Distinct prion conformers from brain and peripheral tissues of gene-targeted mice produce convergent CWD strain properties.

Prions are unique infectious agents because different conformational properties of their constituent proteins are responsible for the manifestation of distinct strains. While prion replication in humans with sporadic Creutzfeldt-Jakob disease and cattle with bovine spongiform encephalopathy is primarily limited to the central nervous system (CNS), a seminal feature of chronic wasting disease (CWD) in cervids is high infectious titers in peripheral tissues, including skeletal muscles and the lymphoreticular system. Although extensive studies have assessed prion properties in the CNS, our understanding of prions in peripheral tissues remains limited. Here, we compared the strain properties of CWD prions in peripheral and CNS tissues of gene-targeted (Gt) mice. Our studies reveal differences in the biochemical and conformational properties of CWD prions, as well as the prion levels, between peripheral and CNS tissues. While this finding suggested that these tissues harbored distinct CWD prions, transmissions of muscle, spleen, and brain homogenates to Gt mice by the intraperitoneal route produced convergent strain properties. Importantly, transmission of these tissues by the intracerebral route resulted in different disease phenotypes than intraperitoneal inoculations. Additionally, while prion infection of CWD-susceptible cells revealed different titers in muscle, spleen, and brain tissues, the conformational properties of the resulting de novo prions were indistinguishable. While our findings support a role for tissue-specific cofactors that affect the biochemical and conformational properties of prions, they also show that these parameters do not solely dictate disease outcomes and that additional factors, particularly the route of inoculation, exert a more pronounced influence on strain outcomes.