Prion replication without host adaptation during interspecies transmissions

Jifeng Bian, Vadim Khaychuk, Rachel C. Angers, Natalia Fernández-Borges, Enric Vidal, Crystal Meyerett-Reid, Sehun Kim, Carla L. Calvi, Jason C. Bartz, Edward A. Hoover, Umberto Agrimi, Jürgen A. Richt, Joaquín Castilla, Glenn C. Telling

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Abstract

Adaptation of prions to new species is thought to reflect the capacity of the host-encoded cellular form of the prion protein (PrPC) to selectively propagate optimized prion conformations from larger ensembles generated in the species of origin. Here we describe an alternate replicative process, termed nonadaptive prion amplification (NAPA), in which dominant conformers bypass this requirement during particular interspecies transmissions. To model susceptibility of horses to prions, we produced transgenic (Tg) mice expressing cognate PrPC. Although disease transmission to only a subset of infected TgEq indicated a significant barrier to EqPrPC conversion, the resulting horse prions unexpectedly failed to cause disease upon further passage to TgEq. TgD expressing deer PrPC was similarly refractory to deer prions from diseased TgD infected with mink prions. In both cases, the resulting prions transmitted to mice expressing PrPC from the species of prion origin, demonstrating that transmission barrier eradication of the originating prions was ephemeral and adaptation superficial in TgEq and TgD. Horse prions produced in vitro by protein misfolding cyclic amplification of mouse prions using horse PrPC also failed to infect TgEq but retained tropism for wild-type mice. Concordant patterns of neuropathology and prion deposition in susceptible mice infected with NAPA prions and the corresponding prion of origin confirmed preservation of strain properties. The comparable responses of both prion types to guanidine hydrochloride denaturation indicated this occurs because NAPA precludes selection of novel prion conformations. Our findings provide insights into mechanisms regulating interspecies prion transmission and a framework to reconcile puzzling epidemiological features of certain prion disorders.

Original languageEnglish (US)
Pages (from-to)1141-1146
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number5
DOIs
Publication statusPublished - Jan 31 2017

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Bian, J., Khaychuk, V., Angers, R. C., Fernández-Borges, N., Vidal, E., Meyerett-Reid, C., ... Telling, G. C. (2017). Prion replication without host adaptation during interspecies transmissions. Proceedings of the National Academy of Sciences of the United States of America, 114(5), 1141-1146. https://doi.org/10.1073/pnas.1611891114