Abstract
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.
Highlights
Mammalian prions are proteinaceous pathogens causing fatal neurodegenerative diseases termed transmissible spongiform encephalopathies (TSE) in humans and animals
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
proteinase K (PK)-resistant PrPSc (PrPres) is 19K-type in the brain but 21K-type in the spleen of high expresser tg338 mice intracerebrally inoculated with LAN sheep scrapie isolates
Summary
Mammalian prions are proteinaceous pathogens causing fatal neurodegenerative diseases termed transmissible spongiform encephalopathies (TSE) in humans and animals. Prion strains exhibit specific incubation periods, stereotyped clinical signs and neuropathology, and specific tropism for regions of the central nervous system (CNS) and the lymphoid tissue (for review [7, 8]). Certain prions can replicate early and at fairly high levels in tissues of the lympho-reticular system such as the Peyer’s patches, spleen and lymph nodes [9,10,11]. Lymphotropic prions are transported from these early reservoirs of infectivity to the brain either by the enteric nervous system (Peyer’s patches) or by the peripheral nervous system and the spinal cord (spleen, lymph nodes) [9, 12, 13]. Of concern are BSE/variant CJD prions which are suspected to accumulate in human lymphoid tissue without neuroinvasion. Of concern are BSE/variant CJD prions which are suspected to accumulate in human lymphoid tissue without neuroinvasion. 1:2000 exposed individuals in the UK may be silent carriers in the lymphoid tissue [25], causing risks of secondary transmission [26]
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