Primary transmission of chronic wasting disease versus scrapie prions from small ruminants to transgenic mice expressing ovine and cervid prion protein

Authors: MADSEN-BOUTERSE, SALLY - Washington State University; Schneider, David; Zhuang, Dongyue; DASSANAYAKE, ROHANA - Washington State University; BALACHANDRAN, ARU - Canadian Food Inspection Agency; MITCHELL, GORDON - Canadian Food Inspection Agency; O'ROURKE, KATHERINE - Washington State University

Submitted to: Journal of General Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/6/2016
Publication Date: 7/8/2016
Citation: Madsen-Bouterse, S.A., Schneider, D.A., Zhuang, D., Dassanayake, R.P., Balachandran, A., Mitchell, G.B., O'Rourke, K.I. 2016. Primary transmission of chronic wasting disease versus scrapie prions from small ruminants to transgenic mice expressing ovine and cervid prion protein. Journal of General Virology. 97(9):2451-2460.

Interpretive Summary: Developing an assay to identify prion reservoirs that could contribute to re-emergence of disease is critical to scrapie eradication efforts in sheep and goats. Chronic wasting disease (CWD) is a natural prion disease of elk and deer and is regionally endemic in North America. Presently, it is not possible to determine when disease in a small ruminant is caused by CWD and there is debate as to whether this naturally occurs. In this study, brain samples obtained from animals with clinical disease were used to determine if bioassay using two strains of transgenic mice could discriminate infection by these prions. The results demonstrate that only TgElk mice (which express elk prion protein) were robustly susceptible to CWD derived from naturally infected white-tailed deer, and that only Tg338 mice (which express sheep prion protein) were robustly susceptible to scrapie derived from naturally infected sheep or goats. While TgElk mice were also robustly susceptible to CWD derived from experimentally infected sheep, this source of prions caused only minimal evidence of infection in Tg338 mice before the study endpoint (500 days). Thus, this two mouse strain bioassay could differentiate between clinical infections of sheep with these prion isolates, demonstrating potential usefulness to surveillance efforts when there is the theoretical possibility of natural CWD transmission to sheep and goats.

Technical Abstract: Identifying transmissible spongiform encephalopathy (TSE) reservoirs that could lead to disease re-emergence is imperative to U.S. scrapie eradication efforts. Transgenic mice expressing the cervid (TgElk) or ovine (Tg338) prion protein have aided characterization of chronic wasting disease (CWD) and scrapie, respectively. This study describes transmission of classical scrapie versus CWD-origin prions from small ruminants (goats or sheep) with clinical TSE disease to TgElk and Tg338 mice. Transgenic mice (>5/homogenate) inoculated with brain homogenate from small ruminants with naturally-acquired classical scrapie, white-tailed deer with naturally-acquired CWD (WTD-CWD), or sheep experimentally inoculated with elk-CWD (sheep-passaged-CWD) were assessed for clinical signs associated with TSE disease and brain PrPres accumulation. Inoculation with classical scrapie prions resulted in clinical disease and 100'% attack rates in Tg338, but no clinical disease at an endpoint >300'days post inoculation and low attack rates (6.8'%) in TgElk. Inoculation with WTD-CWD prions yielded no clinical disease or brain PrPres accumulation in Tg338 culled at an endpoint >500 days post inoculation, but rapid onset (~121 days post inoculation) of clinical disease and 100'% attack rate in TgElk. Sheep-passaged-CWD resulted in transmission to both mouse lines with 100'% attack rates at endpoint in Tg338 and an attack rate of ~73'% in TgElk with some culled due to clinical disease. Thus, primary transmission of the inocula tested here demonstrates the potential of bioassay in Tg338 and TgElk mice to help differentiate possible infection with CWD versus classical scrapie prions in sheep and goats.