Abstract
Sheep are natural hosts of the prion disease, scrapie. They are also susceptible to experimental challenge with various scrapie strains and with bovine spongiform encephalopathy (BSE), which affects cattle and has been accidentally transmitted to a range of other species, including man. Incidence and incubation period of clinical disease in sheep following inoculation is controlled by the PRNP gene, which has different alleles defined on the basis of polymorphisms, particularly at codons 136, 154 and 171, although other codons are associated with survival time, and the exact responses of the sheep may be influenced by other breed-related differences. Here we report the results of a long term single study of experimental scrapie and BSE susceptibility of sheep of Cheviot, Poll Dorset and Suffolk breeds, originating from New Zealand and of a wide range of susceptible and resistant PRNP genotypes. Responses were compared with those of sheep from a closed Cheviot flock of UK origin (Roslin Cheviot flock). The unusually long observation period (6–8 years for most, but up to 12 years for others) allows us to draw robust conclusions about rates of survival of animals previously regarded as resistant to infection, particularly PRNP heterozygotes, and is the most comprehensive such study reported to date. BSE inoculation by an intracerebral route produced disease in all genotype groups with differing incubation periods, although M112T and L141F polymorphisms seemed to give some protection. Scrapie isolate SSBP/1, which has the shortest incubation period in sheep with at least one VRQ PRNP allele, also produced disease following sub-cutaneous inoculation in ARQ/ARQ animals of New Zealand origin, but ARQ/ARQ sheep from the Roslin flock survived the challenge. Our results demonstrate that the links between PRNP genotype and clinical prion disease in sheep are much less secure than previously thought, and may break down when, for example, a different breed of sheep is moved into a new flock.
Highlights
Classical scrapie in sheep is the prototype of the group of diseases known as transmissible spongiform encephalopathies (TSEs) or prion diseases, which include bovine spongiform encephalopathy (BSE) in cattle and Creutzfeld-Jakob disease (CJD) in man
The sheep were housed throughout the study in a purpose-built experimental unit at the Institute for Animal Health (IAH), Compton, with strict procedures in place to minimize the risks of cross-contamination between groups, as previously described [17]
The outcome of experimental TSE infection in a permissive host, in terms of attack rate, incubation period and neuroanatomical distribution of brain lesions, is influenced by many different factors
Summary
Classical scrapie in sheep is the prototype of the group of diseases known as transmissible spongiform encephalopathies (TSEs) or prion diseases, which include bovine spongiform encephalopathy (BSE) in cattle and Creutzfeld-Jakob disease (CJD) in man. These are fatal neurodegenerative disorders, characterised by long incubation periods (months to years) and typical histopathological changes (e.g. vacuolation, astrogliosis, neuronal loss). Studies in sheep and mice have revealed a strong genetic component to disease susceptibility, with survival time and incubation period principally under the control of a single gene, known as PRNP, which encodes PrP (prion protein), a normal host glycoprotein expressed widely in nervous and other tissues [1]. Selective breeding programmes based on the three codon (136, 154, 171) genotype have been used successfully to reduce the incidence of classical scrapie at flock, breed and national levels by increasing the frequencies of resistant genotypes [8]
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