Scrapie: research

What did humanised mouse transmission show for classical scrapie?

Cassard and colleagues inoculated a panel of sheep scrapie prions into several lines of transgenic mice overexpressing human prion protein, models that propagate human prions with no apparent transmission barrier and that had been used to confirm the zoonotic ability of BSE. The scrapie isolates transmitted with an efficiency comparable to that of cattle BSE, and serial transmission of different isolates led to prions phenotypically identical to those causing sporadic CJD. The authors conclude that scrapie prions have zoonotic potential and that this raises questions about a possible link between animal and human prions.

This result must be held alongside the opposite finding in a different model, described on food chain, where mice overexpressing human PrP developed disease after BSE challenge but not after classical or atypical scrapie challenge. The two experiments used different transgenic lines, different isolate panels and different passage schemes. The honest summary is that the species barrier between sheep prions and human PrP is low in some models and apparently intact in others, and that neither outcome measures risk to people from sheep exposure.

The phenotypic identity claim also cuts both ways. If serial passage of sheep prions can produce an agent indistinguishable from sporadic CJD prions, then strain typing cannot be used to rule out an animal origin for a human case, and it equally cannot be used to establish one.

And for atypical Nor98 scrapie?

Marin-Moreno and colleagues serially inoculated brain tissue from field and laboratory atypical scrapie isolates into transgenic mice overexpressing human PrP with the Met129 allele, assessing clinical outcome and prions in brain and spleen.

Nothing transmitted on primary passage: no clinical disease and no pathological prion protein in brain or spleen. On later passages one isolate gradually adapted and produced prions resembling those of MM1-type sporadic CJD. Further characterisation in vivo and in vitro established that the two agents were different strains, which the authors describe as phenotypic convergence rather than identity. No classical BSE prions emerged, including in spleen, which is the more permissive tissue for BSE cross-species transmission. They conclude that atypical scrapie has low zoonotic potential, with rare adaptation able to produce prions phenotypically resembling those that form spontaneously in people.

The second part of that conclusion is the part that complicates surveillance, and it is the same problem as in the classical scrapie work: convergence of phenotype without identity of strain means phenotype alone does not identify origin.

Do scrapie forms map onto sporadic CJD types?

Wemheuer and colleagues compared prion characteristics of different forms of sheep scrapie with sporadic CJD phenotypes, using paraffin-embedded tissue blotting for deposition pattern and guanidine hydrochloride denaturation for aggregate stability. They report parallels between sporadic CJD type 1 and atypical Nor98 scrapie on both measures, and between sporadic CJD type 2 and classical scrapie. Their reading is that distinct groups of prion disease exist across species, and that this should be taken into account in discussions of interspecies transmission.

A parallel in deposition pattern and denaturation behaviour is a similarity of two readouts, not a demonstration of a shared agent. The same two assays also separate FFI from both sporadic types, as described on fatal familial insomnia.

How is atypical scrapie monitored?

Because within-flock incidence is low, atypical scrapie is thought not to transmit between animals, and intensified monitoring, meaning testing all animals leaving a positive flock for two years after detection, was the mechanism for collecting data to test that. EU-wide intensified monitoring stopped in 2021 and continued in Great Britain. Arnold and colleagues modelled the effect of stopping it there, and estimated that about 0.34 cases per year would be missed (95 percent CI 0.18 to 0.54), against roughly 10 cases per year (95 percent CI 4 to 17) detected through fallen stock and abattoir surveillance. They conclude that stopping the intensified monitoring would have little impact on surveillance or on the power of the data to infer whether atypical scrapie is contagious.

Antemortem diagnosis remains rare. Prins and colleagues describe a 7-year-old Herdwick ewe referred in March 2022 with circling and ill thrift, in which blood, biochemistry and CSF analyses were unremarkable while post-mortem MRI showed diffuse, bilateral, symmetrical forebrain atrophy and ventriculomegaly, and immunohistochemistry confirmed PrPSc mainly in cerebellum. They report this as the first description of MRI findings in atypical scrapie and recommend keeping scrapie in the differential for sheep with progressive neurological signs lasting weeks.

Related: BSE, chronic wasting disease, sporadic CJD subtypes and the EFSA entry.