Dengue virus infection perturbs lipid homeostasis in infected mosquito cells.
Dengue virus infection perturbs lipid homeostasis in infected mosquito cells.
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DOI：
10.1371/journal.ppat.1002584
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Kuhn RJ
中科院分区：
文献类型：
--
作者：
Perera R;Riley C;Isaac G;Hopf-Jannasch AS;Moore RJ;Weitz KW;Pasa-Tolic L;Metz TO;Adamec J;Kuhn RJ
登革病毒每年导致1.5亿至1亿人感染，因此被认为是全球最具侵略性的节肢动物传播的人类病原体之一。在其复制过程中，登革病毒诱导受感染细胞的细胞内膜发生显著变化。这种现象在人和载体衍生的细胞中都观察到。利用蚊子细胞的高分辨率质谱，我们表明这种膜重塑与登革热病毒感染诱导的独特脂质库直接相关。具体而言，在DENV感染和未感染的细胞之间检测到的15%的代谢物显著不同，而在分离的复制复合物膜中检测到的85%的代谢物显著不同。此外，我们表明，细胞内的脂质再分配诱导的脂肪酸合成酶，在脂质生物合成的限速酶的抑制，是足够的细胞存活，但抑制登革病毒的复制。具有使膜不稳定和改变膜曲率的能力的脂质以及改变膜渗透性的脂质在登革病毒感染的细胞中富集。参与控制膜融合、分裂和运输的几种鞘脂和其他生物活性信号分子以及影响细胞骨架重组的分子在登革热感染期间也上调。这些观察揭示了脂质在病毒感染过程中塑造膜和蛋白质环境的新作用，并提出了可能影响病毒诱导的细胞内膜结构的膜组织原则。登革病毒是世界上最具侵略性的人类病原体之一。它每年造成5000万至1亿人感染，但目前没有有效的疫苗或抗病毒药物。该病毒通过埃及伊蚊和白纹伊蚊传播，并且病毒在蚊子载体内复制是传播到新的人类宿主所必需的。在这个复制周期中，病毒引起感染细胞膜组织的显著变化。这些病毒诱导的膜改变有助于组装病毒复制工厂阵列，并帮助病毒逃避宿主的抗病毒防御机制。在此之前，已经做了大量的努力来尝试识别有助于病毒复制的病毒和细胞蛋白质效应物。在这项研究中，我们探讨了脂质在蚊子细胞中形成这些广泛的膜平台中的作用。使用高分辨率质谱，我们已经分析了登革病毒感染的蚊子细胞的脂质组成，并将其与未感染的细胞进行比较。通过这一点，我们已经确定了几个脂质类，在登革病毒复制过程中的差异调节。使用脂质生物合成的抑制剂，我们还鉴定了抑制病毒复制的脂质库。登革病毒如何利用细胞脂质和下游信号通路来促进其复制的知识将提供可用于开发有效抗病毒药物的新靶点。这项研究也是未来比较分析病毒复制所需的人类宿主和载体膜环境的先驱。
Dengue virus causes ∼50–100 million infections per year and thus is considered one of the most aggressive arthropod-borne human pathogen worldwide. During its replication, dengue virus induces dramatic alterations in the intracellular membranes of infected cells. This phenomenon is observed both in human and vector-derived cells. Using high-resolution mass spectrometry of mosquito cells, we show that this membrane remodeling is directly linked to a unique lipid repertoire induced by dengue virus infection. Specifically, 15% of the metabolites detected were significantly different between DENV infected and uninfected cells while 85% of the metabolites detected were significantly different in isolated replication complex membranes. Furthermore, we demonstrate that intracellular lipid redistribution induced by the inhibition of fatty acid synthase, the rate-limiting enzyme in lipid biosynthesis, is sufficient for cell survival but is inhibitory to dengue virus replication. Lipids that have the capacity to destabilize and change the curvature of membranes as well as lipids that change the permeability of membranes are enriched in dengue virus infected cells. Several sphingolipids and other bioactive signaling molecules that are involved in controlling membrane fusion, fission, and trafficking as well as molecules that influence cytoskeletal reorganization are also up regulated during dengue infection. These observations shed light on the emerging role of lipids in shaping the membrane and protein environments during viral infections and suggest membrane-organizing principles that may influence virus-induced intracellular membrane architecture. Dengue virus is one of the most aggressive human pathogens worldwide. It causes 50–100 million infections per year but there is no vaccine or antiviral that is currently effective against the disease. The virus is spread by Aedes aegyptii and Aedes albopictus mosquitoes and viral replication within the mosquito vector is required for transmission to a new human host. During this replication cycle, the virus causes significant changes to the membrane organization of infected cells. These virus-induced membrane alterations help to assemble arrays of viral replication factories and aid the virus to evade host antiviral defense mechanisms. Previously, much effort has been placed in trying to identify viral and cellular protein effectors that aid virus replication. In this study we have explored the role of lipids in the formation of these extensive membrane platforms in mosquito cells. Using high-resolution mass spectrometry we have profiled the lipid composition of dengue virus infected mosquito cells and compared it to uninfected cells. Through this we have identified several lipid classes that are differentially regulated during dengue virus replication. Using inhibitors of lipid biosynthesis we have also identified a lipid repertoire that is inhibitory to viral replication. Knowledge of how dengue virus utilizes cellular lipids and downstream signaling pathways to facilitate its replication will provide novel targets that could be utilized for developing effective antivirals. This study is also a forerunner for future comparative analyses of the human host and vector membrane environments required for viral replication.
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影响因子：
4.8
作者：
Cao-Lormeau, Van-Mai
通讯作者：
Cao-Lormeau, Van-Mai
影响因子：
5.4
作者：
Gillespie, Leah K.;Hoenen, Antje;Mackenzie, Jason M.
通讯作者：
Mackenzie, Jason M.
影响因子：
3.4
作者：
Chernomordik, L
通讯作者：
Chernomordik, L
影响因子：
5.4
作者：
Hanon, E;Meyer, G;Pastoret, PP
通讯作者：
Pastoret, PP
DOI：
10.1073/pnas.1010811107
发表时间：
2010-10-05
影响因子：
11.1
作者：
Heaton, Nicholas S.;Perera, Rushika;Randall, Glenn
通讯作者：
Randall, Glenn