE agent in sheep or an increased susceptibility of humans to BSE prions following passage through a sheep. However, these data confirm that, contrary to previous predictions, it is possible that a sheep prion is transmissible to humans and that BSE from other species is a public health risk.The transmissible spongiform encephalopathies (TSEs) are a group of fatal infectious neurodegenerative diseases that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeldt-Jakob disease (CJD) in humans. TSEs are characterized by the accumulation in the brain of PrP Sc , which is a conformational variant of the normal cellular host prion protein (PrP C ). The abnormal form of the protein is protease resistant and detergent insoluble, and it aggregates in diffuse or amyloid deposits in the central nervous system (CNS) and lymphoreticular system of infected animals. TSEs are infectious diseases and can be transmitted between animals of the same and different species by a number of routes, including oral, environmental, or iatrogenic exposure. The host range is a specific characteristic of each strain, but TSE agents usually transmit more readily within rather than between species. Low transmission rates often are observed upon transmission to a new species, but on further passage in the new species increased transmission rates and shorter incubation times usually are observed. This effect is referred to as the species barrier. The ability of individual TSE agents to cross a species barrier can be examined experimentally by the direct inoculation of different species or modeled in transgenic mice expressing PrP sequences from these species. Modeling species barriers in mice is particularly important when assessing the risks of infection in humans. Such experiments can assess risk posed by different TSE agents and also the potential for the mu...

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“…ID 50 /g and mice 10 5.0 (i.c + i.p.) ID 50 /g [40]. Moreover, it has been suggested that the increased susceptibility of transgenic mice results rather from the heterologous PrP C overexpression than from a homology effect.…”

Section: Transgenic Mice As Ultra-sensitive Biological Prion Detectiomentioning

confidence: 99%

Rodent models for prion diseases

Groschup

Buschmann

2008

Vet. Res.

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-Until today most prion strains can only be propagated and the infectivity content assayed by experimentally challenging conventional or transgenic animals. Robust cell culture systems are not available for any of the natural and only for a few of the experimental prion strains. Moreover, the pathogenesis of different transmissible spongiform encephalopathies (TSE) can be analysed systematically by using experimentally infected animals. While, in the beginning, animals belonging to the natural host species were used, more and more rodent model species have been established, mostly due to practical reasons. Nowadays, most of these experiments are performed using highly susceptible transgenic mouse lines expressing cellular prion proteins, PrP, from a variety of species like cattle, sheep, goat, cervidae, elk, hamster, mouse, mink, pig, and man. In addition, transgenic mice carrying specific mutations or polymorphisms have helped to understand the molecular pathomechanisms of prion diseases. Transgenic mouse models have been utilised to investigate the physiological role of PrP C , molecular aspects of species barrier effects, the cell specificity of the prion propagation, the role of the PrP glycosylation, the mechanisms of the prion spread, the neuropathological roles of PrP C and of its abnormal isoform PrP D (D for disease) as well as the function of PrP Doppel. Transgenic mouse models have also been used for mapping of PrP regions involved in or required for the PrP conversion and prion replication as well as for modelling of familial forms of human prion diseases.

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Comparative titration of experimental ovine BSE infectivity in sheep and mice

Cited by 19 publications

References 15 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

Increased Susceptibility of Human-PrP Transgenic Mice to Bovine Spongiform Encephalopathy Infection following Passage in Sheep

Rodent models for prion diseases

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