title: Intraperitoneal Infection of Wild-Type Mice with Synthetically Generated Mammalian Prion.
abstract: The prion hypothesis postulates that the infectious agent in transmissible spongiform encephalopathies (TSEs) is an unorthodox protein conformation based agent. Recent successes in generating mammalian prions in vitro with bacterially expressed recombinant prion protein provide strong support for the hypothesis. However, whether the pathogenic properties of synthetically generated prion (rec-Prion) recapitulate those of naturally occurring prions remains unresolved. Using end-point titration assay, we showed that the in vitro prepared rec-Prions have infectious titers of around 104 LD50/μg. In addition, intraperitoneal (i.p.) inoculation of wild-type mice with rec-Prion caused prion disease with an average survival time of 210-220 days post inoculation. Detailed pathological analyses revealed that the nature of rec-Prion induced lesions, including spongiform change, disease specific prion protein accumulation (PrP-d) and the PrP-d dissemination amongst lymphoid and peripheral nervous system tissues, the route and mechanisms of neuroinvasion were all typical of classical rodent prions. Our results revealed that, similar to naturally occurring prions, the rec-Prion has a titratable infectivity and is capable of causing prion disease via routes other than direct intra-cerebral challenge. More importantly, our results established that the rec-Prion caused disease is pathogenically and pathologically identical to naturally occurring contagious TSEs, supporting the concept that a conformationally altered protein agent is responsible for the infectivity in TSEs.
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, United States of America; Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Xinhe
authors.initials: X
authors.lastname: Wang
authors.affiliation: Animal and Plant Health Agency, Lasswade Laboratory, Pentlands Science Park, Penicuik, Midlothian, Scotland.
authors.forename: Gillian
authors.initials: G
authors.lastname: McGovern
authors.affiliation: Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio, United States of America; Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, United States of America; Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Liang
authors.initials: L
authors.lastname: Zha
authors.affiliation: Animal and Plant Health Agency, Lasswade Laboratory, Pentlands Science Park, Penicuik, Midlothian, Scotland.
authors.forename: Martin
authors.initials: M
authors.lastname: Jeffrey
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, United States of America; Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio, United States of America; Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Jiyan
authors.initials: J
authors.lastname: Ma
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D051379:Mice; D017096:Prion Diseases / Q000473:pathology*; D011328:Prions / Q000008:administration & dosage / Q000472:pathogenicity*; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000138:chemical synthesis
chemical_list: D011328:Prions; D011994:Recombinant Proteins