Prions are pathogens formed from abnormal conformers (PrP Sc ) of the host-encoded cellular prion protein (PrP C ). PrP Sc conformation to disease phenotype relationships extensively vary among prion strains. In particular, prions exhibit a strain-specific tropism for lymphoid tissues. Prions can be composed of several substrain components. There is evidence that these substrains can propagate in distinct tissues (e.g. brain and spleen) of a single individual, providing an experimental paradigm to study the cause of prion tissue selectivity. Previously, we showed that PrP C  expression levels govern prion substrain selection in the brain. Transmission of sheep scrapie isolates (termed LAN) to multiple lines of transgenic mice expressing varying levels of ovine PrP C  in the brain resulted in the phenotypic expression of the dominant sheep substrain in mice expressing near physiological PrP C  levels, whereas a minor substrain replicated preferentially on high-expressors. Considering that PrP C  expression levels are markedly decreased in the spleen compared to the brain, we interrogate whether spleen PrP C  dosage could drive prion selectivity. The outcome of the transmission of a large cohort of LAN-like scrapie isolates in the spleen from high-expressors correlated with the replication rate dependency on PrP C  amount; There was a prominent spleen colonization by the substrain preferentially replicating on low-expressors and a relative incapacity of the substrain with higher-PrP C  level need to propagate in the spleen. Early colonization of the spleen allowed neuropathological expression of the lymphoid substrain after intraperitoneal inoculation. In addition, a pair of substrain variants resulting from the adaptation of human prions to ovine high-expressors, and exhibiting differing brain versus spleen tropism, showed different tropism on transmission to low-expressors, with the lymphoid substrain colonizing the brain. Overall, these data suggest that PrP C  expression levels are instrumental in prion substrain lymphotropism.

Host prion protein expression levels impact prion tropism for the spleen