Efficient lymphoreticular prion propagation requires PrPc in stromal and hematopoietic cells

In most prion diseases, infectivity accumulates in lymphoreticular organs e arly after infection, Defects in hematopoietic compartments, such as impair ed B-cell maturation, or in stromal compartments, such as abrogation of fol licular dendritic cells, can delay or prevent Lymphoreticular prion coloniz ation. However, the nature of the compartment in which prion replication ta kes place is controversial, and it is unclear whether this compartment coin cides with that expressing the normal prion protein (PrPc). Here we studied the distribution of infectivity in splenic fractions of wild-type and feta l liver chimeric mice carrying the gene that encodes PrPc (Prnp) solely on hematopoietic or on stromal cells. We fractionated spleens at various times after intraperitoneal challenge with prions and assayed infectivity by bio assay, Upon high-dose challenge, chimeras carrying PrPc on hematopoietic ce lls accumulated prions in stroma and in purified splenocytes, In contrast, after low-dose challenge ablation of Prnp in either compartment prevented s plenic accumulation of infectivity, indicating that optimal prion replicati on requires PrPc expression by both stromal and hematopoietic compartments.