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 (PrPC) molecules varying in amino acid composition. These PrPC 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 PrPC polymorphisms. We observed that transmission through hosts with distinct PrPC sequences diversifies the PrPCWD 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 PrPCWD 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 PrPC polymorphisms during prion strain evolution.
Highlights
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 (PrPC) molecules varying in amino acid composition
Replication of a prion isolate, from hunter-harvested WT/WT white-tailed deer (passage 0 (P0)), in deer expressing PrPC polymorphisms resulted in PrPCWD with different glycotype patterns and epitope binding (Fig. 1, A and B)
In the His-95/Ser-96 deer brain, this C3–PrP existed in an abundantly glycosylated state with an apparent mass of 30 kDa prior to glycan removal (Fig. 2C). Both polymorphisms occur within the 93WGQGG97 epitope of the 12B2 monoclonal antibodies (mAbs), preventing detection of both His-95 and Ser-96 PrPCWD and PrPC (Figs. 1A and 2C)
Summary
Coileus virginanus) to CWD (15, 19 –22). The protective effect of the Ser-96 –PrPC transmission barrier has been implicated in the increased frequency of Ser-96 –PRNP alleles in deer populations chronically exposed to CWD [23]. To determine the effects of nonhomologous prion replication, we measured the biochemical, biophysical, and infectious properties of CWD prions generated in white-tailed deer expressing combinations (i.e. allotypes) of His-95, Ser-96, or Gln-95/Gly-96 (WT) PrPC. All deer were dosed with the same prion isolate (Wisc-1), deer expressing His-95–PrPC accumulated a mixture of an emergent strain H95ϩ and invading Wisc-1. We demonstrate the conformational diversification of cervid prions during replication in nonhomologous host–PrPC environments and how that diversification leads to the emergence of a new CWD strain
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