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Proceedings of the National Academy of Sciences of the United States of America2017; 114(5); 1141-1146; doi: 10.1073/pnas.1611891114

Prion replication without host adaptation during interspecies transmissions.

Abstract: Adaptation of prions to new species is thought to reflect the capacity of the host-encoded cellular form of the prion protein (PrP) 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 PrP Although disease transmission to only a subset of infected TgEq indicated a significant barrier to EqPrP conversion, the resulting horse prions unexpectedly failed to cause disease upon further passage to TgEq. TgD expressing deer PrP was similarly refractory to deer prions from diseased TgD infected with mink prions. In both cases, the resulting prions transmitted to mice expressing PrP 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 PrP 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.
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Publication Date: 2017-01-17 PubMed ID: 28096357PubMed Central: PMC5293081DOI: 10.1073/pnas.1611891114Google Scholar: Lookup
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  • Comparative Study
  • Journal Article
  • Research Support
  • N.I.H.
  • Extramural

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The study concentrates on how prions – infectious agents known for causing severe diseases in mammals – replicate without adapting to their host during interspecies transmissions. This ‘nonadaptive prion amplification’ revealed surprising results that expand our understanding of interspecies prion transmission and offer resolutions to the perplexing features of certain prion disorders.

Nonadaptive Prion Amplification

The researchers presented an alternative replicative process known as nonadaptive prion amplification (NAPA). Unlike the usual expectation where prions adapt to new species, NAPA denotes dominant conformers that can propagate without this necessity. This happens specifically during particular interspecies transmissions.

Modeling Horse Susceptibility to Prions

  • To understand the susceptibility of horses to prions, the researchers developed transgenic mice expressing a cognate Prion Protein (PrP).
  • Interestingly, only a subset of the infected transgenic horses indicated a significant barrier to Equine PrP conversion. Despite this, the horse prions intriguingly didn’t lead to any disease upon further passage to the transgenic horses.

Transmittance of Deer Prions

  • Similarly, prions from deer that were infected with mink prions exhibited resistance towards transmission in transgenic deers.
  • Nevertheless, these prions transmitted successfully to mice expressing PrP from the deer species, showing that the eradication of the transmission barrier for the originating prions was merely fleeting and the adaptation was shallow in transgenic horses and deer.

Protein Misfolding Cyclic Amplification of Prions

  • In another aspect of the study, horse prions produced in vitro by protein misfolding cyclic amplification of mouse prions using horse PrP failed to infect transgenic horses but managed to retain tropism for wild-type mice.
  • This indicates that NAPA managing to bypass selection of novel prion conformations is the reason for the horse prions’ denaturation in response to guanidine hydrochloride.

Preserving Strain Properties and Conclusions

  • Moreover, the researchers found that the corresponding prions of origin and NAPA prions exhibited similar forms of neuropathology and prion deposition in susceptible mice, confirming the preservation of strain properties.
  • The research’s findings suggest that different mechanisms are at work in the regulation of interspecies prion transmission. These insights contribute to a structure to understand and resolve the confusing features of certain prion disorders.

Cite This Article

APA
Bian J, Khaychuk V, Angers RC, Fernández-Borges N, Vidal E, Meyerett-Reid C, Kim S, Calvi CL, Bartz JC, Hoover EA, Agrimi U, Richt JA, Castilla J, Telling GC. (2017). Prion replication without host adaptation during interspecies transmissions. Proc Natl Acad Sci U S A, 114(5), 1141-1146. https://doi.org/10.1073/pnas.1611891114

Publication

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
NlmUniqueID: 7505876
Country: United States
Language: English
Volume: 114
Issue: 5
Pages: 1141-1146

Researcher Affiliations

Bian, Jifeng
  • Prion Research Center (PRC), Colorado State University, Fort Collins, CO 80525.
  • Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80525.
Khaychuk, Vadim
  • Prion Research Center (PRC), Colorado State University, Fort Collins, CO 80525.
  • Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80525.
Angers, Rachel C
  • Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40506.
Fernández-Borges, Natalia
  • Center for Cooperative Research in Biosciences (CIC bioGUNE), Parque Tecnológico de Bizkaia, Derio 48160, Bizkaia, Spain.
Vidal, Enric
  • Centre for Research into Animal Health (CReSA), Institute of Agri-Food Research and Technology (IRTA), Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Barcelona, Catalonia, Spain.
Meyerett-Reid, Crystal
  • Prion Research Center (PRC), Colorado State University, Fort Collins, CO 80525.
  • Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80525.
Kim, Sehun
  • Prion Research Center (PRC), Colorado State University, Fort Collins, CO 80525.
  • Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80525.
Calvi, Carla L
  • Prion Research Center (PRC), Colorado State University, Fort Collins, CO 80525.
  • Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80525.
Bartz, Jason C
  • Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178.
Hoover, Edward A
  • Prion Research Center (PRC), Colorado State University, Fort Collins, CO 80525.
  • Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80525.
Agrimi, Umberto
  • Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, 00161 Rome, Italy.
Richt, Jürgen A
  • Diagnostic Medicine Pathobiology, Kansas State University, Manhattan, KS 66506.
Castilla, Joaquín
  • Center for Cooperative Research in Biosciences (CIC bioGUNE), Parque Tecnológico de Bizkaia, Derio 48160, Bizkaia, Spain.
  • Basque Foundation for Science (IKERBASQUE), Bilbao 48011, Bizkaia, Spain.
Telling, Glenn C
  • Prion Research Center (PRC), Colorado State University, Fort Collins, CO 80525; glenn.telling@colostate.edu.
  • Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80525.

MeSH Terms

  • Animals
  • Deer
  • Guanidine / pharmacology
  • Horses
  • Host Specificity / physiology
  • Mice
  • Mice, Inbred C57BL
  • PrPC Proteins / chemistry
  • PrPC Proteins / genetics
  • PrPC Proteins / physiology
  • Prion Diseases / transmission
  • Prion Diseases / veterinary
  • Prions / chemistry
  • Prions / physiology
  • Protein Conformation
  • Protein Denaturation
  • Rabbits
  • Sheep
  • Species Specificity
  • Structure-Activity Relationship

Grant Funding

  • P01 AI077774 / NIAID NIH HHS
  • P30 GM103509 / NIGMS NIH HHS
  • R01 NS040334 / NINDS NIH HHS
  • R01 NS061902 / NINDS NIH HHS

Conflict of Interest Statement

The authors declare no conflict of interest.

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Citations

This article has been cited 43 times.
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