Transmissions of bovine spongiform encephalopathy (BSE) from seven unrelated cattle sources have given remarkably uniform disease characteristics in mice, differing from over twenty previous and contemporary transmissions of sheep and goat scrapie. Transmissions to mice of spongiform encephalopathy from six species (including sheep and goats) which have been experimentally or naturally infected with BSE have given similar results to direct BSE transmissions from cattle. Therefore the BSE agent has retained its identity when passaged through a range of species and the 'donor' species has little specific influence on disease characteristics in mice, adding to evidence for an agent-specific informational molecule. On transmission of BSE or scrapie to mice the incubation periods are long compared with subsequent mouse-to-mouse passages (the 'species barrier'). Contributing factors include a low efficiency of infection on interspecies transmission, the apparent failure of intracerebrally injected 'foreign' inoculum to establish infection directly in mouse brain and the selection of variant strains of agent which replicate most readily in the new host species.

Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the species barrier

Man and sheep are the two species in which spongiform encephalopathies occur naturally, and in which there are recognized genetic components that predispose an individual person or sheep to clinical disease. In both species mutations/polymorphisms in the PrP gene have been linked to the incidence of natural disease, but only in sheep is it possible to investigate by deliberate exposure to infection whether these polymorphisms are directly correlated with survival time. Cheviot sheep of different PrP genotypes were challenged with one of two isolates of scrapie or an isolate of bovine spongiform encephalopathy and the survival time and incidence of disease were monitored. Genotype analysis showed that dimorphisms in codons 136 and 171 of the ovine PrP gene correlated with control of disease incidence and modulation of incubation time. Crucially, the functional effects of these domains of PrP were shown to alternate depending on the isolate of infecting agent.

PrP genotype and agent effects in scrapie: change in allelic interaction with different isolates of agent in sheep, a natural host of scrapie

A better understanding of the infectious process in scrapie was sought by studying the temporal distribution of virus in naturally infected Suffolk sheep. Virus was detected (by mouse inoculation) first in lymphatic tissues and intestine of clinically normal lambs (age, 10-14 months). Titers were generally low. Infection of the central nervous system was first detected in a 25-month-old clinically normal sheep whose nonneural tissues had moderate amounts of virus. In sheep affected with scrapie, similar amounts in nonneural tissues accompanied high concentrations in the central nervous system, notably in sites of severest neurohistologic changes. No virus was found in clinically normal high-risk sheep 54 to 104 months old. The early appearance of virus in tonsil, retropharyngeal and mesenteric-portal lymph nodes, and intestine suggests that primary infection occurs by way of the alimentary tract, either prenatally from virus in amniotic fluid or postnatally from virus in a contaminated environment.

https://www.jstor.org/stable/pdfplus/30112442.pdf

Natural Infection of Suffolk Sheep with Scrapie Virus

Mouse lines which are congenic for Sinc, the major gene controlling scrapie incubation period, have been produced by selective breeding from the inbred C57BL(Sinc
s7) and VM(Sinc
p7) strains; the s7 allele of Sinc has been introduced into a VM background by 18 serial backcrosses, at each generation selecting on the basis of the incubation period with the ME7 scrapie strain. The characteristics of the disease produced by seven scrapie strains have been compared in Sinc
s7 and Sinc
p7 congenic mice and in the F1 cross between them. As previously found in non-congenic mice, each scrapie strain has a characteristic, precisely reproducible incubation period pattern in the three Sinc genotypes. The Sinc gene controls the incubation period for all scrapie strains tested but the direction of allelic action and the apparent dominance pattern differs between scrapie strains. Comparison with non-congenic mice shows that other genes also have a minor effect on incubation period. The distribution of vacuolar degeneration in the brain depends mainly on the scrapie strain but is also influenced by Sinc and other unspecified mouse genes. Restriction fragment length polymorphism analysis has already shown that the close linkage between Sinc and the gene encoding PrP has been maintained in the Sinc congenic lines, strengthening the possibility that PrP is the Sinc gene product. The present study confirms that scrapie strains carry information which is independent of the host but nevertheless suggests that host PrP protein interacts with this information to regulate the progression of the disease.

The disease characteristics of different strains of scrapie in Sinc congenic mouse lines: implications for the nature of the agent and host control of pathogenesis.

Dickinson Ag

Papers

Scrapie in sheep and goats.