Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
PLoS Pathog. 2018 Jun 21;14(6):e1007093. doi: 10.1371/journal.ppat.1007093. eCollection 2018 Jun.
The main risk of emergence of prion diseases in humans is associated with a cross-species transmission of prions of zoonotic origin. Prion transmission between species is regulated by a species barrier. Successful cross-species transmission is often accompanied by strain adaptation and result in stable changes of strain-specific disease phenotype. Amino acid sequences of host PrPC and donor PrPSc as well as strain-specific structure of PrPSc are believed to be the main factors that control species barrier and strain adaptation. Yet, despite our knowledge of the primary structures of mammalian prions, predicting the fate of prion strain adaptation is very difficult if possible at all. The current study asked the question whether changes in cofactor environment affect the fate of prions adaptation. To address this question, hamster strain 263K was propagated under normal or RNA-depleted conditions using serial Protein Misfolding Cyclic Amplification (PMCA) conducted first in mouse and then hamster substrates. We found that 263K propagated under normal conditions in mouse and then hamster substrates induced the disease phenotype similar to the original 263K. Surprisingly, 263K that propagated first in RNA-depleted mouse substrate and then normal hamster substrate produced a new disease phenotype upon serial transmission. Moreover, 263K that propagated in RNA-depleted mouse and then RNA-depleted hamster substrates failed to induce clinical diseases for three serial passages despite a gradual increase of PrPSc in animals. To summarize, depletion of RNA in prion replication reactions changed the rate of strain adaptation and the disease phenotype upon subsequent serial passaging of PMCA-derived materials in animals. The current studies suggest that replication environment plays an important role in determining the fate of prion strain adaptation.
朊病毒疾病在人类中的主要风险与源于动物的朊病毒的跨物种传播有关。物种间的朊病毒传播受到物种屏障的调节。跨物种的成功传播通常伴随着菌株适应，导致菌株特异性疾病表型的稳定变化。宿主 PrPC 和供体 PrPSc 的氨基酸序列以及 PrPSc 的菌株特异性结构被认为是控制物种屏障和菌株适应的主要因素。然而，尽管我们了解哺乳动物朊病毒的主要结构，但预测朊病毒菌株适应的命运是非常困难的，如果可能的话。本研究提出了这样一个问题，即辅助因子环境的变化是否会影响朊病毒适应的命运。为了解决这个问题，使用连续的蛋白质错误折叠循环扩增（PMCA），首先在小鼠底物中，然后在仓鼠底物中，在正常或 RNA 耗尽的条件下繁殖仓鼠株 263K。我们发现，在正常条件下在小鼠底物中繁殖然后在仓鼠底物中繁殖的 263K 诱导出与原始 263K 相似的疾病表型。令人惊讶的是，首先在 RNA 耗尽的小鼠底物中繁殖然后在正常仓鼠底物中繁殖的 263K 在连续传代后产生了新的疾病表型。此外，尽管动物中 PrPSc 逐渐增加，但在 RNA 耗尽的小鼠和然后在 RNA 耗尽的仓鼠底物中繁殖的 263K 在连续传代 3 次后未能引起临床疾病。总之，在动物中进行 PMCA 衍生材料的连续传代时，朊病毒复制反应中 RNA 的缺失改变了菌株适应的速度和疾病表型。目前的研究表明，复制环境在决定朊病毒菌株适应的命运方面起着重要作用。
