Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada.
Canadian and WOAH Reference Laboratory for BSE, Canadian Food Inspection Agency, Lethbridge, Canada.
PLoS Pathog. 2024 Jul 8;20(7):e1012370. doi: 10.1371/journal.ppat.1012370. eCollection 2024 Jul.
Prions can exist as different strains that consist of conformational variants of the misfolded, pathogenic prion protein isoform PrPSc. Defined by stably transmissible biological and biochemical properties, strains have been identified in a spectrum of prion diseases, including chronic wasting disease (CWD) of wild and farmed cervids. CWD is highly contagious and spreads via direct and indirect transmission involving extraneural sites of infection, peripheral replication and neuroinvasion of prions. Here, we investigated the impact of infection route on CWD prion conformational selection and propagation. We used gene-targeted mouse models expressing deer PrP for intracerebral or intraperitoneal inoculation with fractionated or unfractionated brain homogenates from white-tailed deer, harboring CWD strains Wisc-1 or 116AG. Upon intracerebral inoculation, Wisc-1 and 116AG-inoculated mice differed in conformational stability of PrPSc. In brains of mice infected intraperitoneally with either inoculum, PrPSc propagated with identical conformational stability and fewer PrPSc deposits in most brain regions than intracerebrally inoculated animals. For either inoculum, PrPSc conformational stability in brain and spinal cord was similar upon intracerebral infection but significantly higher in spinal cords of intraperitoneally infected animals. Inoculation with fractionated brain homogenates resulted in lower variance of survival times upon intraperitoneal compared to intracerebral infection. In summary, we demonstrate that extraneural infection mitigates the impact of PrPSc quaternary structure on infection and reduces conformational variability of PrPSc propagated in the brain. These findings provide new insights into the evolution of stable CWD strains in natural, extraneural transmissions.
朊病毒可以存在不同的株型，这些株型由错误折叠的致病性朊病毒蛋白异构体 PrPSc 的构象变体组成。根据稳定可传播的生物学和生物化学特性来定义，已经在一系列朊病毒疾病中鉴定出了株型，包括野生和养殖鹿的慢性消耗病（CWD）。CWD 具有高度传染性，通过涉及感染的神经外部位、外周复制和朊病毒的神经入侵的直接和间接传播传播。在这里，我们研究了感染途径对 CWD 朊病毒构象选择和传播的影响。我们使用表达鹿 PrP 的基因靶向小鼠模型进行脑内或腹腔内接种，接种物为携带 CWD 株型 Wisc-1 或 116AG 的白尾鹿的分级或未分级脑匀浆。在脑内接种时，Wisc-1 和 116AG 接种的小鼠在 PrPSc 的构象稳定性上存在差异。在通过任何接种物感染的小鼠的大脑中，PrPSc 的传播具有相同的构象稳定性，并且在大多数脑区的 PrPSc 沉积物比脑内接种的动物少。对于任何接种物，脑内接种时脑和脊髓中的 PrPSc 构象稳定性相似，但腹腔内接种的动物的脊髓中的 PrPSc 构象稳定性明显更高。与脑内感染相比，用分级脑匀浆接种会导致腹腔内感染的存活时间变异性降低。总之，我们证明了神经外感染减轻了 PrPSc 四级结构对感染的影响，并降低了在大脑中传播的 PrPSc 的构象变异性。这些发现为在自然的、神经外传播中稳定的 CWD 株型的进化提供了新的见解。
