title: 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 (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 PrPCAlthough disease transmission to only a subset of infected TgEq indicated a significant barrier to EqPrPCconversion, the resulting horse prions unexpectedly failed to cause disease upon further passage to TgEq. TgD expressing deer PrPCwas similarly refractory to deer prions from diseased TgD infected with mink prions. In both cases, the resulting prions transmitted to mice expressing PrPCfrom 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 PrPCalso 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.
authors.affiliation: Prion Research Center (PRC), Colorado State University, Fort Collins, CO 80525.|Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80525.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Bian
authors.affiliation: Prion Research Center (PRC), Colorado State University, Fort Collins, CO 80525.|Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80525.
authors.forename: Vadim
authors.initials: V
authors.lastname: Khaychuk
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40506.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Angers
authors.affiliation: Center for Cooperative Research in Biosciences (CIC bioGUNE), Parque Tecnológico de Bizkaia, Derio 48160, Bizkaia, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Fernández-Borges
authors.affiliation: 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.
authors.forename: Enric
authors.identifier: 0000-0002-4965-3286
authors.initials: E
authors.lastname: Vidal
authors.affiliation: Prion Research Center (PRC), Colorado State University, Fort Collins, CO 80525.|Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80525.
authors.forename: Crystal
authors.initials: C
authors.lastname: Meyerett-Reid
authors.affiliation: Prion Research Center (PRC), Colorado State University, Fort Collins, CO 80525.|Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80525.
authors.forename: Sehun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Prion Research Center (PRC), Colorado State University, Fort Collins, CO 80525.|Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80525.
authors.forename: Carla L
authors.initials: CL
authors.lastname: Calvi
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Bartz
authors.affiliation: Prion Research Center (PRC), Colorado State University, Fort Collins, CO 80525.|Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80525.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Hoover
authors.affiliation: Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Agrimi
authors.affiliation: Diagnostic Medicine Pathobiology, Kansas State University, Manhattan, KS 66506.
authors.forename: Jürgen A
authors.initials: JA
authors.lastname: Richt
authors.affiliation: 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.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Castilla
authors.affiliation: 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.
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Telling
mesh_terms: D000818:Animals; D003670:Deer; D019791:Guanidine / Q000494:pharmacology; D006736:Horses; D058507:Host Specificity / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018621:PrPC Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017096:Prion Diseases / Q000635:transmission* / Q000662:veterinary*; D011328:Prions / Q000737:chemistry / Q000502:physiology*; D011487:Protein Conformation; D011489:Protein Denaturation; D011817:Rabbits; D012756:Sheep; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D018621:PrPC Proteins; D011328:Prions; D019791:Guanidine
keywords: adaptation; conformational selection; prion strains; species barriers; transgenic mice