The paradoxical dynamics of prion disease latency

A salient characteristic of the prion diseases--including Creutzfeldt-Jakob disease and bovine spongiform encephalopathy in cattle--is an extended asymptomatic incubation period followed by a rapid and often fatal clinical phase. We present a kinetic model of progression of infection based upon the existence of a bottleneck in the natural protein pathways within the cell. The model can reconcile the different time-scales of the pre-clinical and clinical phases, and is able to account for the dependency of the duration of the incubation period on several important governing factors, including the inoculum size, the phenotype of the host, and the phenotype of the pathogenic form of the prion protein. Our results suggest that saturation events--first of the rate of pathogenic transformation (an auto-catalysis ceiling), and subsequently of the bottleneck in the protein pathways--could be fundamental in determining the dynamics of infection.