title: Prion protein amino acid determinants of differential susceptibility and molecular feature of prion strains in mice and voles.
abstract: The bank vole is a rodent susceptible to different prion strains from humans and various animal species. We analyzed the transmission features of different prions in a panel of seven rodent species which showed various degrees of phylogenetic affinity and specific prion protein (PrP) sequence divergences in order to investigate the basis of vole susceptibility in comparison to other rodent models. At first, we found a differential susceptibility of bank and field voles compared to C57Bl/6 and wood mice. Voles showed high susceptibility to sheep scrapie but were resistant to bovine spongiform encephalopathy, whereas C57Bl/6 and wood mice displayed opposite features. Infection with mouse-adapted scrapie 139A was faster in voles than in C57Bl/6 and wood mice. Moreover, a glycoprofile change was observed in voles, which was reverted upon back passage to mice. All strains replicated much faster in voles than in mice after adapting to the new species. PrP sequence comparison indicated a correlation between the transmission patterns and amino acids at positions 154 and 169 (Y and S in mice, N and N in voles). This correlation was confirmed when inoculating three additional rodent species: gerbils, spiny mice and oldfield mice with sheep scrapie and 139A. These rodents were chosen because oldfield mice do have the 154N and 169N substitutions, whereas gerbil and spiny mice do not have them. Our results suggest that PrP residues 154 and 169 drive the susceptibility, molecular phenotype and replication rate of prion strains in rodents. This might have implications for the assessment of host range and molecular traceability of prion strains, as well as for the development of improved animal models for prion diseases.
authors.affiliation: Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Rome, Italy. umberto.agrimi@iss.it
authors.forename: Umberto
authors.initials: U
authors.lastname: Agrimi
authors.forename: Romolo
authors.initials: R
authors.lastname: Nonno
authors.forename: Giacomo
authors.initials: G
authors.lastname: Dell'Omo
authors.forename: Michele Angelo
authors.initials: MA
authors.lastname: Di Bari
authors.forename: Michela
authors.initials: M
authors.lastname: Conte
authors.forename: Barbara
authors.initials: B
authors.lastname: Chiappini
authors.forename: Elena
authors.initials: E
authors.lastname: Esposito
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Guardo
authors.forename: Otto
authors.initials: O
authors.lastname: Windl
authors.forename: Gabriele
authors.initials: G
authors.lastname: Vaccari
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Lipp
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D003411:Arvicolinae; D002525:Cerebellar Cortex / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005849:Gerbillinae; D008136:Longevity; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D018620:PrPSc Proteins / Q000737:chemistry / Q000472:pathogenicity*; D011328:Prions / Q000737:chemistry / Q000472:pathogenicity*; D012608:Scrapie / Q000235:genetics / Q000276:immunology* / Q000635:transmission; D012756:Sheep
chemical_list: D000596:Amino Acids; D018620:PrPSc Proteins; D011328:Prions