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. 2014 Apr 3;10(4):e1003990.
doi: 10.1371/journal.ppat.1003990. eCollection 2014 Apr.

Evidence that bank vole PrP is a universal acceptor for prions

Joel C Watts  1 , Kurt Giles  1 , Smita Patel  2 , Abby Oehler  3 , Stephen J DeArmond  4 , Stanley B Prusiner  1
Affiliations

Evidence that bank vole PrP is a universal acceptor for prions

Joel C Watts et al. PLoS Pathog. .

Abstract

Bank voles are uniquely susceptible to a wide range of prion strains isolated from many different species. To determine if this enhanced susceptibility to interspecies prion transmission is encoded within the sequence of the bank vole prion protein (BVPrP), we inoculated Tg(M109) and Tg(I109) mice, which express BVPrP containing either methionine or isoleucine at polymorphic codon 109, with 16 prion isolates from 8 different species: humans, cattle, elk, sheep, guinea pigs, hamsters, mice, and meadow voles. Efficient disease transmission was observed in both Tg(M109) and Tg(I109) mice. For instance, inoculation of the most common human prion strain, sporadic Creutzfeldt-Jakob disease (sCJD) subtype MM1, into Tg(M109) mice gave incubation periods of ∼200 days that were shortened slightly on second passage. Chronic wasting disease prions exhibited an incubation time of ∼250 days, which shortened to ∼150 days upon second passage in Tg(M109) mice. Unexpectedly, bovine spongiform encephalopathy and variant CJD prions caused rapid neurological dysfunction in Tg(M109) mice upon second passage, with incubation periods of 64 and 40 days, respectively. Despite the rapid incubation periods, other strain-specified properties of many prion isolates--including the size of proteinase K-resistant PrPSc, the pattern of cerebral PrPSc deposition, and the conformational stability--were remarkably conserved upon serial passage in Tg(M109) mice. Our results demonstrate that expression of BVPrP is sufficient to engender enhanced susceptibility to a diverse range of prion isolates, suggesting that BVPrP may be a universal acceptor for prions.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Analysis of PK-resistant PrPSc in Tg(M109) mice inoculated with diverse prion isolates.
Except for one undigested lane (−), brain samples were digested with PK (+ in panel A). All inoculation experiments resulted in the generation of PK-resistant PrPSc. (A) Detergent-extracted brain homogenates from Tg(M109) mice that were inoculated with the indicated prion isolates. Brain homogenate from an uninoculated, 97-d-old mouse (None) is shown as a control. (B–K) PK-resistant PrPSc in the inocula (Inoc.), and after 1st and 2nd passages in Tg(M109) mice. Inocula were sCJD(MM1) (B); sCJD(MM2) (C); sCJD(VV2) (D); vCJD (E); BSE (F); CWD (G); scrapie SSBP/1 (H); Sc237 (I); RML (J); 301V(A) or 301V(B) (K) prions. With the exception of 301V, the electrophoretic mobility of PK-resistant PrPSc for each strain following passage in Tg(M109) mice was similar to the original isolate. In all panels, loading quantities were adjusted prior to immunoblotting to give similar signal intensities across all samples. Molecular weight measurements are shown in kDa. PrP was detected using the antibody HuM-P.
Figure 2
Figure 2. Patterns of cerebral PrPSc deposition in Tg(M109) mice inoculated with diverse prion isolates.
Patterns of PrPSc deposition in the brain following first (left column) and second (right column) passage of sCJD(MM1) (A, B); sCJD(VV2) (C, D); vCJD (E, F); BSE (G, H); CWD (I, J); scrapie SSBP/1 (K, L); Sc237 (M, N); RML (O, P); or 301V(A) (Q, R) prions in Tg(M109) mice. For individual prion isolates, patterns of PrPSc deposition were maintained upon serial passage in Tg(M109) mice and were generally reminiscent of the PrPSc deposition characteristics of the original isolates. Brain regions with characteristic PrPSc deposition for the inoculum are shown: Bs, brainstem; FC, frontal cortex; Mb, midbrain; Th, thalamus; Hp, hippocampus. PrPSc deposits were detected using the antibody HuM-D18. Scale bar in A represents 50 µm and applies to all panels.
