Efficient Transmission and Characterization of Creutzfeldt–Jakob Disease Strains in Bank Voles

Abstract

Transmission of prions between species is limited by the “species barrier,” which hampers a full characterization of human prion strains in the mouse model. We report that the efficiency of primary transmission of prions from Creutzfeldt–Jakob disease patients to a wild rodent species, the bank vole (Clethrionomys glareolus), is comparable to that reported in transgenic mice carrying human prion protein, in spite of a low prion protein–sequence homology between man and vole. Voles infected with sporadic and genetic Creutzfeldt–Jakob disease isolates show strain-specific patterns of spongiform degeneration and pathological prion protein–deposition, and accumulate protease-resistant prion protein with biochemical properties similar to the human counterpart. Adaptation of genetic Creutzfeldt–Jakob disease isolates to voles shows little or no evidence of a transmission barrier, in contrast to the striking barriers observed during transmission of mouse, hamster, and sheep prions to voles. Our results imply that in voles there is no clear relationship between the degree of homology of the prion protein of the donor and recipient species and susceptibility, consistent with the view that the prion strain gives a major contribution to the species barrier. The vole is therefore a valuable model to study human prion diversity and, being susceptible to a range of animal prions, represents a unique tool for comparing isolates from different species.

Prion agent diversity and species barrier

“…Moreover the incubation time observed on primary inoculation to voles was similar to that in transgenic mice overexpressing human PrP [5,22]. Parallel transmission of the same CJD cases to inbred mice was inefficient [140], consistent with earlier transmission data [35,78,91]. In contrast, transmission to mice of variant CJD cases of the same PrP genotype was efficient [35], whereas transmission to bank voles was inefficient (U. Agrimi, personal communication).…”

“…Similar observations have been obtained with other prions. Thus, sporadic and genetic CJD isolates can be experimentally propagated in bank voles, a newly discovered rodent TSE model, with a low transmission barrier despite the divergence between human and vole PrP sequences [140]. Moreover the incubation time observed on primary inoculation to voles was similar to that in transgenic mice overexpressing human PrP [5,22].…”

“…While a few inoculated mice accumulated PrP res and had spongiform lesions, even a second passage in mice failed to transmit the disease, suggesting no adaptation. Nonetheless parallel reinoculation into bank voles induced disease as efficiently as CJD directly, and with a similar phenotype [140]. In experiments aimed at modeling the potential susceptibility of humans homozygous for valine at codon 129 to the BSE agent, transgenic mice expressing this allele were inoculated with natural isolates [201].…”

A prion disease of cervids: Chronic wasting disease

“…However, strain features including histologic profile, target organs, and glycoform patterns will not necessarily remain the same upon crossing species barriers [5,6,8,57]. The PrP Sc form is cleaved by proteinase-K (PK) at different sites depending on the conformation of the protein and may aid determination of whether the PrP Sc conformation is similar.…”

Rodent models for prion diseases

“…tga20, TgbovXV, Tg338, Tgshp, Tgshp) as well as to bank voles [26,66]. Bank voles (Clethrionomys glareolus) have recently been described to be as susceptible to a Creutzfeldt-Jakob disease (CJD) infection as human PrP transgenic mice [66], although there is only a comparably low sequence homology between the PrP of humans and bank voles. Research with this species will therefore be intensified in the future.…”