Bovine adapted transmissible mink encephalopathy is similar to L-BSE after passage through sheep with the VRQ/VRQ genotype but not VRQ/ARQ

Authors: Cassmann, Eric; MOORE, SARA, J, SARA - Orise Fellow; KOKEMULLAR, ROBYN - Non ARS Employee; BALKEMA-BUSCHMAN, A - Friedrich-Loeffler-institute; GROSCHUP, M - Friedrich-Loeffler-institut; Nicholson, Eric; Greenlee, Justin

Submitted to: BMC Veterinary Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/2/2020
Publication Date: 10/8/2020
Citation: Cassmann, E.D., Moore, Sara, J, S.J., Kokemullar, R.D., Balkema-Buschman, A., Groschup, M., Nicholson, E.M., Greenlee, J.J. 2020. Bovine adapted transmissible mink encephalopathy is similar to L-BSE after passage through sheep with the VRQ/VRQ genotype but not VRQ/ARQ. BMC Veterinary Research. 16. Article 383. https://doi.org/10.1186/s12917-020-02611-0.
DOI: https://doi.org/10.1186/s12917-020-02611-0

Interpretive Summary: Transmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal brain diseases that affect livestock species. A prion disease of cattle known as Mad Cow Disease, or classical bovine spongiform encephalopathy (C-BSE), broke out in the UK from 1986-1998. The disease affected millions of cattle and over 180,000 were confirmed positive. Food products from affected cattle that were consumed by humans led to a disease in people called variant Creutzfeldt-Jakob disease. Another example of cross-species transmission occurs in mink. Mink that are fed prion contaminated food results in a disease called transmissible mink encephalopathy (TME). The present study was designed to determine the effect of cross-species transmission of prion diseases in livestock on the ability to infect mice expressing the cattle prion protein. We found that passing cattle adapted TME prions from cattle to sheep changed the ability of the prions to infect mice. These results were compared to atypical BSE (L-BSE type) and Classical BSE. Depending on the genotype of sheep used, the disease in mice appeared similar to either L-BSE or C-BSE. These results indicate a shift in the disease outcome based on transmission through sheep with different genotypes. This information gives insight into the genesis of new prion strains. It also supports the hypothesis that TME can originate from feeding mink protein from cattle afflicted with L-BSE.

Technical Abstract: Transmissible mink encephalopathy (TME) is a fatal neurologic disease of farmed mink. Epidemiological and experimental evidence indicates that TME and L-BSE are similar and may be linked in some outbreaks of TME. We previously transmitted bovine adapted TME (bTME) to sheep; the present study compared ovine bTME (o-bTME) to C-BSE and L-BSE in transgenic mice expressing wild type bovine prion protein (TgBovXV). Sheep donor genotype elicited variable disease phenotypes in bovinized mice. Inoculum derived from a sheep with the VRQ/VRQ genotype (o-bTMEVV) resulted in an attack rate, incubation period, immunoblot profile, and neuropathology most similar to bTME and L-BSE. Conversely, sheep with the VRQ/ARQ genotype (o-bTMEAV) elicited a phenotype distinct from the bTME and L-BSE. Instead, o-bTMEAV led to a disease phenotype with partial similarity to C-BSE. To determine the transmission efficiency of all TSEs in this study, we considered attack rate, mean incubation period, and the relative quantity of PrPSc in the samples. The TSE with the highest transmission capability in bovinized mice was L-BSE. The tendency to efficiently transmit to TgBovXV mice decreased in the following order bTME, C-BSE, o-bTMEVV, and o-bTMEAV. The transmission efficiency of L-BSE was approximately 1.3 times higher than o-bTMEVV and 4 times higher than o-bTMEAV. Our findings provide insight on how sheep host genotype modulates strain genesis and influences interspecies transmission characteristics. Given the similarities between TME and L-BSE, their efficient interspecies transmission capabilities, and previous reports of L-BSE transmission to mice expressing the human prion protein, continued monitoring for atypical BSE is advisable in order to prevent occurrences of interspecies transmission that may affect humans or other species.