Propagation of distinct CWD prion strains during peripheral and intracerebral challenges of gene-targeted mice

Authors: JOSEPH, DEFRANCO - Colorado State University; Bian, Jifeng; SEHUN, KIM - Colorado State University; JENNA, CROWELL - Colorado State University; TOMAS, BARRIO - Colorado State University; BAILEY, WEBSTER - Colorado State University; ZOE, ATKINS - Colorado State University; GLENN, TELLING - Colorado State University

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/23/2024
Publication Date: 7/31/2024
Citation: Joseph, D.P., Bian, J., Sehun, K., Jenna, C., Tomas, B., Bailey, W.K., Zoe, A.N., Glenn, T.C. 2024. Propagation of distinct CWD prion strains during peripheral and intracerebral challenges of gene-targeted mice. Proceedings of the National Academy of Sciences (PNAS). https://doi.org/10.1073/pnas.2402726121.
DOI: https://doi.org/10.1073/pnas.2402726121

Interpretive Summary: Prion disease is a deadly brain disorder that affects both humans and animals. It occurs when a normal prion protein of the host incorrectly folds into an abnormal shape and starts to spread, causing damage to the brain. Chronic wasting disease (CWD) is a highly contagious prion disease of cervids in North America, South Korea, and Scandinavian countries. Abnormal CWD prions transmit through direct contact with infected animals, or the contaminated soil, grass, or water. Scientists typically study CWD by injecting abnormal prions into the brain of susceptible animals. Intracranial prion injections are favored because they typically produce shorter incubation periods and higher disease attack rates. However, our research suggests that this inoculation method can cause the prion strains to change in a way that does not accurately reflect how the disease spreads naturally. Instead, we found that using a combination of peripheral inoculation (injection outside the brain) and novel gene-targeted mice gives a more accurate picture of how CWD behaves in the real world. Our study also provides an important strategy to precisely assess the zoonotic potentials of CWD and other animal prion diseases during natural routes of transmission using gene-targeted mice.

Technical Abstract: Prion strain phenotypes, which are enciphered by the conformations of their constituent infectious proteins, are subject to adaptation in response to selective pressures. While certain prions, including those causing chronic wasting disease (CWD), replicate in both peripheral and central nervous system tissues, their strain properties are thought to remain constant when propagated by these different routes of infection. To examine this notion in the context of CWD, we inoculated gene-targeted GtE and GtQ mice expressing physiologically accurate levels of elk or deer PrP by peripheral or intracerebral routes. Whereas oral and intraperitoneal transmissions preserved the convergent conformations of elk and deer prions and produced identical neuropathological outcomes in cognate GtE and GtQ mice, intracerebral transmissions generated divergent conformers with strain properties that were unrelated to their native counterparts. While CWD replication kinetics remained unchanged during iterative peripheral transmissions and brain titers reflected those found in native hosts, intracerebral transmissions produced 10-fold higher titers and accelerated incubation times during serial passages. Our findings that peripherally- and intracerebrally-challenged Gt mice propagate distinct CWD strain conformers reveal that prions adapt in response to varying routes of transmission. This discovery is consistent with the selection of optimized conformers from strain mixtures by tissue-specific factors. Since peripheral transmissions in Gt mice preserved the natural features of elk and deer prions whereas adaptive events during intracerebral propagation produced distorted strain estimates, our findings underscore the importance of experimental characterizations in hosts that not only abrogate species barriers but also recapitulate natural transmission routes of native strains.