The innate immune system provides the first line of defence against infectious agents and damaged cells and proteins. Abnormal protein aggregates, such as PrPCJD that causes CJD, trigger the innate immune system through receptors, called TLRs, on the cell surface. We have shown that activation of specific TLRs can reduce prion infections in cell cultures, leading to our hypothesis that up-regulation of these TLRs, early in an infection or disease course in animals/humans, will decrease accumulation of the misfolded prion protein, therefore, slowing or stopping disease progression. We will confirm these results from cell culture models in transgenic mouse models expressing human prion protein and infected with CJD. The long-term goal is identification of a signalling pathways with targets for prophylactic and therapeutic interventions.