Transmissible spongiform encephalopathies are accompanied by the accumulation of a pathologic
isoform of a host-encoded
protein, termed
prion protein (PrP). Despite the widespread distribution of the cellular
isoform of PrP (
protease-sensitive PrP;
PrP-sen), the disease-associated
isoform (
protease-resistant PrP;
PrP-res) appears to be primarily restricted to cells of the nervous and lymphoreticular systems. In order to study why
scrapie infection appears to be restricted to certain cells, we followed acute and persistent
PrP-res formation upon exposure of cells to different
scrapie agents. We found that, independent of the cell type and
scrapie strain, initial
PrP-res formation occurred rapidly in cells. However, sustained generation of
PrP-res and
persistent infection did not necessarily follow acute
PrP-res formation. Persistent
PrP-res formation and
scrapie infection was restricted to one cell line inoculated with the mouse
scrapie strain 22L. In contrast to cells that did not become
scrapie-infected, the level of
PrP-res in the 22L-infected cells rapidly increased in the absence of a concomitant increase in the number of
PrP-res-producing cells. Furthermore, the
protein banding pattern of
PrP-res in these cells changed over time as the cells became chronically infected. Thus, our results suggest that the events leading to the initial formation of
PrP-res may differ from those required for sustained
PrP-res formation and
infection. This may, at least in part, explain the observation that not all
PrP-sen-expressing cells appear to support
transmissible spongiform encephalopathy agent replication.