Oral inoculation of sheep with the agent of bovine spongiform encephalopathy (BSE). 1. Onset and distribution of disease-specific PrP accumulation inbrain and viscera

Sixty-three Romney sheep aged 6 months, consisting of three groups (PrPARQ/ ARQ, PrPARQ/ARR, and PrPARR/ARR genotypes) of 21 animals, were infected ora lly with brain tissue from BSL-infected cattle. Sub-groups of the 21 PrPARQ /ARQ animals were killed, together with uninflected control, 4, 10. 16, 22 or 24-28 (after the development of full clinical disease) months post-inocu lation (mpi). One sheep from each of the two groups of four killed at 4 or 10 mpi were shown by immunohistochemical examination to possess disease-spe cific PrP accumulations in single lymph nodes. At 16 mpi, such accumulation s were detected ill two of four infected sheep in some viscera and in the s pinal cord and brain. At 22 mpi, three of five infected sheep had widesprea d disease-specific PrP accumulations in all tissues examined. but the remai ning two animals gave positive results only in the central nervous system. Clinical disease appeared at 20-28 mpi. Three sheep killed with advanced cl inical signs showed widespread PrP accumulation in brain, spinal cord and p eripheral tissues. These results confirmed that PrPARQ/ARQ Romney sheep arc susceptible to experimental infection with the BSE agent. The different si tes at which initial PrP accumulations were detected suggested that the poi nt of entry of infection varied. Once established, however, infection appea red to spread rapidly throughout the lymphoreticular system. The result,; s uggested that in some BSE-infected sheep neuroinvasion occurred in the abse nce of detectable PrP accumulations in the viscera or peripheral nervous sy stem. In contrast to cattle with BSE, however, most sheep showed disease-sp ecific PrP accumulations in the lymphoreticular system. In this respect. BS E-inflected resembled scrapie-infected sheep; it is possible, however, that future research will reveal differences in respect of targeting of cell ty pes within the lymphoreticular and peripheral nervous systems. The PrPARQ/ARQ and PrPARR/ARR sheep were also killed in sub-group, at inter vals after inoculation. Up to 24 mpi, however, none of these animals showed disease-specific PrP accumulations. Further results will be reported later .