Species-barrier-independent prion replication in apparently resistant species

Abstract

Transmission of prions between mammalian species is thought to be limited by a "species barrier," which depends on differences in the primary structure of prion proteins in the infecting inoculum and the host. Here we demonstrate that a strain of hamster prions thought to be nonpathogenic for conventional mice leads to prion replication to high levels in such mice but without causing clinical disease. Prions pathogenic in both mice and hamsters are produced. These results demonstrate the existence of subclinical forms of prion infection with important public health implications, both with respect to iatrogenic transmission from apparently healthy humans and dietary exposure to cattle and other species exposed to bovine spongiform encephalopathy prions. Current definitions of the species barrier, which have been based on clinical end-points, need to be fundamentally reassessed.

Figure 1

Western blot analysis of brain homogenates treated with proteinase K using anti-PrP antibodies R073, which detects both mouse and hamster PrP (lanes 1–3) and 3F4, which detects hamster PrP only (lanes 4–6) (40). Lanes 1 and 4: Sc237-inoculated hamster; lanes 2 and 5: Sc237-inoculated CD-1 mouse positive for murine PrP^Sc; lanes 3 and 6: Sc237-inoculated mouse negative for PrP^Sc. Numbers adjacent to horizontal lines indicate positions of molecular mass markers (kDa). Ten microliters of a 10% brain homogenate was loaded in each lane.

Figure 2

Neuropathological examination of Sc237-inoculated (a) and (b) and PBS-inoculated (c) and (d) CD-1 mice (41). (a and c) Hematoxylin- and eosin-stained sections showing spongiform neurodegeneration in a. (b and d) PrP immunohistochemistry showing abnormal PrP immunoreactivity including PrP-positive plaques in b. (c and d) Normal appearances. Magnifications: ×150.

Figure 3

Western blot analysis of proteinase K-treated brain homogenates using anti-PrP antibody R073 to determine PrP^Sc types (40). Lane 1: Sc237-inoculated Syrian hamster; lane 2: Sc237-inoculated CD-1 mouse; lanes 3–5: passage of Sc237-inoculated CD-1 mouse into Syrian hamster (lane 3), CD-1 mouse (lane 4), and Tg20 mouse (lane 5). Numbers adjacent to horizontal lines indicate positions of molecular mass markers (kDa).