The pathogenesis of intraperitoneally injected ME7 scrapie has been studied in two genotypes of mice which gave predictable but widely different incubation periods. Comparisons were made with three other mouse scrapie models and one model in hamsters (involving different strains of agent and an untyped isolate from sheep). Average incubation periods ranged from 114 days in the fastest model (263K/hamsters) to 482 days in the slowest (ME7/ mice). There were only small differences between models in the times of onset of replication in spleen and cervical lymph nodes. We suggest that the lymphoreticular stage of pathogenesis initiates neuroinvasion in the peripheral nervous system within a few days to a few weeks of infection. Thereafter, pathogenesis appears to be dominated by neural events and replication in brain becomes detectable after approximately 54% of the remaining incubation period has elapsed, irrespective of its length. It is concluded that the differences between incubation periods of the six scrapie models depend mainly on the rate of a continuous process of replication and spread of infection in the peripheral and central nervous system, which is predetermined by scrapie strain and host genotype. The unpredictability of some other scrapie models (and the natural disease) could be explained by additional factors which restrict neuroinvasion from the lymphoreticular system.


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