Chronic Wasting Disease Prion Strain Emergence and Host Range Expansion

Human and mouse prion proteins share a structural motif that regulates resistance to common chronic wasting disease (CWD) prion strains. Successful transmission of an emergent strain of CWD prion, H95+, into mice resulted in infection. Thus, emergent CWD prion strains may have higher zoonotic potential than common strains.

Human and mouse prion proteins share a structural motif that regulates resistance to common chronic wasting disease (CWD) prion strains. Successful transmission of an emergent strain of CWD prion, H95 + , into mice resulted in infection. Thus, emergent CWD prion strains may have higher zoonotic potential than common strains. C hronic wasting disease (CWD) is a contagious prion previously identified 2 strains of CWD prion in white-tailed deer (3), Wisc-1 and H95 + ; these strains exhibit distinct biological properties in deer and transgenic cervidized mice. To ascertain the host range of different strains from cervids, we inoculated CWD prions isolated from experimentally infected deer with different PRNP genotypes (Q95G96 [wild type (wt)], S96/wt, H95/wt, and H95/S96) and from elk (CWD2 strain) into hamsters and mice. All isolates have been successfully transmitted into transgenic mice expressing wt cervid PrP and contain high titers of CWD prions (3).
In contrast to mice, hamsters succumbed to clinical disease when inoculated with Wisc-1 CWD prions but were less susceptible to H95 + CWD prions (Table). Clinical signs of CWD in hamsters began with lethargy and, upon arousal, retrocollis; as the disease progressed, lethargy declined with increased dystonic movement including ataxia and tremors. Hyperesthesia was not observed. Subclinical disease (no clinical signs but PrP-res positive by Western blot) was observed in a subset of hamsters (online Technical Appendix).
Successful interspecies prion transmission at the molecular level depends on the compatibility of the invading prion conformers and structural determinants imposed by host PrP C . One structural motif is the loop region between β sheet 2 and α helix 2 of PRP C at aa 170-174 (online Technical Appendix). Host species containing PrP C molecules with a flexible β2-α2 loop (mice and humans) are hypothesized to be incompatible with prions derived from species containing a rigid loop (deer and elk) (4,5). Previous attempts to transmit CWD to mice have failed (6,7). Our data show that prions from a prototypic rigid-loop species (deer) can transmit to a flexible-loop species (mice). The transmission is strain dependent. H95 + overrides the conformational restriction imposed by the mouse PrP flexible loop that Wisc-1 and CWD2 cannot overcome, suggesting that the invading prion strain is a dominant contributor to the species/transmission barrier. How the N terminal amino acid polymorphism (Q95H) affects the conformation of PrP, altering the deer-to-mouse transmission barrier, is unknown. Further structural studies may clarify the effect of N terminal residues on β2-α2 loop rigidity.
Transmission of H95 + CWD prions to mice further confirms the value of specifying strain when defining species barriers. Experimental transmission of CWD prion into macaques and transgenic mice expressing human PrP suggests a considerable transmission barrier to CWD prions (although squirrel monkeys are susceptible), and human prion protein is converted inefficiently in vitro (8,9). Successful infection of a flexible-loop species (mice) with H95 + CWD raises concerns for the potential pathogenicity of H95 + prions to other flexible-loop species. Transmission studies with Wisc-1 and H95 + in transgenic humanized and bovinized mice are ongoing.
The increasing prevalence of CWD indicates selection for cervids with resistance alleles, such as S96 and H95. Genetic resistance to a given prion strain selects for the emergence of novel prion strains with altered properties such as H95 + and Nor98 (3,10). The iterative transmission of CWD prions to cervids with protective alleles of PrP C and the consequent emergence of new CWD prion strains highlights the dynamics of the CWD panzootic and the value of characterizing the host range of emergent CWD prion strains.