More than half of the world population is at risk of dengue virus (DENV) infection because of the global distribution of its mosquito vectors. DENV is an envelope virus that relies on host lipid membranes for its life-cycle. Here, we characterized how DENV hijacks the mosquito lipidome to identify targets for novel transmission-blocking interventions. To describe metabolic changes throughout the mosquito DENV cycle, we deployed a Liquid chromatography-high resolution mass spectrometry (LC-HRMS) workflow including spectral similarity annotation in cells, midguts and whole mosquitoes at different times post infection. We revealed a major aminophospholipid reconfiguration with an overall early increase, followed by a reduction later in the cycle. We phylogenetically characterized acylglycerolphosphate acyltransferase (AGPAT) enzyme isoforms to identify those that catalyze a rate-limiting step in phospholipid biogenesis, the acylation of lysophosphatidate to phosphatidate. We showed that DENV infection decreased AGPAT1, but did not alter AGPAT2 expression in cells, midguts and mosquitoes. Depletion of either AGPAT1 or AGPAT2 increased aminophospholipids and partially recapitulated DENV-induced reconfiguration before infection in vitro. However, only AGPAT1 depletion promoted infection by maintaining high aminophospholipid concentrations. In mosquitoes, AGPAT1 depletion also partially recapitulated DENV-induced aminophospholipid increase before infection and enhanced infection by maintaining high aminophospholipid concentrations. These results indicate that DENV inhibition of AGPAT1 expression promotes infection by increasing aminophospholipids, as observed in the mosquito's early DENV cycle. Furthermore, in AGPAT1-depleted mosquitoes, we showed that enhanced infection was associated with increased consumption/redirection of aminophospholipids. Our study suggests that DENV regulates aminophospholipids, especially phosphatidylcholine and phosphatidylethanolamine, by inhibiting AGPAT1 expression to increase aminophospholipid availability for virus multiplication.

中文翻译：

---

登革热病毒降低 AGPAT1 表达以改变磷脂并增强埃及伊蚊的感染。

由于蚊媒分布在全球，超过一半的世界人口面临登革热病毒 (DENV) 感染的风险。DENV 是一种包膜病毒，其生命周期依赖于宿主脂质膜。在这里，我们描述了 DENV 如何劫持蚊子脂质组，以确定新型传播阻断干预措施的目标。为了描述整个蚊子 DENV 周期的代谢变化，我们部署了液相色谱-高分辨率质谱 (LC-HRMS) 工作流程，包括感染后不同时间细胞、中肠和整个蚊子的光谱相似性注释。我们揭示了主要的氨基磷脂重构，早期总体增加，随后在周期后期减少。我们对酰基甘油磷酸酰基转移酶（AGPAT）酶亚型进行系统发育表征，以鉴定那些催化磷脂生物合成中限速步骤（溶血磷脂酸酰化为磷脂酸）的酶亚型。我们发现 DENV 感染会降低细胞、中肠和蚊子中 AGPAT1 的表达，但不会改变 AGPAT2 的表达。AGPAT1 或 AGPAT2 的缺失增加了氨基磷脂，并部分重现了体外感染前 DENV 诱导的重构。然而，只有 AGPAT1 耗尽才能通过维持高氨基磷脂浓度来促进感染。在蚊子中，AGPAT1 缺失也部分重现了感染前 DENV 诱导的氨基磷脂增加，并通过维持高氨基磷脂浓度增强了感染。这些结果表明，如在蚊子的早期 DENV 周期中观察到的，DENV 对 AGPAT1 表达的抑制通过增加氨基磷脂来促进感染。此外，在 AGPAT1 耗尽的蚊子中，我们发现感染的增强与氨基磷脂消耗/重定向的增加有关。我们的研究表明，DENV 通过抑制 AGPAT1 表达来调节氨基磷脂，特别是磷脂酰胆碱和磷脂酰乙醇胺，以增加病毒增殖的氨基磷脂可用性。