Castro Mario, Lythe Grant, Smit Jolanda, Molina-París Carmen
Grupo Interdisciplinar de Sistemas Complejos (GISC) and Instituto de Investigación Tecnológica (IIT), Universidad Pontificia Comillas, Madrid, Spain.
Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, UK.
Sci Rep. 2021 Apr 12;11(1):7845. doi: 10.1038/s41598-021-86877-w.
Endosomes are intracellular vesicles that mediate the communication of the cell with its extracellular environment. They are an essential part of the cell's machinery regulating intracellular trafficking via the endocytic pathway. Many viruses, which in order to replicate require a host cell, attach themselves to the cellular membrane; an event which usually initiates uptake of a viral particle through the endocytic pathway. In this way viruses hijack endosomes for their journey towards intracellular sites of replication and avoid degradation without host detection by escaping the endosomal compartment. Recent experimental techniques have defined the role of endosomal maturation in the ability of enveloped viruses to release their genetic material into the cytoplasm. Endosome maturation depends on a family of small hydrolase enzymes (or GTPases) called Rab proteins, arranged on the cytoplasmic surface of its membrane. Here, we model endosomes as intracellular compartments described by two variables (its levels of active Rab5 and Rab7 proteins) and which can undergo coagulation (or fusion) and fragmentation (or fission). The key element in our approach is the "per-cell endosomal distribution" and its dynamical (Boltzmann) equation. The Boltzmann equation allows us to derive the dynamics of the total number of endosomes in a cell, as well as the mean and the standard deviation of its active Rab5 and Rab7 levels. We compare our mathematical results with experiments of Dengue viral escape from endosomes. The relationship between endosomal active Rab levels and pH suggests a mechanism that can account for the observed variability in viral escape times, which in turn regulate the viability of a viral intracellular infection.
内体是介导细胞与其细胞外环境进行通讯的细胞内囊泡。它们是细胞通过内吞途径调节细胞内运输机制的重要组成部分。许多病毒为了复制需要宿主细胞，它们会附着在细胞膜上；这一事件通常会引发病毒颗粒通过内吞途径被摄取。通过这种方式，病毒劫持内体以前往细胞内的复制位点，并通过逃离内体区室来避免降解且不被宿主检测到。最近的实验技术已经明确了内体成熟在包膜病毒将其遗传物质释放到细胞质中的能力方面所起的作用。内体成熟取决于一类称为Rab蛋白的小水解酶（或GTP酶）家族，它们排列在其膜的细胞质表面。在这里，我们将内体建模为通过两个变量（其活性Rab5和Rab7蛋白的水平）描述的细胞内区室，并且可以经历凝聚（或融合）和碎片化（或裂变）。我们方法中的关键要素是“每个细胞的内体分布”及其动力学（玻尔兹曼）方程。玻尔兹曼方程使我们能够推导出细胞内体总数的动力学，以及其活性Rab5和Rab7水平的均值和标准差。我们将我们的数学结果与登革热病毒从内体逃逸的实验进行了比较。内体活性Rab水平与pH之间的关系表明了一种机制，该机制可以解释观察到的病毒逃逸时间的变异性，进而调节病毒细胞内感染的活力。
