Host prion protein expression levels impact prion tropism for the spleen

Abstract

AbstractPrions are pathogens formed from abnormal conformers (PrPSc) of the host-encoded cellular prion protein (PrPC). PrPScconformation 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 PrPCexpression 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 PrPCin the brain resulted in the phenotypic expression of the dominant sheep substrain in mice expressing near physiological PrPClevels, whereas a minor substrain replicated preferentially on high-expressors. Considering that PrPCexpression levels are markedly decreased in the spleen compared to the brain, we interrogate whether spleen PrPCdosage 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 PrPCamount; There was a prominent spleen colonization by the substrain preferentially replicating on low-expressors and a relative incapacity of the substrain with higher-PrPClevel 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 PrPCexpression levels are instrumental in prion substrain lymphotropism.Author summaryThe cause of prion phenotype variation among prion strains remains poorly understood. In particular prions replicate in a strain-dependent manner in the spleen. This can result in prion asymptomatic carriers. Based on our previous observations that dosage of the prion precursor (PrP) determined prion substrain selection in the brain, we examine whether PrP levels in the spleen could drive prion replication in this tissue, due to the low levels of the protein. We observe that the prion substrain with higher PrP need for replication did barely replicate in the spleen, while the component with low PrP need replicated efficiently. In addition, other human co-propagating prions with differing spleen and brain tropism showed different tropism on transmission to mice expressing low PrP levels, with the lymphoid substrain colonizing the brain. PrPCexpression levels may thus be instrumental in prion tropism for the lymphoid tissue. From a diagnostic point of view, given the apparent complexity of prion diseases with respect to prion substrain composition, these data advocate to type extraneural tissues or fluids for a comprehensive identification of the circulating prions in susceptible mammals.