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Article Dans Une Revue PLoS Pathogens Année : 2020

Host prion protein expression levels impact prion tropism for the spleen

Résumé

Prions are pathogens formed from abnormal conformers (PrPSc) of the host-encoded cellular prion protein (PrPC). PrPSc conformation to disease phenotype relationships extensively vary among prion strains. In particular, prions exhibit a strain-dependent 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 PrPC expression levels feature in prion substrain selection in the brain. Transmission of sheep scrapie isolates (termed LAN) to multiple lines of transgenic mice expressing varying levels of ovine PrPC in their brains resulted in the phenotypic expression of the dominant sheep substrain in mice expressing near physiological PrPC levels, whereas a minor substrain replicated preferentially on high expresser mice. Considering that PrPC expression levels are markedly decreased in the spleen compared to the brain, we interrogate whether spleen PrPC dosage could drive prion selectivity. The outcome of the transmission of a large cohort of LAN isolates in the spleen from high expresser mice correlated with the replication rate dependency on PrPC amount. There was a prominent spleen colonization by the substrain preferentially replicating on low expresser mice and a relative incapacity of the substrain with higher-PrPC level need to propagate in the spleen. Early colonization of the spleen after intraperitoneal inoculation allowed neuropathological expression of the lymphoid substrain. In addition, a pair of substrain variants resulting from the adaptation of human prions to ovine high expresser mice, and exhibiting differing brain versus spleen tropism, showed different tropism on transmission to low expresser mice, with the lymphoid substrain colonizing the brain. Overall, these data suggest that PrPC expression levels are instrumental in prion lymphotropism. Author summary: The 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 does barely replicate in the spleen, while the component with low PrP need replicates 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. PrPC expression 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.
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hal-02927405 , version 1 (13-04-2021)

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Vincent Béringue, Philippe Tixador, Olivier Andréoletti, Fabienne Reine, Johan Castille, et al.. Host prion protein expression levels impact prion tropism for the spleen. PLoS Pathogens, 2020, 16 (7), pp.e1008283. ⟨10.1371/journal.ppat.1008283⟩. ⟨hal-02927405⟩
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