Adaptive selection of a prion strain conformer corresponding to established North American CWD during propagation of novel emergent Norwegian strains in mice expressing elk or deer prion protein

Jifeng Bian,Sandra Pritzkow,Gordon Mitchell,Glenn C Telling,Jenna Crowell,Turid Vikøren,Julie A Moreno,Claudio Soto,Romolo Nonno,Sarah J Kane,Julianna L Sun,Knut Madslien,Emily Burnett,Linh Tran,Eri Saijo,Sylvie L Benestad,Damian Gorski,Sehun Kim,Michael W Miller,Aru Balachandran,Jørn Våge,Terry J Kreeger,Tram Thu Vuong,James E Dilisio ,Jeffrey R Christiansen

doi:10.1371/journal.ppat.1009748

Abstract

Prions are infectious proteins causing fatal, transmissible neurodegenerative diseases of animals and humans. Replication involves template-directed refolding of host encoded prion protein, PrPC, by its infectious conformation, PrPSc. Following its discovery in captive Colorado deer in 1967, uncontrollable contagious transmission of chronic wasting disease (CWD) led to an expanded geographic range in increasing numbers of free-ranging and captive North American (NA) cervids. Some five decades later, detection of PrPSc in free-ranging Norwegian (NO) reindeer and moose marked the first indication of CWD in Europe. To assess the properties of these emergent NO prions and compare them with NA CWD we used transgenic (Tg) and gene targeted (Gt) mice expressing PrP with glutamine (Q) or glutamate (E) at residue 226, a variation in wild type cervid PrP which influences prion strain selection in NA deer and elk. Transmissions of NO moose and reindeer prions to Tg and Gt mice recapitulated the characteristic features of CWD in natural hosts, revealing novel prion strains with disease kinetics, neuropathological profiles, and capacities to infect lymphoid tissues and cultured cells that were distinct from those causing NA CWD. In support of strain variation, PrPSc conformers comprising emergent NO moose and reindeer CWD were subject to selective effects imposed by variation at residue 226 that were different from those controlling established NA CWD. Transmission of particular NO moose CWD prions in mice expressing E at 226 resulted in selection of a kinetically optimized conformer, subsequent transmission of which revealed properties consistent with NA CWD. These findings illustrate the potential for adaptive selection of strain conformers with improved fitness during propagation of unstable NO prions. Their potential for contagious transmission has implications for risk analyses and management of emergent European CWD. Finally, we found that Gt mice expressing physiologically controlled PrP levels recapitulated the lymphotropic properties of naturally occurring CWD strains resulting in improved susceptibilities to emergent NO reindeer prions compared with over-expressing Tg counterparts. These findings underscore the refined advantages of Gt models for exploring the mechanisms and impacts of strain selection in peripheral compartments during natural prion transmission.

Highlights

Prions are infectious proteins that cause inexorable degenerative diseases of the central nervous system (CNS) in humans and animals
We show, using mice engineered to express deer or elk PrP, that Norwegian reindeer and moose chronic wasting disease (CWD) are caused by novel prion strains with properties distinct from those of North American CWD
We found that selection and propagation of North American and Norwegian CWD strains was controlled by a key amino acid residue in host PrP

Summary

Introduction

Prions are infectious proteins that cause inexorable degenerative diseases of the central nervous system (CNS) in humans and animals. During disease PrPSc interacts with and imparts its infective βsheet conformation on α-helical PrPC by template-directed refolding The upshot of this cyclical process is exponential prion accumulation, resultant neurodegeneration, and inevitable death [3]. Strain properties define prion host range potentials [10] and full or even partial acclimatization is not an obligatory consequence of disease transmission to a new host species [11], strain adaptation is a customary outcome [12,13] The efficiency of this process is dictated by several parameters which influence the interplay between PrPSc constituting infectious prions and host encoded PrPC. Heritable strain information is enciphered by distinct PrPSc conformations [14,15]; second, strain adaptation following interspecies transmission to a new host [16] or in response to other selective pressures [17] is associated with concomitant changes in PrPSc conformation; and third, prion transmission between species is facilitated when primary structures of PrPSc constituting the infectious agent match those of PrPC expressed in the newly infected host species [18]

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Conclusion