Crossing Species Barriers Relies on Structurally Distinct Prion Assemblies and Their Complementation

Abstract

Background: Prion replication results from the autocatalytic templated assisted conversion of the host-encoded prion protein PrPC into misfolded, polydisperse PrPSc conformers.Structurally distinct PrPSc conformers can give rise to multiple prion strains. Within and between prion strains, the biological activity (replicative efficacy and specific infectivity) of PrPSc assemblies is size dependent and thus reflects an intrinsic structural heterogeneity. The contribution of such PrPSc heterogeneity across species prion adaptation, which is believed to be based on fit adjustment between PrPSc tem-plate(s) and host PrPC, has not been explored.To define the structural-to-fitness PrPSc landscape, we measured the relative capacity of sizefractionated PrPSc assemblies from different prion strains to cross mounting species barriers in transgenic mice expressing foreign PrPC. In the absence of a transmission barrier, the relative efficacy of the isolated PrPSc assemblies to induce the disease is like the efficacy observed in the homotypic context. However, in the presence of a transmission barrier, size fractionation overtly delays and even abrogates prion pathogenesis in both the brain and spleen tissues, independently of the infectivity load of the isolated assemblies. Altering by serial dilution PrPSc assembly content of non-fractionated inocula aberrantly reduces their specific infectivity, solely in the presence of a transmission barrier. This suggests that synergy between structurally distinct PrPSc assemblies in the inoculum is requested for crossing the species barrier. Our data support a mechanism whereby overcoming prion species barrier requires complementation between structurally distinct PrPSc assemblies. This work provides key insight into the "quasispecies" concept applied to prions, which would not necessarily rely on prion substrains as constituent but on structural PrPSc heterogeneity within prion population.

Prion potentiation after life-long dormancy in mice devoid of PrP

“…This 400-day limit is consistent with the fact that in all our end-point titrations performed so far (in the homotypic PrP context), the incubation period fold increase between the incubation duration at the lowest and at the limiting dilution is 2.17 ± 0.32. 8 Applying this value to MM1-sCJD titration (mean incubation duration between 150 and 160 days) 30 , 47 would result in a theoretical incubation duration value at the limiting dose between ∼280 and ∼400 days. This 400-day limit is also consistent with MM1-sCJD end-point titrations with other transgenic mouse lines expressing human PrP.…”

“… 70 The third one which is linked to recent compelling evidence that prion assemblies are not a continuum of assemblies of different size with the same core structure. 7 , 8 , 12 , 13 , 71 , 72 Synergies between these sub-assemblies are key to prion replication, diversification, and adaptation. A simple urea-induced disassembling process 7 , 13 or dilution process 8 can alter certain sub-assemblies with respect to their conformation, impacting directly prion biological activity.…”

“… 7 PrP Sc assembly diversification may occur during the pathogenesis and participate to neurotoxicity and adaptation. 8–12 At the molecular level, PrP Sc assemblies are formed from elementary bricks of PrP. 13 These sub-elements, termed suPrP are of low-size and exhibit strong resistance to denaturant treatments such as urea.…”

Characterizing the demographic history and prion protein variation to infer susceptibility to chronic wasting disease in a naïve population of white-tailed deer (Odocoileus virginianus)

“…Conversely, we might also expect the homogenous population to facilitate the spread of CWD if anthropogenic activity were to introduce the disease into the focal population (Escobar et al, 2020). The movement of infected wildlife might also pose a potential risk to human health at the wildlife-human-livestock interface as CWD can cross species barriers (Igel-Egalon et al, 2020). Sustained monitoring across CWD-free regions where deer are managed for sustainability or where food security is threatened should continue, but consider population-level responses to climate change (i.e.…”

Zombie deer and the species barrier. Should humans worry about it?

“…Cross-species transmissions require certain cellular similarities [6]. An invading prion conformer may carry disease if it has certain structural features, the most important of which are the loop region between the β-sheet 2 and α-helix 2 [7].…”