PrPSc formation and clearance as determinants of prion tropism

Abstract

Prion strains are characterized by strain-specific differences in neuropathology but can also differ in incubation period, clinical disease, host-range and tissue tropism. The hyper (HY) and drowsy (DY) strains of hamster-adapted transmissible mink encephalopathy (TME) differ in tissue tropism and susceptibility to infection by extraneural routes of infection. Notably, DY TME is not detected in the secondary lymphoreticular system (LRS) tissues of infected hosts regardless of the route of inoculation. We found that similar to the lymphotropic strain HY TME, DY TME crosses mucosal epithelia, enters draining lymphatic vessels in underlying laminae propriae, and is transported to LRS tissues. Since DY TME causes disease once it enters the peripheral nervous system, the restriction in DY TME pathogenesis is due to its inability to establish infection in LRS tissues, not a failure of transport. To determine if LRS tissues can support DY TME formation, we performed protein misfolding cyclic amplification using DY PrPSc as the seed and spleen homogenate as the source of PrPC. We found that the spleen environment can support DY PrPSc formation, although at lower rates compared to lymphotropic strains, suggesting that the failure of DY TME to establish infection in the spleen is not due to the absence of a strain-specific conversion cofactor. Finally, we provide evidence that DY PrPSc is more susceptible to degradation when compared to PrPSc from other lymphotrophic strains. We hypothesize that the relative rates of PrPSc formation and clearance can influence prion tropism.

Cofactor and glycosylation preferences for in vitro prion conversion are predominantly determined by strain conformation

“…While the rate of prion formation and clearance has been shown to influence strain tropism at an organ level (i.e. tropism to the brain and spleen) [45], no mechanisms for strain-specific degradation have been identified to date. The PrP Sc glycosylation hypothesis proposes that neurons distinguish between different prion strains based on their PrP Sc glycosylation status.…”

Prion Strains and Transmission Barrier Phenomena

“…Therefore, lymphoid compartment will have a balanced influence on peripherally acquired prion fate: in one hand, macrophage and in particular splenic scavenging functions will actively degrade or neutralize prion infectivity, while, on the other hand, FDCs will actively replicate prions that are then shuttled to the terminal nerves ending near the germinal centres [ 140 ]. Thus, the resulting lymphoid tropism could be the net result from this balance, as claimed recently by Bartz and colleagues [ 141 ], who were able to detect Drowsy infectivity within hours after inoculation but also reported that these prions disappeared thereafter as a consequence of an increased susceptibility to proteases (in vitro PK assay). Prion replication in periphery could otherwise be dictated by strain features.…”

“…Other hypotheses involve a tissue specific clearance metabolism as responsible for the different strain tropism [ 141 ]. As mentioned previously in a former section, the authors describe the successful PMCA amplification of Drowsy TME in the spleen of peripherally-inoculated hamsters, although this strain was not supposed to replicate in that tissue.…”

Independent amplification of co-infected long incubation period low conversion efficiency prion strains

“…Western blot analysis was performed as previously described [ 76 ]. Briefly, samples were digested with 100 U/ml of proteinase K (PK) at 37°C for 30 minutes with constant agitation (Roche Diagnostics Corporation, Indianapolis, IN).…”