Crossing Species Barriers Relies on Structurally Distinct Prion Assemblies and Their Complementation

Prion replication results from the autocatalytic templated assisted conversion of the host-encoded prion protein PrP C into misfolded, polydisperse PrP Sc conformers. Structurally distinct PrP Sc conformers can give rise to multiple prion strains. Within and between prion strains, the biological activity (replicative efficacy and specific infectivity) of PrP Sc assemblies is size dependent and thus reflects an intrinsic structural heterogeneity. The contribution of such PrP Sc heterogeneity across species prion adaptation, which is believed to be based on fit adjustment between PrP Sc template(s) and host PrP C , has not been explored. To define the structural-to-fitness PrP Sc landscape, we measured the relative capacity of size-fractionated PrP Sc assemblies from different prion strains to cross mounting species barriers in transgenic mice expressing foreign PrP C . In the absence of a transmission barrier, the relative efficacy of the isolated PrP Sc assemblies to induce the disease is like the efficacy observed in the homotypic context. However, in the presence of a transmission barrier, size fractionation overtly delays and even abrogates prion pathogenesis in both the brain and spleen tissues, independently of the infectivity load of the isolated assemblies. Altering by serial dilution PrP Sc assembly content of non-fractionated inocula aberrantly reduces their specific infectivity, solely in the presence of a transmission barrier. This suggests that synergy between structurally distinct PrP Sc assemblies in the inoculum is requested for crossing the species barrier. Our data support a mechanism whereby overcoming prion species barrier requires complementation between structurally distinct PrP Sc assemblies. This work provides key insight into the “quasispecies” concept applied to prions, which would not necessarily rely on prion substrains as constituent but on structural PrP Sc heterogeneity within prion population.