Deer Prion Proteins Modulate the Emergence and Adaptation of Chronic Wasting Disease Strains
ABSTRACTTransmission of chronic wasting disease (CWD) between cervids is influenced by the primary structure of the host cellular prion protein (PrPC). In white-tailed deer,PRNPalleles encode the polymorphisms Q95 G96 (wild type [wt]), Q95 S96 (referred to as the S96 allele), and H95 G96 (referred to as the H95 allele), which differentially impact CWD progression. We hypothesize that the transmission of CWD prions between deer expressing different allotypes of PrPCmodifies the contagious agent affecting disease spread. To evaluate the transmission properties of CWD prions derived experimentally from deer of fourPRNPgenotypes (wt/wt, S96/wt, H95/wt, or H95/S96), transgenic (tg) mice expressing the wt allele (tg33) or S96 allele (tg60) were challenged with these prion agents. Passage of deer CWD prions into tg33 mice resulted in 100% attack rates, with the CWD H95/S96 prions having significantly longer incubation periods. The disease signs and neuropathological and protease-resistant prion protein (PrP-res) profiles in infected tg33 mice were similar between groups, indicating that a prion strain (Wisc-1) common to all CWD inocula was amplified. In contrast, tg60 mice developed prion disease only when inoculated with the H95/wt and H95/S96 CWD allotypes. Serial passage in tg60 mice resulted in adaptation of a novel CWD strain (H95+) with distinct biological properties. Transmission of first-passage tg60CWD-H95+isolates into tg33 mice, however, elicited two prion disease presentations consistent with a mixture of strains associated with different PrP-res glycotypes. Our data indicate that H95-PRNPheterozygous deer accumulated two CWD strains whose emergence was dictated by the PrPCprimary structure of the recipient host. These findings suggest that CWD transmission between cervids expressing distinct PrPCmolecules results in the generation of novel CWD strains.IMPORTANCECWD prions are contagious among wild and captive cervids in North America and in South Korea. We present data linking the amino acid variant Q95H in white-tailed deer cellular prion protein (PrPC) to the emergence of a novel CWD strain (H95+). We show that, upon infection, deer expressing H95-PrPCmolecules accumulated a mixture of CWD strains that selectively propagated depending on thePRNPgenotype of the host in which they were passaged. Our study also demonstrates that mice expressing the deer S96-PRNPallele, previously shown to be resistant to various cervid prions, are susceptible to H95+CWD prions. The potential for the generation of novel strains raises the possibility of an expanded host range for CWD.