Figure 3
Figure 3. Conformational stability measurements of Tg(M109)-passaged prion isolates.
Conformational stability assays were performed on the original prion isolates used as inocula (Inoc.) and on brain homogenates from clinically ill Tg(M109) mice following two passages of sCJD(MM1) (A), sCJD(VV2) (B), vCJD (C), BSE (D), CWD (E), Sc237 (F), or RML (G) prions. The calculated GdnHCl1/2 values for each isolate remained similar. For all panels, molecular weight measurements are shown in kDa. PK-resistant PrPSc was detected using the antibody HuM-P.
Figure 4
Figure 4. Analysis of PK-resistant PrPSc and cerebral PrPSc deposition following retrotransmission of Tg(M109)-passaged prion isolates.
Following retrotransmission of Tg(M109)-passaged prion isolates, the biochemical characteristics (A–D) and deposition patterns (E–J) of PrPSc were similar. sCJD(MM1) (A, E, F); Sc237 (B, G, H); RML (C, I, J); and 301V(A) (D) prions were respectively injected into Tg(HuPrP), Tg(SHaPrP), Tg(MoPrP), and Tg(MoPrP) mice. The same inocula were also passaged once in Tg(M109) mice, then injected into the same respective lines. In the immunoblots, the electrophoretic mobility and glycosylation profile are identical in mice infected with the original inoculum and with the inoculum passaged in Tg(M109) mice. Each of the duplicate lanes for the retrotransmission samples represents an individual mouse. PK-resistant PrPSc was detected using the antibody HuM-P. In the micrographs, PrPSc was detected in the brainstem using antibody 3F4 (E–F) and in the hippocampus using antibody HuM-D18 (G–J). In panels A–D, molecular weight measurements are shown in kDa. Scale bar in E represents 50 µm and applies to panels F–J.
Figure 5
Figure 5. Prion strain diversity following passage of sCJD(MM1) and CWD prions in Tg(I109) mice.
(A) Age-adjusted Kaplan-Meier survival curves for Tg(I109) mice inoculated with sCJD(MM1) prions (two independent cases) or sCJD(MM1) prions that were passaged in Tg(HuPrP) mice (green lines, n = 6–7 each); CWD prions (blue line, n = 7); Sc237 prions (orange line, n = 7); or RML prions (red line, n = 8). There was substantial overlap between the appearance of spontaneous signs of neurologic illness in uninoculated Tg(I109) mice (black line, n = 13) and the survival of Tg(I109) mice inoculated with CWD and sCJD(MM1) prions. For all inoculation experiments, the mice were inoculated at ∼60 days of age. (B–H) Analysis of PK-resistant PrPSc in the brains of Tg(I109) mice inoculated with sCJD(MM1) (C, D); sCJD(MM1) prions that were passaged in Tg(HuPrP) mice (E); CWD (F); Sc237 (G); and RML prions (H). With the exception of one lane in panel B (−), all samples were digested with PK. All inoculation experiments resulted in the generation of PK-resistant PrPSc. Brain homogenate from an uninoculated, 171-d-old asymptomatic Tg(I109) mouse (None) is shown as a control. In panels C–H, each lane represents the PK-resistant PrPSc in the brain of an individual animal within the experiment. For each prion isolate, PK-resistant PrPSc in the brain of an infected Tg(M109) mouse is shown for comparison. Whereas inoculation of Tg(I109) mice with RML or Sc237 prions resulted in PK-resistant PrPSc conformers with the same electrophoretic mobility as those present in Tg(M109) mice (black arrows), inoculation with CWD or sCJD(MM1) isolates resulted in the emergence of novel PK-resistant PrPSc conformers with different electrophoretic mobilities (red arrows) in some animals. For all immunoblots, loading quantities were adjusted prior to immunoblotting to give similar signal intensities across all samples. Lowercase letters below blots identify samples referred to in the main text. In panels B–H, molecular weight measurements are shown in kDa. PrP was detected using the antibody HuM-P.
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