Following peripheral exposure to
transmissible spongiform encephalopathies (TSEs), infectivity usually accumulates in lymphoid tissues before neuroinvasion. The host
prion protein (PrPc) is critical for TSE agent replication and accumulates as an abnormal,
detergent insoluble, relatively
proteinase-resistant
isoform (PrPSc) in diseased tissues. Early PrPSc accumulation takes place on follicular dendritic cells (FDCs) within germinal centers in lymphoid tissues of patients with
variant Creutzfeldt-Jakob disease (vCJD), sheep with natural
scrapie or rodents following experimental peripheral
infection with
scrapie. In mouse
scrapie models, the absence of FDCs blocks
scrapie replication and PrPSc accumulation in the spleen, and neuroinvasion is significantly impaired. The mechanisms by which the TSE agent initially localizes to lymphoid follicles and interacts with FDCs are unknown.
Antigens are trapped and retained on the surface of FDCs through interactions between
complement and cellular
complement receptors. Here we show that in mice, both temporary depletion of
complement component C3 or genetic deficiency of C1q significantly delays the onset of disease following peripheral
infection, and reduces the early accumulation of PrPSc in the spleen. Thus, in the early stages of
infection, C3 and perhaps C1q contribute to the localization of TSE infectivity in lymphoid tissue and may be therapeutic targets.