Minor prion substrains overcome transmission barriers

Authors: STEADMAN, BENJAMIN - Creighton University; Bian, Jifeng; SHIKIYA, RONALD - Creighton University; BARTZ, JASON - Creighton University

Submitted to: mBio
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/26/2024
Publication Date: N/A
Citation: N/A

Interpretive Summary: Prion diseases are a group of devastating transmissible brain disorders affecting both animals and humans, caused by a misfolded version of a host cellular prion protein. Research suggests that prions exist in different forms, with one main strain and several minor strains. While we know prions can infect different species, we don’t fully understand how much the minor strains contribute to the interspecies transmission. Previously, we discovered that a hamster prion strain, known as drowsy (DY) contains several minor strains. In this study, we found that these minor strains can readily infect hamster prion protein-expressing cells whereas the DY main strain could not. Using a method called protein misfolding cyclic amplification (PMCA), we observed that these minor strains significantly differ in their efficiency at causing prion disease in hamster compared to the DY main strain. Interestingly, when we attempted to use the DY main strain to convert mouse prion protein using PMCA, it was unsuccessful. However, the minor strains we isolated from DY readily converted mouse prion protein in vitro. The data indicate that these minor prion strains might play a key role in prions jumping from one species to another. This finding helps us better understand how prions jump from one species to another and highlights the importance of considering all prion types when assessing the risk of prion diseases spreading to humans or other animals.

Technical Abstract: Prion diseases are infectious neurodegenerative diseases caused by the self-templating form of the prion protein, PrPSc. Much evidence supports the hypothesis that prions exist as a mixture of a dominant strain and minor prion strains. While it is known that prions can infect new species, the relative contribution of the dominant prion strain and minor strains in crossing the species barrier is unknown. We previously identified preexisting minor prion strains from a biologically cloned drowsy (DY) strain of hamster-adapted transmissible mink encephalopathy (TME). Here we show that these minor prion strains have increased transmission efficiency to RK13 cells that express hamster PrPC compared to the parental strain DY TME. Using protein misfolding cyclic amplification (PMCA), we found that the PMCA seeding efficiency for the minor prion strains tested was significantly different from each other, from the long-incubation parental strain DY TME, and from the short-incubation period prion strain HY TME. This suggests that substrain diversity may be greater than previously anticipated. Interspecies PMCA using the parental strain DY TME failed to convert mouse PrPC to PrPSc, even after several serial passages. In contrast, the minor prion strains isolated from biologically cloned DY TME robustly converted mouse PrPC to PrPSc in the first round of PMCA. This observation suggests that minor prion strains from the mutant spectra may contribute to crossing the species barrier. This further expands our understanding of the mechanisms underlying the species barrier effect and has implications for assessing the zoonotic potential of prions.