Chronic wasting disease (CWD) prion strains evolve via adaptive diversification of conformers in hosts expressing prion protein polymorphisms.

ABSTRACT: Chronic wasting disease (CWD) is caused by an unknown spectrum of prions and has become enzootic in populations of cervid species that express cellular prion protein (PrP^C) molecules varying in amino acid composition. These PrP^C polymorphisms can affect prion transmission, disease progression, neuropathology, and emergence of new prion strains, but the mechanistic steps in prion evolution are not understood. Here, using conformation-dependent immunoassay, conformation stability assay, and protein-misfolding cyclic amplification, we monitored the conformational and phenotypic characteristics of CWD prions passaged through deer and transgenic mice expressing different cervid PrP^C polymorphisms. We observed that transmission through hosts with distinct PrP^C sequences diversifies the PrP^CWD conformations and causes a shift toward oligomers with defined structural organization, replication rate, and host range. When passaged in host environments that restrict prion replication, distinct co-existing PrP^CWD conformers underwent competitive selection, stabilizing a new prion strain. Nonadaptive conformers exhibited unstable replication and accumulated only to low levels. These results suggest a continuously evolving diversity of CWD conformers and imply a critical interplay between CWD prion plasticity and PrP^C polymorphisms during prion strain evolution.

SUBMITTER: Duque Velasquez C 

PROVIDER: S-EPMC7152757 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature