Stability of murine scrapie strain 87V after passage in sheep and comparison with the CH1641 ovine strain

Abstract

Breed-and prion protein (PRNP) genotype-related disease phenotype variability has been observed in sheep infected with the 87V murine scrapie strain. Therefore, the stability of this strain was tested by inoculating sheep-derived 87V brain material back into VM mice. As some sheep-adapted 87V disease phenotypes were reminiscent of CH1641 scrapie, transgenic mice (Tg338) expressing ovine prion protein (PrP) were inoculated with the same sheep-derived 87V sources and with CH1641. Although at first passage in VM mice the sheep-derived 87V sources showed some divergence from the murine 87V control, all the characteristics of murine 87V infection were recovered at second passage from all sheep sources. These included 100 % attack rates and indistinguishable survival times, lesion profiles, immunohistochemical features of disease-associated PrP accumulation in the brain and PrP biochemical properties. All sheepderived 87V sources, as well as CH1641, were transmitted to Tg338 mice with identical clinical, pathological, immunohistochemical and biochemical features. While this might potentially indicate that sheep-adapted 87V and CH1641 are the same strain, profound divergences were evident, as murine 87V was unable to infect Tg338 mice but was lethal for VM mice, while the reverse was true for CH1641. These combined data suggest that: (i) murine 87V is stable and retains its properties after passage in sheep; (ii) it can be isolated from sheep showing a CH1641-like or a more conventional scrapie phenotype; and (iii) sheep-adapted 87V scrapie, with conventional or CH1641-like phenotype, is biologically distinct from experimental CH1641 scrapie, despite the fact that they behave identically in a single transgenic mouse line.

Divergent prion strain evolution driven by PrPC expression level in transgenic mice

“…In any case, it is of interest that the combined propagation of a single isolate on low and high expresser mice recapitulated part of the natural scrapie strains variation as documented by transmission to high expresser mice9. In particular, LA19K and the reference scrapie strain CH1641 exhibit identical features44. Thus panels of transgenic mice harbouring various PrP C levels might represent a relevant tool in an attempt to learn more about the determinism underlying the diversity and evolution of natural prions.…”

Characterization of goat prions demonstrates geographical variation of scrapie strains in Europe and reveals the composite nature of prion strains

“…In the case of tg-shVRQ mice, a recent seminal paper showed that the overexpression of PrP determines the selection of the 19 K strain component in these mice 46 . Furthermore, the 19 K scrapie-derived strain showed strain features indistinguishable from CH1641 in tg-shVRQ 46,50 . Finally, experimental transmission per se could have favoured the propagation of the 19 K component, as it has been shown that experimental challenge of sheep with classical scrapie can lead to the emergence of a 19 K CH1641-like component, which was hidden in the homotypic inoculum 51 .…”

Mixtures of prion substrains in natural scrapie cases revealed by ovinised murine models

“…Importantly, both murine lines were able to propagate this conformer. The phenotype associated to this form of the agent resembled that of CH1641-like isolates 46,47,59,60 . CH1641 scrapie is associated with a PrP res banding pattern with low (19-20 kDa) NG species and possesses distinctive biological properties.…”