Pathogenesis of Transmissible Spongiform Encephalopathies : data from the scrapie model

Abstract

Among Transmissible Spongiform Encephalopathies (TSE), scrapie in sheep represents a model of natural infection, which is characterised by a panel of diverse strains of the prion, by the major role played by genetic determinants controlling sensibility and susceptibility, and by a frequent inter-individual transmission. Contamination occur mainly by the oral route. In genetically predisposed animals (PrP VRQ/VRQ) (the first clinical signs are detected between 20 and 24 months), the PrPsc protein has been detected in the ileal Peyer patches as early as the 21st day of age. Most of the secondary lymphoid structures become contaminated after 3 to 6 months. In the lymphoid tissues, PrPsc accumulates first in CD68⁺ cells (dendritic cells or macrophages), then in follicular dendritic cells. From the myenteric nervous plexus, PrPsc may reach the central nervous system via sympathetic and parasympathetic nerves. Schwann cells may be at play during this transfer. Spinal cord invasion begins at about the age of 9 to 10 months, in the dorsal node of the vagus nerve, and the T4-T9 medullary segments. From the lymphoid and nervous organs, PrPsc contaminates other tissues, in particular the placenta and the muscles. The mode of dissemination, through the blood stream or nervous tissue, remains evasive. In the placenta of infected ewes, PrPsc accumulation in the trophoblast cells is controlled by the genotype of the fetus. In the muscles, during the incubation and clinical phases, PrPsc can be detected in particular structures, the neuromuscular tubes, at concentrations which are 5000-fold lower than those measured in the obex of clinically affected animals. For scrapie, these data (sites of replication, kinetics) are strongly related to the PrP genotype of the host and probably to the prion strain. Generalisation to other animal or human situations should be cautious.