# Oral Transmission of Classical Bovine Spongiform Encephalopathy in ARR/ARR Sheep

## TL;DR

Sheep with a specific genetic variant (ARR/ARR) can still develop bovine spongiform encephalopathy (c-BSE) after oral exposure, though with a longer incubation period than other sheep.

## Contribution

The study reveals that ARR/ARR sheep are susceptible to c-BSE despite being resistant to classical scrapie, challenging assumptions about their protective role.

## Key findings

- ARR/ARR sheep developed prion disease after oral c-BSE exposure, albeit with longer incubation times than ARQ/ARQ sheep.
- The tissue distribution of abnormal prion protein in ARR/ARR sheep was similar to that in ARQ/ARQ sheep.
- Transmission through ARR/ARR sheep did not increase the zoonotic potential of c-BSE.

## Abstract

Selection for the A136R154R171
PRNP allele is known to curb classical scrapie in sheep, and we expected it to minimize the risk for classical bovine spongiform encephalopathy (c-BSE) propagation. We orally challenged newborn ARR/ARR and ARQ/ARQ lambs with ovine-passaged c-BSE. Contrary to our expectations, prion disease developed in all ARR/ARR lambs after markedly longer incubation times (≈50 months) than ARQ/ARQ controls (≈20 months). Tissue distribution of the abnormal isoform of prion protein (PrP) in clinically affected ARR/ARR sheep largely mirrored tissue distribution seen in ARQ/ARQ animals. Bioassays in bovine- and human-PrP transgenic mice showed that passage through ARR/ARR sheep did not increase the agent’s zoonotic potential. Transmission efficiency in human normal cellular isoform PrP-expressing mice remained similar to cattle c-BSE and lower than ARQ-passaged c-BSE. Our data reveal the limitations of breeding exclusively for ARR when the objective is to mitigate c-BSE risk and underscore the need to maintain specific-risk-material removal and surveillance programs.