Comparative Susceptibility of Sheep of Different Origins, Breeds and PRNP Genotypes to Challenge with Bovine Spongiform Encephalopathy and Scrapie

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.

Fig 1. Detection of disease-related PrP^Sc in IHC of brain and lymphoid tissues of TSE inoculated sheep.

IHC carried out using anti-PrP antibody BG4. (A), (B) and (C) positive staining in tissues from three sheep clinically affected following intracerebral inoculation with BSE. (A) ALRQ/ALRQ thalamus (x10); (B) AFRQ/AFRQ medulla (x10); (C) ALRQ/ALRQ mesenteric lymph node (x10). (D), (E) and (F) positive staining in tissues from three sheep clinically affected following sub-cutaneous inoculation with SSBP/1 scrapie. (D) VLRQ/VLRQ frontal cortex (x4); (E) VLRQ/ALRQ basal ganglia (x20); (F) VLRQ/AFRQ prescapular lymph node. (G) negative staining in tonsil of non-clinical AFRQ/ALRR BSE inoculated sheep. (H) negative staining in basal ganglia of non-clinical SSBP/1 ALRR/ALRR inoculated sheep.