Novel strain of the chronic wasting disease agent isolated from experimentally inoculated elk with LL132 prion protein

Authors: MOORE, S J - Orise Fellow; Tatum, Trudy; Hwang, Soyoun; Vrentas, Catherine; WEST GREENLEE, M - Iowa State University; KONG, QINGZHONG - Case Western Reserve University (CWRU); Nicholson, Eric; Greenlee, Justin

Submitted to: Nature Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/4/2020
Publication Date: 2/21/2020
Citation: Moore, S., Tatum, T.L., Hwang, S., Vrentas, C.E., West Greenlee, M.H., Kong, Q., Nicholson, E.M., Greenlee, J.J. 2020. Novel strain of the chronic wasting disease agent isolated from experimentally inoculated elk with LL132 prion protein. Nature Scientific Reports. 10:1-13. Article 3148. https://doi.org/10.1038/s41598-020-59819-1.
DOI: https://doi.org/10.1038/s41598-020-59819-1

Interpretive Summary: Chronic wasting disease (CWD) is a fatal disease of deer and elk that causes damaging changes in the brain. The infectious agent is an abnormal protein called a prion that has misfolded from its normal state. Whether or not an elk will get CWD is affected by their genetics. This study evaluated transmission of abnormal prion protein from elk of 3 different genotypes that were infected with CWD to transgenic mice expressing the elk prion protein. Previous work demonstrated that there are differences in incubation periods, patterns of abnormal prion accumulation in the brain, and fibril stability features in these different genotypes of elk. This study demonstrates that elk donor genotype-associated differences in relative incubation periods, fibril stability, and lesions in the brain were maintained across first and second passages to mice suggesting that these are different CWD strains that may require different approaches for prevention and eradication. This information is useful to wildlife managers and captive wildlife owners that are selectively breeding animals and could impact future regulations for the control of CWD in the U.S.

Technical Abstract: Chronic wasting disease (CWD) is a fatal, transmissible neurodegenerative disease that affects a number of cervid species, including Rocky mountain elk (Cervus elaphus nelsoni). The Rocky Mountain elk prion protein gene exhibits amino acid polymorphism at codon 132, with L132 (leucine) and M132 (methionine) allelic variants present in the population. We previously demonstrated that following experimental oral challenge with CWD the incubation periods of LL132 elk are prolonged, while incubation times for LM132 elk are intermediate, and incubation times for MM132 elk are short. The purpose of this study was to investigate potential mechanisms underlying variations in incubation time in elk of different prion protein genotypes using bioassay in Tg12 mice that express M132 elk prion protein. Groups of mice were inoculated intracranially with brain homogenate from individual elk of each genotype (LL132, LM132, MM132) and were necropsied upon development of clinical disease. Formalin-fixed, paraffin-embedded brains were examined by light microscopy for the presence of spongiform change and accumulation of disease-associated prion protein (PrPSc). Frozen brain tissue was assessed for PrPSc western blot migration (WB) pattern, fibril stability, and amyloid formation rate. On first passage, mice challenged with LL132 elk inoculum had prolonged incubation periods and more stable PrPSc as compared to mice challenged with MM132 or LM132 inoculum. On second passage there was a reduction in between group differences in fibril stability and amyloid formation rate indicating an adaptive change in the conformational properties of PrPSc induced by the mouse model. However, elk donor genotype-associated differences in relative incubation periods, WB profiles, and neuropathology were maintained across first and second passages that suggests that M132 PrPSc is able to propagate some biophysical properties of the L132 conformation. Characterization of CWD strains is important to inform strategies to limit the spread of CWD in captive and free-ranging cervids.