Centro de Investigación en Sanidad Animal, CISA-INIA, Madrid, Spain.
Centro de Investigación en Sanidad Animal, CISA-INIA, Madrid, Spain
J Virol. 2018 Nov 27;92(24). doi: 10.1128/JVI.01086-18. Print 2018 Dec 15.
Co-occurrence of different prion strains into the same host has been recognized as a natural phenomenon for several sporadic Creutzfeldt-Jakob disease (sCJD) patients and natural scrapie cases. The final outcome of prion coinfection is not easily predictable. In addition to the usual factors that influence prion conversion, the replication of one strain may entail positive or negative consequences to the other. The main aim of this study was to gain insights into the prion coinfection and interference concepts and their potential therapeutic implications. Here, different mouse models were challenged with several combinations of prion strains coupled on the basis of the lengths of their incubation periods and the existence/absence of a species barrier in the tested animal model. We found that nontransmissible strains can interfere the replication of fully transmissible strains when there is a species transmission barrier involved, as happened with the combination of a mouse (22L) and a human (sCJD) strain. However, this phenomenon seems to be strain dependent, since no interference was observed when the human strain coinoculated was vCJD. For the other combinations tested in this study, the results suggest that both strains replicate independently without effect on the replication of one over the other. It is common that the strain with more favorable conditions (e.g., a higher speed of disease development or the absence of a species barrier) ends being the only one detectable at the terminal stage of the disease. However, this does not exclude the replication of the least favored strain, leading to situations of the coexistence of prion strains. As a general conclusion, the outcome of prion coinfection is strongly dependent on the strain combination and the model utilized and is therefore difficult to predict. The coexistence of several prion strains may remain undetected if one of the strains has more favorable conditions to replicate in the host. The use of several models (such as a transgenic mouse expressing PrP from different species) to analyze field prion isolates is recommended to avoid this situation. The inference effect exerted by nonreplicative prion strains should be considered an interesting tool to advance in new therapeutic strategies for treating prion diseases; it may even be a proper therapeutic strategy.
不同朊病毒株共同感染同一宿主已被认为是几种散发性克雅氏病（sCJD）患者和天然瘙痒病的自然现象。朊病毒混合感染的最终结果不易预测。除了通常影响朊病毒转化的因素外，一种毒株的复制可能对另一种毒株产生积极或消极的影响。本研究的主要目的是深入了解朊病毒混合感染和干扰的概念及其潜在的治疗意义。在这里，根据潜伏期的长短和所测试动物模型中是否存在物种传播障碍，用几种朊病毒株组合来挑战不同的小鼠模型。我们发现，当涉及物种传播障碍时，非传染性毒株可以干扰完全可传播毒株的复制，就像用一种小鼠（22L）和一种人类（sCJD）毒株的组合一样。然而，这种现象似乎取决于毒株，因为当 coinoculated 的人类毒株是 vCJD 时，没有观察到干扰。对于本研究中测试的其他组合，结果表明两种毒株独立复制，彼此之间的复制没有影响。通常情况下，具有更有利条件（例如，疾病发展速度更快或不存在物种障碍）的毒株最终会在疾病的终末期成为唯一可检测到的毒株。然而，这并不排除最不利毒株的复制，导致朊病毒株共存的情况。一般来说，朊病毒混合感染的结果强烈依赖于毒株组合和所使用的模型，因此难以预测。如果其中一种毒株在宿主中有更有利的条件进行复制，则可能会检测不到几种朊病毒株的共存。建议使用几种模型（例如，表达来自不同物种的 PrP 的转基因小鼠）来分析田间朊病毒分离物，以避免这种情况。非复制性朊病毒株施加的推断效应应被视为一种有趣的工具，可用于推进治疗朊病毒病的新治疗策略；它甚至可能是一种适当的治疗策略。
