title: Human prion protein sequence elements impede cross-species chronic wasting disease transmission.
abstract: Chronic wasting disease (CWD) is a fatal prion disease of North American deer and elk and poses an unclear risk for transmission to humans. Human exposure to CWD occurs through hunting activities and consumption of venison from prion-infected animals. Although the amino acid residues of the prion protein (PrP) that prevent or permit human CWD infection are unknown, NMR-based structural studies suggest that the β2-α2 loop (residues 165-175) may impact species barriers. Here we sought to define PrP sequence determinants that affect CWD transmission to humans. We engineered transgenic mice that express human PrP with four amino acid substitutions that result in expression of PrP with a β2-α2 loop (residues 165-175) that exactly matches that of elk PrP. Compared with transgenic mice expressing unaltered human PrP, mice expressing the human-elk chimeric PrP were highly susceptible to elk and deer CWD prions but were concurrently less susceptible to human Creutzfeldt-Jakob disease prions. A systematic in vitro survey of amino acid differences between humans and cervids identified two additional residues that impacted CWD conversion of human PrP. This work identifies amino acids that constitute a substantial structural barrier for CWD transmission to humans and helps illuminate the molecular requirements for cross-species prion transmission.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Kurt
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.forename: Natalia
authors.initials: N
authors.lastname: Fernández-Borges
authors.forename: Cyrus
authors.initials: C
authors.lastname: Bett
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Tom
authors.initials: T
authors.lastname: Yang
authors.forename: Terry R
authors.initials: TR
authors.lastname: Spraker
authors.forename: Joaquín
authors.initials: J
authors.lastname: Castilla
authors.forename: David
authors.initials: D
authors.lastname: Eisenberg
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Kong
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Sigurdson
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry; D017124:Conserved Sequence; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism / Q000635:transmission; D003670:Deer; D060467:Disease Resistance; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D018621:PrPC Proteins / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013045:Species Specificity; D013329:Structure-Activity Relationship; D034081:Wasting Disease, Chronic / Q000635:transmission*
chemical_list: D018621:PrPC Proteins; D011993:Recombinant Fusion Proteins