Transmission of
chronic wasting disease (CWD) between cervids is influenced by the primary structure of the host cellular
prion protein (PrP(C)). In white-tailed deer, PRNP alleles 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 PrP(C) modifies the contagious agent affecting disease spread. To evaluate the transmission properties of CWD
prions derived experimentally from deer of four PRNP genotypes (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-PRNP heterozygous deer accumulated two CWD strains whose emergence was dictated by the PrP(C) primary structure of the recipient host. These findings suggest that CWD transmission between cervids expressing distinct PrP(C) molecules results in the generation of novel CWD strains.
IMPORTANCE: CWD
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 (PrP(C)) to the emergence of a novel CWD strain (H95(+)). We show that, upon
infection, deer expressing H95-PrP(C) molecules accumulated a mixture of CWD strains that selectively propagated depending on the PRNP genotype of the host in which they were passaged. Our study also demonstrates that mice expressing the deer S96-PRNP allele, 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.