Antibody-Mediated Immobilization of Virions in Mucus
Antibody-Mediated Immobilization of Virions in Mucus
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DOI：
10.1007/s11538-019-00653-6
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发表时间：
2019-10-01
影响因子：
3.5
通讯作者：
McKinley, Scott A.
中科院分区：
文献类型：
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作者：
Jensen, Melanie A.;Wang, Ying-Ying;McKinley, Scott A.
已显示抗体阻碍宫颈阴道粘液中的单纯疱疹病毒病毒粒子以及其他粘液分泌物中的其他病毒的运动。然而，目前还不可能直接观察到这种现象背后的机制，因此对病毒-抗体-粘蛋白相互作用的性质仍然知之甚少。在这项工作中，我们分析了来自单粒子追踪实验的数千个病毒粒子痕迹，以解释抗体如何在相对较长的时间内与病毒粒子合作。首先，使用聚类分析，我们观察到两类病毒体行为之间的明确分离：自由扩散和固定。虽然自由扩散的病毒粒子的比例随抗体浓度降低，但其扩散率的大小并不随抗体浓度降低，这意味着抗体的路径效应存在全有或全无的二分法。在所有结合事件都是可逆的假设下进行，我们使用了一种新的开关点检测方法得出结论，在20 s的实验时间尺度上，状态开关很少（如果有的话）。为了理解这种缓慢的状态转换，我们分析了最近提出的连续时间马尔可夫链模型的结合动力学和病毒体运动。模型分析表明，病毒体固定化需要多个抗体同时结合到病毒体和粘蛋白基质的合作，并且当病毒体固定化时，存在加速抗体-粘蛋白结合的缠结现象。除了开发一个广泛适用的框架来分析多态粒子行为外，这项工作还大大增强了我们对抗体如何增强粘液屏障对抗被动入侵物种的机制理解。
Antibodies have been shown to hinder the movement of herpes simplex virus virions in cervicovaginal mucus, as well as other viruses in other mucus secretions. However, it has not been possible to directly observe the mechanisms underlying this phenomenon, so the nature of virion-antibody-mucin interactions remain poorly understood. In this work, we analyzed thousands of virion traces from single particle tracking experiments to explicate how antibodies must cooperate to immobilize virions for relatively long time periods. First, using a clustering analysis, we observed a clear separation between two classes of virion behavior: freely diffusing and immobilized. While the proportion of freely diffusing virions decreased with antibody concentration, the magnitude of their diffusivity did not, implying an all-or-nothing dichotomy in the pathwise effect of the antibodies. Proceeding under the assumption that all binding events are reversible, we used a novel switch-point detection method to conclude that there are very few, if any, state switches on the experimental timescale of 20 s. To understand this slow state switching, we analyzed a recently proposed continuous-time Markov chain model for binding kinetics and virion movement. Model analysis implied that virion immobilization requires cooperation by multiple antibodies that are simultaneously bound to the virion and mucin matrix and that there is an entanglement phenomenon that accelerates antibody-mucin binding when a virion is immobilized. In addition to developing a widely applicable framework for analyzing multistate particle behavior, this work substantially enhances our mechanistic understanding of how antibodies can reinforce a mucus barrier against passive invasive species.