Transmissible spongiform encephalopathies (TSEs) are neurological diseases that are associated with the conversion of the normal host-encoded
prion protein (
PrP-sen) to an abnormal
protease-resistant form,
PrP-res. Transmission of the TSE agent from one species to another is usually inefficient and accompanied by a prolonged incubation time. Species barriers to
infection by the TSE agent are of particular importance given the apparent transmission of
bovine spongiform encephalopathy to humans. Among the few animal species that appear to be resistant to
infection by the TSE agent are rabbits. They survive challenge with the human
kuru and Creutzfeldt-Jakob agents as well as with
scrapie agent isolated from sheep or mice. Species barriers to the TSE agent are strongly influenced by the PrP amino acid sequence of both the donor and recipient animals. Here we show that rabbit
PrP-sen does not form
PrP-res in murine tissue culture cells persistently infected with the mouse-adapted
scrapie agent. Unlike other TSE species barriers that have been studied, critical
amino acid residues that inhibit
PrP-res formation are located throughout the rabbit PrP sequence. Our results suggest that the resistance of rabbits to
infection by the TSE agent is due to multiple rabbit PrP-specific
amino acid residues that result in a PrP structure that is unable to refold to the abnormal
isoform associated with disease.