Infection-Induced Changes Within the Endocytic Recycling Compartment Suggest a Roadmap of Human Cytomegalovirus Egress.
Infection-Induced Changes Within the Endocytic Recycling Compartment Suggest a Roadmap of Human Cytomegalovirus Egress.
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DOI：
10.3389/fmicb.2018.01888
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发表时间：
2018
影响因子：
5.2
通讯作者：
Pellett PE
中科院分区：
文献类型：
--
作者：
Close WL;Glassbrook JE;Gurczynski SJ;Pellett PE
人类巨细胞病毒 (HCMV) 是发育中的胎儿、新生儿和免疫系统受损个体的重要病原体。我们对病毒粒子组装所需机制的理解存在差距，阻碍了针对病毒复制后期的抗病毒药物的开发。在感染过程中，HCMV 会引起宿主内分泌系统的剧烈重组，导致细胞质病毒粒子组装复合体 (cVAC) 的形成，即病毒粒子组装的部位。作为 cVAC 生物发生的一部分，内分泌细胞器的组成和行为发生变化。为了更全面地了解 HCMV 感染对细胞内吞回收室 (ERC) 组成部分的影响，我们使用之前发布的转录和蛋白质组数据集来预测 ERC 运输方向的变化。我们发现了与感染相关的基因表达变化，这表明内吞和胞吐再循环途径之间的平衡发生了变化，导致 cVAC 内形成分泌陷阱。相反，相应的转变有利于分泌囊泡的出境运输，表明其在病毒粒子流出中具有潜在作用。这些观察结果与之前描述信号分子（例如 IL-6）的隔离以及成熟 HCMV 病毒颗粒的突触小泡样特性的研究一致。我们的分析使得能够开发出一个精炼模型，该模型融合了与 HCMV 复制过程中 ERC 行为相关的新旧信息。虽然受到集成系统级数据缺乏的限制，但该模型为开发与 HCMV 病毒体成熟和流出机制相关的可实验测试的假设提供了知情基础。这些实验的信息将为合理开发针对 HCMV 和相关病毒的新型抗病毒药物提供强有力的路线图。
Human cytomegalovirus (HCMV) is an important pathogen in developing fetuses, neonates, and individuals with compromised immune systems. Gaps in our understanding of the mechanisms required for virion assembly stand in the way of development of antivirals targeting late stages of viral replication. During infection, HCMV causes a dramatic reorganization of the host endosecretory system, leading to the formation of the cytoplasmic virion assembly complex (cVAC), the site of virion assembly. As part of cVAC biogenesis, the composition and behavior of endosecretory organelles change. To gain more comprehensive understanding of the impact HCMV infection has on components of the cellular endocytic recycling compartment (ERC), we used previously published transcriptional and proteomic datasets to predict changes in the directionality of ERC trafficking. We identified infection-associated changes in gene expression that suggest shifts in the balance between endocytic and exocytic recycling pathways, leading to formation of a secretory trap within the cVAC. Conversely, there was a corresponding shift favoring outbound secretory vesicle trafficking, indicating a potential role in virion egress. These observations are consistent with previous studies describing sequestration of signaling molecules, such as IL-6, and the synaptic vesicle-like properties of mature HCMV virions. Our analysis enabled development of a refined model incorporating old and new information related to the behavior of the ERC during HCMV replication. While limited by the paucity of integrated systems-level data, the model provides an informed basis for development of experimentally testable hypotheses related to mechanisms involved in HCMV virion maturation and egress. Information from such experiments will provide a robust roadmap for rational development of novel antivirals for HCMV and related viruses.
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影响因子：
4
作者：
Handley MT;Haynes LP;Burgoyne RD
通讯作者：
Burgoyne RD
影响因子：
6.7
作者：
Alwine JC
通讯作者：
Alwine JC
影响因子：
5.4
作者：
Das, Subhendu;Pellett, Philip E.
通讯作者：
Pellett, Philip E.
影响因子：
5.4
作者：
Buchkovich, Nicholas J.;Maguire, Tobi G.;Alwine, James C.
通讯作者：
Alwine, James C.
影响因子：
5.4
作者：
Gurczynski, Stephen J.;Das, Subhendu;Pellett, Philip E.
通讯作者：
Pellett, Philip E.