Bocharova Olga, Makarava Natallia, Pandit Narayan P, Molesworth Kara, Baskakov Ilia V
Center for Biomedical Engineering and Technology, Baltimore, Maryland, USA.
Department of Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
bioRxiv. 2023 Oct 27:2023.10.24.563743. doi: 10.1101/2023.10.24.563743.
The transmission of prions across species is a critical aspect of their dissemination among mammalian hosts, including humans. This process often necessitates strain adaptation. In this study, we sought to investigate the mechanisms underlying prion adaptation while mitigating biases associated with the history of cross-species transmission of natural prion strains. To achieve this, we utilized the synthetic hamster prion strain S05. Propagation of S05 using mouse PrP in Protein Misfolding Cyclic Amplification did not immediately overcome the species barrier. This finding underscores the involvement of factors beyond disparities in primary protein structures. Subsequently, we performed five serial passages to stabilize the incubation time to disease in mice. The levels of PrP increased with each passage, reaching a maximum at the third passage, and declining thereafter. This suggests that only the initial stage of adaptation is primarily driven by an acceleration in PrP replication. During the protracted adaptation to a new host, we observed significant alterations in the glycoform ratio and sialylation status of PrP N-glycans. These changes support the notion that qualitative modifications in PrP contribute to a more rapid disease progression. Furthermore, consistent with the decline in sialylation, a cue for "eat me" signaling, the newly adapted strain exhibited preferential colocalization with microglia. In contrast to PrP dynamics, the intensity of microglia activation continued to increase after the third passage in the new host. In summary, our study elucidates that the adaptation of a prion strain to a new host is a multi-step process driven by several factors.
朊病毒在物种间的传播是其在包括人类在内的哺乳动物宿主中扩散的一个关键方面。这一过程通常需要毒株适应。在本研究中，我们试图探究朊病毒适应的潜在机制，同时减轻与天然朊病毒毒株跨物种传播历史相关的偏差。为实现这一目标，我们使用了合成仓鼠朊病毒毒株S05。在蛋白质错误折叠循环扩增中使用小鼠PrP来繁殖S05并不能立即克服物种屏障。这一发现强调了除一级蛋白质结构差异之外的其他因素的参与。随后，我们进行了五次连续传代，以稳定小鼠发病的潜伏期。每次传代时PrP水平都会升高，在第三次传代时达到最高，此后下降。这表明只有适应的初始阶段主要由PrP复制加速驱动。在对新宿主的长期适应过程中，我们观察到PrP N -聚糖的糖型比例和唾液酸化状态发生了显著变化。这些变化支持了PrP的定性修饰有助于疾病更快进展这一观点。此外，与唾液酸化下降一致，“吃我”信号的一个提示，新适应的毒株表现出与小胶质细胞的优先共定位。与PrP动态变化不同，在新宿主中第三次传代后小胶质细胞激活的强度持续增加。总之，我们的研究阐明了朊病毒毒株对新宿主的适应是一个由多种因素驱动的多步骤过程。
