Role of human enterocytes and the 37 kDa/67 kDa laminin receptor LRP/LR on the develepment of zoonotic prion diseases

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TSEs show a species-specific barrier depending on the kind of the incoming prion strain as well as the kind of target organism to be infected. The species barrier results either in altered disease incubation times, or even insusceptibility to specific prion strains.Recently, we found, that BSE-derived prions bound to and became internalized by human enterocytes, the major cell population of the intestinal epithelium, via the 37 kDa/67 kDa laminin receptor LRP/LR, acting as a receptor for the cellular prion protein PrPc and infectious PrPSc. In contrast, mouse adapted scrapie prions failed to bind to human enterocytes, which can be explained by a possible failure of this prion strain to bind to cell surface LRP/LR. This result might be a first hint that also scrapie prions from sheep might be unable to bind to human enterocytes and therefore, fail to cause a zoonosis.In the proposed study, we will investigate the species-specific entry barrier in the enterocyte cell system addressing the question whether different animal prion strains such as scrapie in sheep and chronic wasting disease (CWD) in elk and deer have the potential to cause a zoonotic disease. The role of LRP/LR in the binding and internalization processes will be investigated. With this in vitro cell system we mimic one of the first steps of non-human prions entering the human body. The intestine might represent the crucial barrier for prions deciding upon the development of a zoonotic prion disease, which might be caused by sheep scrapie and CWD. Very recently, infectious prions have been detected in blood and saliva of deer suffering from CWD. Since this finding enhances the infection risk for humans getting in contact with body fluids from cervids suffering from CWD, the investigation of a possible uptake of CWD prions by human enterocytes might significantly contribute to the estimation of an infection risk of humans by CDW prions.