Pathogenesis of experimental scrapie.

Most of our understanding of the pathogenesis of the unconventional slow infections comes from studies of experimental scrapie in mice and hamsters. After injection by non-neural peripheral routes, pathogenesis necessarily involves the lymphoreticular system (LRS) before the central nervous system (CNS). Available evidence indicates haematogenous spread from the site of injection to the scrapie replication sites in the LRS; later, infection spreads along visceral autonomic nerves from the LRS to the thoracic spinal cord, and thence to brain. The cells in the LRS which are important to scrapie pathogenesis are long lived. Neuroinvasion and spread of infection within the CNS probably involve neuronal pathways. We suggest that disease develops after infection has reached certain clinical target areas in the CNS but only when scrapie replication there has caused sufficient functional damage. Restriction of the replication process in both LRS and CNS is indicated by the occurrence of plateau concentrations of infectivity, especially in some long incubation scrapie models. A remarkable feature of these is that both neuroinvasion and clinical disease occur long after infectivity plateaux have been reached in the LRS and CNS, respectively. We propose that the slowness of scrapie is related to (1) limitations of cell-to-cell spread of infection from LRS to CNS, and (2) limitations on spread between neurons, coupled with restrictions on replication in brain.