Generation of human chronic wasting disease in transgenic mice

Authors: WANG, ZERUI - Case Western Reserve University (CWRU); QIN, KEFENG - University Of Chicago; CAMACHO, MANUEL - Case Western Reserve University (CWRU); CALI, IGNAZIO - Case Western Reserve University (CWRU); YUAN, JUE - Case Western Reserve University (CWRU); SHEN, PINGPING - Case Western Reserve University (CWRU); GILLILAND, TRICIA - Case Western Reserve University (CWRU); SHAH, SYED ZAHID ALI - Case Western Reserve University (CWRU); GERASIMENKO, MARIA - Case Western Reserve University (CWRU); TANG, MICHELLE - Case Western Reserve University (CWRU); RAJAMANICKAM, SARADA - Case Western Reserve University (CWRU); YADATI, ANIKA - Case Western Reserve University (CWRU); SCHONBERGER, LAWRENCE - Centers For Disease Control And Prevention (CDC) - United States; Greenlee, Justin; KONG, QINGZHONG - Case Western Reserve University (CWRU); MASTRIANNI, JAMES - University Of Chicago; ZOU, WEN-QUAN - Case Western Reserve University (CWRU)

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 6/22/2022
Publication Date: 9/11/2022
Citation: Wang, Z., Qin, K., Camacho, M.V., Cali, I., Yuan, J., Shen, P., Gilliland, T., Shah, S., Gerasimenko, M., Tang, M., Rajamanickam, S., Yadati, A., Schonberger, L.B., Greenlee, J.J., Kong, Q., Mastrianni, J.A., Zou, W. 2022. Generation of human chronic wasting disease in transgenic mice. Prion 2022 Conference abstracts: pushing the boundaries. 16(1):243. https://doi.org/10.1080/19336896.2022.2091286.
DOI: https://doi.org/10.1080/19336896.2022.2091286

Interpretive Summary:

Technical Abstract: Chronic wasting disease (CWD) results from the accumulation of an infectious misfolded conformer (PrPSc) of cellular prion protein (PrPC) in the brains of deer and elk. It has been spreading rapidly throughout many regions of North America, exported inadvertently to South Korea, and more recently identified in Europe. Mad cow disease has caused variant Creutzfeldt-Jakob disease (vCJD) in humans and is currently the only known zoonotic prion disease. Whether CWD is transmissible to humans remains uncertain. The aims of our study were not only to confirm whether CWD prion isolates can convert human brain PrPC into PrPSc in vitro by serial protein misfolding cyclic amplification (sPMCA) but also to determine whether the sPMCA-induced CWD-derived human PrPSc is infectious. Eight CWD prion isolates from 7 elks and 1 deer were used as the seeds while normal human brain homogenates containing either PrP- 129 MM (n = 2) or PrP-129 VV (n = 1) were used as the substrates for sPMCA assay. A normal elk brain tissue sample was used as a negative control seed. Two lines of humanized transgenic (Tg) mice expressing either human PrP-129VV or -129 MM polymorphism were included for transmission studies to determine the infectivity of PMCA-amplified PrPSc. Wester blotting and immunohistochemistry and hematoxylin & eosin staining were used for determining PrPSc and neuropathological changes of inoculated animals. We report here the generation of the first CWD-derived infectious human PrPSc using elk CWD PrPSc to initiate conversion of human PrPC from normal human brain homogenates with PMCA in vitro. Western blotting with a human PrP selective antibody confirmed that the PMCA-generated protease-resistant PrPSc was derived from the human brain PrPC substrate. Two lines of humanized transgenic mice expressing human PrPC with either Val or Met at the polymorphic codon 129 developed clinical prion disease following intracerebral inoculation with the PMCA-generated CWD-derived human PrPSc. Diseased mice exhibited distinct PrPSc patterns and neuropathological changes in the brain. Our study, using PMCA and animal bioassays, provides the first evidence that CWD PrPSc has the potential to overcome the species barrier and directly convert human PrPC into infectious PrPSc that can produce bona fide prion disease when inoculated into humanized transgenic mice.