Transmission Barriers for Bovine, Ovine, and Human Prions in Transgenic Mice

Abstract

Transgenic (Tg) mice expressing full-length bovine prion protein (BoPrP) serially propagate bovine spongiform encephalopathy (BSE) prions without posing a transmission barrier. These mice also posed no transmission barrier for Suffolk sheep scrapie prions, suggesting that cattle may be highly susceptible to some sheep scrapie strains. Tg(BoPrP) mice were also found to be susceptible to prions from humans with variant Creutzfeldt-Jakob disease (CJD); on second passage in Tg(BoPrP) mice, the incubation times shortened by 30 to 40 days. In contrast, Tg(BoPrP) mice were not susceptible to sporadic, familial, or iatrogenic CJD prions. While the conformational stabilities of bovine-derived and Tg(BoPrP)-passaged BSE prions were similar, the stability of sheep scrapie prions was higher than that found for the BSE prions but lower if the scrapie prions were passaged in Tg(BoPrP) mice. Our findings suggest that BSE prions did not arise from a sheep scrapie strain like the one described here; rather, BSE prions may have arisen spontaneously in a cow or by passage of a scrapie strain that maintains its stability upon passage in cattle. It may be possible to distinguish BSE prions from scrapie strains in sheep by combining conformational stability studies with studies using novel Tg mice expressing a chimeric mouse-BoPrP gene. Single-amino-acid substitutions in chimeric PrP transgenes produced profound changes in incubation times that allowed us to distinguish prions causing BSE from those causing scrapie.

Prion agent diversity and species barrier

“…Cattle and mice transgenic for bovine PrP are susceptible to US or European scrapie isolates ( [62,73,115,176] and our unpublished data). None of the disease phenotypes observed so far resemble BSE, not supporting the hypothesis that BSE could originate from a scrapie agent.…”

“…In contrast, transmission to mice of variant CJD cases of the same PrP genotype was efficient [35], whereas transmission to bank voles was inefficient (U. Agrimi, personal communication). Another noticeable example is the ability of certain scrapie isolates to transmit readily to transgenic mice expressing bovine PrP, without significant reduction of incubation time on further passaging ( [176] and our unpublished data), thus indicating a low transmission barrier. There is now a general consensus that both the strain and the PrP sequence of the recipient host are primary determinants of the species barrier [56].…”

“…There is now a general consensus that both the strain and the PrP sequence of the recipient host are primary determinants of the species barrier [56]. A majority of the so-called species barriers could actually be seen as strain barriers [176]. …”

Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes

“…It may be important to emphasize that we did not analyze prion isolates from mice where prolonged incubation times resulted from a mismatch between the sequence of PrP Sc in the inoculum and that of the cellular PrP isoform (PrP C ) expressed by the host. Such extended incubation times are generally because of a species transmission barrier and diminish on second passage in the homologous host (20,21).…”

Nanopore analysis reveals differences in structural stability of ovine PrPCproteins corresponding to scrapie susceptible (VRQ) and resistance (ARR) genotypes

“…4,14 Susceptibility to prion infection from external sources has a genetic component as different sequences of the prion protein gene (PRNP) determine the susceptibility of particular species, as well as the susceptibilities of individuals within a species, to prion infection. [15][16][17] For example, cattle are highly susceptible to prion infection whereas rabbits are generally regarded as being prion resistant (rabbits are not resistant to prions). 18,19 Further, natural sequence variations of PrP C within species contribute to disease susceptibility.…”