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. 2006 Feb;2(2):e12.
doi: 10.1371/journal.ppat.0020012. Epub 2006 Feb 24.

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

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

Romolo Nonno et al. PLoS Pathog. .
Free PMC article

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.

Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Determination of the Molecular Type of PrPSc Produced in Voles following Transmission of sCJD and gCJD
(A) Immunoblot of proteinase K–resistant PrPSc from sCJD and gCJD subtypes in human patients and after first passage in voles. PrPSc produced in voles after primary transmission of mouse-passaged MM1 sCJD and MV1 sCJD, and of the mouse-adapted scrapie strain ME7 is also shown. The identity of the brain sample is designated above each lane. (B) Comparison of proteinase K–resistant PrPSc produced in voles following first and second passages of MV1 sCJD, MM2 sCJD, E200K gCJD, and V210I gCJD. PrPSc produced in voles after first passage of the mouse-adapted scrapie strain ME7 is also shown. The identity of the brain sample is designated above each lane. (C) Scatter-graph of proportions of di-glycosylated and mono-glycosylated PrPSc in human patients (denoted by filled circles, filled inverted triangles, filled diamonds, filled squares, and filled upright triangles) and voles (denoted by open circles, open inverted triangles, open diamonds, open squares, open upright triangles, and asterisks), with MM1 sCJD (denoted by filled squares and open squares), MV1 sCJD (denoted by filled diamonds and open diamonds), MM2 sCJD (denoted by filled circles and open circles), V210I gCJD (denoted by filled inverted triangles and open inverted triangles), E200K gCJD (denoted by filled upright triangles and open upright triangles), and ME7 (denoted by asterisks). (D) Comparison of proteinase K–resistant PrPSc produced in voles following inoculation with MM1 sCJD, MM2 sCJD, and the mouse-adapted scrapie strain ME7. Strep-tagged molecular markers (25 kDa and 20 kDa) are shown. The identity of the brain samples is designated above each lane.
Figure 2
Figure 2. Lesion Profiles in Voles and Mice following Transmission of sCJD and gCJD
Brain-scoring positions are medulla (1), cerebellum (2), superior colliculus (3), hypothalamus (4), thalamus (5), hippocampus (6), septum (7), retrosplenial and adjacent motor cortex (8), and cingulate and adjacent motor cortex (9). (A) Lesion profiles in voles infected with MM1 sCJD (denoted by open squares), MV1 sCJD (denoted by open circles), V210I gCJD (denoted by open diamonds), and E200K gCJD (denoted by open upright triangles). (B) Lesion profiles in voles infected with MM2 sCJD (denoted by open squares) and the mouse-passaged scrapie strain ME7 (denoted by open circles). (C) Lesion profiles in voles infected with human sCJD (denoted by open squares and open circles) and mouse-passaged sCJD (denoted by open diamonds and open upright triangles), MM1 sCJD (denoted by open squares and open diamonds), and MV1 sCJD (denoted by open circles and open upright triangles). (D) Lesion profiles in C3H mice infected with MM1 sCJD (denoted by open circles), MV1 sCJD (denoted by open upright triangles), and V210I gCJD (denoted by open diamonds).
Figure 3
Figure 3. Regional Distribution of Protease-Resistant PrPSc in Voles following Transmission of sCJD and gCJD
PET blots of coronal sections of the forebrain (telencephalon in [A] and diencephalon in [B]), midbrain (C), and hindbrain (D) in voles infected with MM2 sCJD, MM1 sCJD, MV1 sCJD, V210I gCJD, and E200K gCJD. At the lower part of the figure, the labeled coronal sections of a negative control brain are shown. NC, neocortex; Sp, septum; St, striatum; Hp, hippocampus; Th, thalamus; Hy, hypothalamus; SC, superior colliculus; GN, geniculate nuclei; SN, substantia nigra; Cb, cerebellum; MO, medulla oblongata.
Figure 4
Figure 4. Alignment of Human, Vole, and Mouse Prion Protein–Amino Acid Sequences
The sequence numbers of the human (Homo sapiens) amino acids are indicated and refer to the residue under the final digit. In the vole (C. glareolus) and the mouse (Mus musculus) sequences, identical residues to the human are indicated as dots.
Figure 5
Figure 5. Comparison of Transmission Barriers of Human, Sheep, Mouse, and Hamster Prions following Transmission to Voles
In (A–C), inocula are grouped according to the sequence homology of mature PrP between the donor species and voles, from the least to the most divergent (golden hamster, 2.9% divergence; C57BL mouse strain, 2.9% divergence; VM mouse strain, 3.4% divergence; human, 7.1% divergence; and sheep, 7.1% divergence). In (D), inocula are ranked according to the magnitude of the transmission barrier and are grouped according to the original prion source. (A) Survival times following first passage in voles of hamster-passaged scrapie strains 263K and 139H, C57BL mice-passaged BSE strain 301C, C57BL mice-passaged scrapie strains ME7 and 139A, VM mice-passaged BSE strain 301V, VM mice-passaged scrapie strain 22A, human sCJD (MM1, MV1, and MM2 subtypes) and gCJD (E200K and V210I subtypes), sheep-passaged BSE, and sheep natural scrapie isolates from the United Kingdom (SSUK) and Italy (SSIT); error bars represent standard deviation. (B) Survival times following second passage in voles of the same transmissions as in (A); error bars represent standard deviation. (C and D) The magnitude of each transmission barrier is calculated as the ratio of mean survival times observed following first and second passage (a value of 1 denotes an absence of transmission barrier).

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