Regulated coexpression of PrP from different species in mice impacts the replication and host range properties of prion strains.

Our previous demonstration that replacement of murine cellular prion protein (PrPC) expression with elk or deer PrPC eliminated the resistance of mice to chronic wasting disease (CWD) prions from deer, elk, and other cervids highlighted the importance of sequence homology between PrPC and its conformationally altered counterpart (PrPSc) for optimal prion replication. To further investigate the effects of species-specific PrP primary structural variation on the evolution of prion host range and strain properties during interspecies transmissions, we generated mice with precisely controlled expression of both murine and either deer or elk PrPC and challenged them with cervid or murine prions. While CWD prion transmission was inhibited to varying degrees under these conditions, the strain properties and species specificities of the resulting cervid prions were not impacted. By contrast, although murine prions induced conformational conversion of mouse but not coexpressed cervid PrPC, the resulting prions produced disease in mice expressing either cervid or mouse PrPC. Our findings show that while mouse PrPC inhibited conformational conversion of deer or elk PrPC without affecting the host range of CWD prions, coexpression of cervid PrPC influenced the selection of strains with expanded host range properties during conformational conversion of mouse PrPC by murine prions. Our studies reveal diverse influences of bystander PrPC expression on the replication, host range, and strain properties of prions generated during conformational conversion of their coexpressed cognate PrPC. These cooperative or inhibitory effects occur in trans and derive from species-specific primary structural variations between coexpressed PrPC substrates and infectious prions.