Dynamic remodeling of lipids coincides with dengue virus replication in the midgut of Aedes aegypti mosquitoes.
Dynamic remodeling of lipids coincides with dengue virus replication in the midgut of Aedes aegypti mosquitoes.
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DOI：
10.1371/journal.ppat.1006853
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发表时间：
2018-03
期刊：
影响因子：
6.7
通讯作者：
Perera R
中科院分区：
文献类型：
--
作者：
Chotiwan N;Andre BG;Sanchez-Vargas I;Islam MN;Grabowski JM;Hopf-Jannasch A;Gough E;Nakayasu E;Blair CD;Belisle JT;Hill CA;Kuhn RJ;Perera R
我们描述了对埃及伊蚊中肠代谢组的第一次全面分析，埃及伊蚊是登革热、寨卡、基孔肯雅和黄热病病毒等虫媒病毒的主要蚊子载体。这些病毒的传播取决于它们感染、复制和从蚊子媒介中的几个组织传播的能力。这些组织内的代谢环境在这些过程中起着至关重要的作用。由于这些病毒是有包膜的，因此病毒复制、组装和释放发生在通过操纵宿主代谢而引发的细胞膜上。干扰这种病毒感染诱导的代谢环境对人类和蚊子细胞培养模型中的病毒复制是有害的。在这里，我们提出了第一个洞察到埃及伊蚊虫媒病毒复制过程中诱导的代谢环境。使用高分辨率质谱，我们分析了登革热病毒感染中肠组织后发生的时间代谢扰动。这是感染和复制的主要部位，先于系统性病毒传播和传播。我们确定了在感染早期、中期和晚期时间点表现出动态特征的代谢物。我们观察到脂质含量显著增加。甘油磷脂、鞘脂和脂肪酰的增加与病毒复制的动力学一致。甘油脂水平的升高表明，在感染期间，从能量储存到合成途径的资源转移。观察到酰基-肉毒碱水平升高，线粒体功能的信号中断和能量生产的可能转移。鞘脂途径中影响二氢神经酰胺与神经酰胺比例的中心枢纽被确定为对病毒生命周期至关重要。这项研究还导致了埃及伊蚊鞘脂途径的首次重建。鉴于这种载体传播的几种黄病毒复制机制的保守性，我们的研究结果突出了生物化学瓶颈，可以有针对性地破坏这些蚊子传播的多种病原体。埃及伊蚊传播导致登革热、寨卡、基孔肯雅和黄热病的虫媒病毒。这些病毒在世界热带和亚热带地区流行，使25亿人面临感染风险。传播严重依赖于这些病毒在人类和蚊子宿主中的复制。成功的病毒复制受到宿主细胞或组织的生化环境的极大影响，并且黄病毒重新排列该环境以有利于它们的需要。宿主细胞衍生的代谢物如脂质、糖和氨基酸用于产生子代病毒体，帮助逃避宿主免疫系统并使生命周期成功完成。在这项研究中，我们应用高分辨率质谱来了解登革热病毒感染过程中蚊子的生化景观的改变。我们专注于蚊子的中肠，因为这是感染的最初部位。我们确定了几种代谢产物，在病毒感染和复制过程中表现出动态的轮廓。通过精确定位病毒复制所需的生化“瓶颈”，我们可以设计出阻止病毒在蚊子体内复制并防止其传播给人类的策略。
We describe the first comprehensive analysis of the midgut metabolome of Aedes aegypti, the primary mosquito vector for arboviruses such as dengue, Zika, chikungunya and yellow fever viruses. Transmission of these viruses depends on their ability to infect, replicate and disseminate from several tissues in the mosquito vector. The metabolic environments within these tissues play crucial roles in these processes. Since these viruses are enveloped, viral replication, assembly and release occur on cellular membranes primed through the manipulation of host metabolism. Interference with this virus infection-induced metabolic environment is detrimental to viral replication in human and mosquito cell culture models. Here we present the first insight into the metabolic environment induced during arbovirus replication in Aedes aegypti. Using high-resolution mass spectrometry, we have analyzed the temporal metabolic perturbations that occur following dengue virus infection of the midgut tissue. This is the primary site of infection and replication, preceding systemic viral dissemination and transmission. We identified metabolites that exhibited a dynamic-profile across early-, mid- and late-infection time points. We observed a marked increase in the lipid content. An increase in glycerophospholipids, sphingolipids and fatty acyls was coincident with the kinetics of viral replication. Elevation of glycerolipid levels suggested a diversion of resources during infection from energy storage to synthetic pathways. Elevated levels of acyl-carnitines were observed, signaling disruptions in mitochondrial function and possible diversion of energy production. A central hub in the sphingolipid pathway that influenced dihydroceramide to ceramide ratios was identified as critical for the virus life cycle. This study also resulted in the first reconstruction of the sphingolipid pathway in Aedes aegypti. Given conservation in the replication mechanisms of several flaviviruses transmitted by this vector, our results highlight biochemical choke points that could be targeted to disrupt transmission of multiple pathogens by these mosquitoes. The Aedes aegypti mosquito transmits arboviruses that cause dengue, Zika, chikungunya and yellow fever. These viruses are endemic in tropical and subtropical regions of the world placing 2.5 billion people at risk of infection. Transmission is critically dependent upon the replication of these viruses in both human and mosquito hosts. Successful viral replication is greatly influenced by the biochemical environment of the host cell or tissue and flaviviruses rearrange this environment to benefit their needs. Host-cell derived metabolites such as lipids, sugars and amino acids are utilized to produce progeny virions, help evade the host immune system and enable successful completion of the life cycle. In this study, we applied high-resolution mass spectrometry to understand the alteration of the biochemical landscape of the mosquito during infection by dengue virus. We focused on the mosquito midgut, as this is the initial site of infection. We identified several metabolites that exhibited dynamic profiles during the course of viral infection and replication. By pinpointing biochemical “choke points” required for viral replication, we can devise strategies that will stall virus replication in the mosquito and prevent its transmission to humans.
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DOI：
10.1016/0010-406x(64)90001-5
发表时间：
1964-01-01
期刊：
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY
影响因子：
--
作者：
CLAYTON, RB;EDWARDS, AM;SMITH, DA
通讯作者：
SMITH, DA
影响因子：
4.8
作者：
Dawaliby, Rosie;Trubbia, Cataldo;Govaerts, Cedric
通讯作者：
Govaerts, Cedric
影响因子：
3.7
作者：
Aktepe, Turgut E.;Pham, Helen;Mackenzie, Jason M.
通讯作者：
Mackenzie, Jason M.
影响因子：
6.7
作者：
Caragata EP;Rancès E;Hedges LM;Gofton AW;Johnson KN;O'Neill SL;McGraw EA
通讯作者：
McGraw EA
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y