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三维空间解析模型揭示丙型肝炎基因组复制周期的细胞内动态。

3D Spatially Resolved Models of the Intracellular Dynamics of the Hepatitis C Genome Replication Cycle.

机构信息

Dipartimento di Scienze Matematiche (DISMA) "G.L. Lagrange", Politecnico di Torino, Corso Duca degli Abruzzi, 24, 10129 Torino (TO), Italy.

Goethe Center for Scientific Computing (G-CSC), Goethe Universität Frankfurt, Kettenhofweg 139, 60325 Frankfurt am Main, Germany.

出版信息

Viruses. 2017 Sep 30;9(10):282. doi: 10.3390/v9100282.

DOI:10.3390/v9100282
PMID:28973992
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5691296/
Abstract

Mathematical models of virus dynamics have not previously acknowledged spatial resolution at the intracellular level despite substantial arguments that favor the consideration of intracellular spatial dependence. The replication of the hepatitis C virus (HCV) viral RNA (vRNA) occurs within special replication complexes formed from membranes derived from endoplasmatic reticulum (ER). These regions, termed membranous webs, are generated primarily through specific interactions between nonstructural virus-encoded proteins (NSPs) and host cellular factors. The NSPs are responsible for the replication of the vRNA and their movement is restricted to the ER surface. Therefore, in this study we developed fully spatio-temporal resolved models of the vRNA replication cycle of HCV. Our simulations are performed upon realistic reconstructed cell structures-namely the ER surface and the membranous webs-based on data derived from immunostained cells replicating HCV vRNA. We visualized 3D simulations that reproduced dynamics resulting from interplay of the different components of our models (vRNA, NSPs, and a host factor), and we present an evaluation of the concentrations for the components within different regions of the cell. Thus far, our model is restricted to an internal portion of a hepatocyte and is qualitative more than quantitative. For a quantitative adaption to complete cells, various additional parameters will have to be determined through further in vitro cell biology experiments, which can be stimulated by the results deccribed in the present study.

摘要

尽管有大量论据支持考虑细胞内空间相关性，但先前的病毒动力学数学模型并未承认细胞内水平的空间分辨率。丙型肝炎病毒 (HCV) 病毒 RNA (vRNA) 的复制发生在由内质网 (ER) 衍生的特殊复制复合物中。这些区域被称为膜网络，主要通过非结构病毒编码蛋白 (NSP) 和宿主细胞因子之间的特定相互作用产生。NSP 负责 vRNA 的复制，其运动仅限于 ER 表面。因此，在这项研究中，我们开发了 HCV vRNA 复制周期的完全时空分辨模型。我们的模拟是基于源自免疫染色细胞中复制 HCV vRNA 的数据，针对真实重建的细胞结构（即 ER 表面和膜网络）进行的。我们可视化了 3D 模拟，这些模拟再现了我们模型的不同组件（vRNA、NSP 和宿主因子）相互作用产生的动态，并展示了细胞不同区域内各组件浓度的评估。到目前为止，我们的模型仅限于肝细胞的内部部分，定性的比定量的更多。为了对完整细胞进行定量适配，还必须通过进一步的体外细胞生物学实验来确定各种其他参数，本研究中描述的结果可以对此类实验起到刺激作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d634/5691296/462bcb6d2cf5/viruses-09-00282-g012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d634/5691296/4c121f7e8d85/viruses-09-00282-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d634/5691296/21a1c2dd41d1/viruses-09-00282-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d634/5691296/380eeb672d77/viruses-09-00282-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d634/5691296/ae62e47acdc3/viruses-09-00282-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d634/5691296/462bcb6d2cf5/viruses-09-00282-g012.jpg

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