Assessing the Susceptibility of Transgenic Mice Overexpressing Deer Prion Protein to Bovine Spongiform Encephalopathy

Vickery, Christopher M.; Lockey, Richard; Holder, Thomas M.; Thorne, Leigh; Beck, Katy E.; Wilson, Christina; Denyer, Margaret; Sheehan, John P.; Marsh, Sarah; Webb, Paul B.; Dexter, Ian; Norman, Angela; Popescu, Emma; Schneider, Amanda; Holden, Paul; Griffiths, Peter C.; Plater, Jane M.; Dagleish, Mark P.; Martin, Stuart; Telling, Glenn C.; Simmons, Marion; Spiropoulos, John

doi:10.1128/jvi.02762-13

Cited by 12 publications

(13 citation statements)

References 29 publications

(31 reference statements)

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“…Whereas, in both cases, primary transmissions may result in either all inoculated animals developing disease after a prolonged asymptomatic phase, or only a subpopulation of inoculated animals developing disease with variable incubation times, outcomes of secondary transmissions of the resulting prions reflect either adaptive-or nonadaptive amplification. The propagation of TME in TgD by NAPA contrasted the response of TgD to infection with prions from other species including sheep SSBP/1, mouse RML, and cattle BSE, which in all cases resulted in adapted deer prions that caused rapid, synchronous disease upon serial transmission to TgD (9,10,40). Our findings are therefore consistent with the notion that NAPA involves particular prion/PrP C interactions during transspecies transmissions.…”

Section: Discussionsupporting

confidence: 81%

Prion replication without host adaptation during interspecies transmissions

Bian

Khaychuk

Angers

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Adaptation of prions to new species is thought to reflect the capacity of the host-encoded cellular form of the prion protein (PrPC) to selectively propagate optimized prion conformations from larger ensembles generated in the species of origin. Here we describe an alternate replicative process, termed nonadaptive prion amplification (NAPA), in which dominant conformers bypass this requirement during particular interspecies transmissions. To model susceptibility of horses to prions, we produced transgenic (Tg) mice expressing cognate PrPC. Although disease transmission to only a subset of infected TgEq indicated a significant barrier to EqPrPCconversion, the resulting horse prions unexpectedly failed to cause disease upon further passage to TgEq. TgD expressing deer PrPCwas similarly refractory to deer prions from diseased TgD infected with mink prions. In both cases, the resulting prions transmitted to mice expressing PrPCfrom the species of prion origin, demonstrating that transmission barrier eradication of the originating prions was ephemeral and adaptation superficial in TgEq and TgD. Horse prions produced in vitro by protein misfolding cyclic amplification of mouse prions using horse PrPCalso failed to infect TgEq but retained tropism for wild-type mice. Concordant patterns of neuropathology and prion deposition in susceptible mice infected with NAPA prions and the corresponding prion of origin confirmed preservation of strain properties. The comparable responses of both prion types to guanidine hydrochloride denaturation indicated this occurs because NAPA precludes selection of novel prion conformations. Our findings provide insights into mechanisms regulating interspecies prion transmission and a framework to reconcile puzzling epidemiological features of certain prion disorders.

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Section: Discussionsupporting

confidence: 81%

Prion replication without host adaptation during interspecies transmissions

Bian

Khaychuk

Angers

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Out of 10 inocula that were negative in RIII mice, only one became positive when assayed in TgshpXI mice (see Supplementary Table 1a for details). Although TgshpXI mice were inoculated with only 20 ml of inoculum IC and RIII mice were inoculated with 20 ml IC plus 100 ml IP, previous studies in transgenic mice showed no difference between the two inoculation regimes (Beck et al, 2012;Vickery et al, 2014). While PrP d /PrP res is widely considered as the best surrogate marker for TSE infections, its relationship with actual infectivity is not always clear, either in qualitative or quantitative terms.…”

Section: Discussionmentioning

confidence: 97%

Influence of Breed and Genotype on the Onset and Distribution of Infectivity and Disease-associated Prion Protein in Sheep Following Oral Infection with the Bovine Spongiform Encephalopathy Agent

McGovern

Martin

Jeffrey

et al. 2015

Journal of Comparative Pathology

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“…There is no data available on whether this species adaptation might alter the host range or virulence of the isolate, as has been reported previously for classical BSE [52–55]. Previous reports on the transmission of L-BSE to sheep have only described the inoculation of animals that are ARQ/ARQ [40, 41] or ARQ/ARR [41].…”

Section: Discussionmentioning

confidence: 98%

L-BSE experimentally transmitted to sheep presents as a unique disease phenotype

Simmons¹,

Chaplin²,

Konold

et al. 2016

Vet Res

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Apart from prion protein genotype, the factors determining the host range and susceptiblity for specific transmissible spongiform encephalopathy agents remain unclear. It is known that bovine atypical L-BSE can transmit to a range of species including primates and humanised transgenic mice. It is important, therefore, that there is as broad an understanding as possible of how such isolates might present in food animal species and how robust they are on inter- and intra-species transmission to inform surveillance sytems and risk assessments. This paper demonstrates that L-BSE can be intracerebrally transmitted to sheep of several genotypes, with the exception of ARR/ARR animals. Positive animals mostly present with a cataplectic form of disease characterized by collapsing episodes and reduced muscle tone. PrP accumulation is confined to the nervous system, with the exception of one animal with lymphoreticular involvement. In Western blot there was maintenance of the low molecular mass and glycoform profile associated with L-BSE, irrespective of ovine host genotype, but there was a substantially higher N-terminal antibody signal relative to the core-specific antibody, which is similar to the ratio associated with classical scrapie. The disease phenotype was maintained on experimental subpassage, but with a shortened survival time indicative of an original species barrier and subsequent adaptation. Passive surveillance approaches would be unlikely to identify such cases as TSE suspects, but current statutory active screening methods would be capable of detecting such cases and classifying them as unusual and requiring further investigation if they were to occur in the field.Electronic supplementary materialThe online version of this article (doi:10.1186/s13567-016-0394-1) contains supplementary material, which is available to authorized users.

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Assessing the Susceptibility of Transgenic Mice Overexpressing Deer Prion Protein to Bovine Spongiform Encephalopathy

Cited by 12 publications

References 29 publications

Prion replication without host adaptation during interspecies transmissions

Prion replication without host adaptation during interspecies transmissions

Influence of Breed and Genotype on the Onset and Distribution of Infectivity and Disease-associated Prion Protein in Sheep Following Oral Infection with the Bovine Spongiform Encephalopathy Agent

L-BSE experimentally transmitted to sheep presents as a unique disease phenotype

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