Programme in Emerging Infectious Diseases, Duke-NUS Medical School, 169857, Singapore.
UMR 152 PHARMADEV-IRD, Université Paul Sabatier-Toulouse 3, 31400, Toulouse, France.
Proc Natl Acad Sci U S A. 2020 Nov 3;117(44):27627-27636. doi: 10.1073/pnas.2015095117. Epub 2020 Oct 21.
Dengue virus (DENV) subdues cell membranes for its cellular cycle by reconfiguring phospholipids in humans and mosquitoes. Here, we determined how and why DENV reconfigures phospholipids in the mosquito vector. By inhibiting and activating the de novo phospholipid biosynthesis, we demonstrated the antiviral impact of de novo-produced phospholipids. In line with the virus hijacking lipids for its benefit, metabolomics analyses indicated that DENV actively inhibited the de novo phospholipid pathway and instead triggered phospholipid remodeling. We demonstrated the early induction of remodeling during infection by using isotope tracing in mosquito cells. We then confirmed in mosquitoes the antiviral impact of de novo phospholipids by supplementing infectious blood meals with a de novo phospholipid precursor. Eventually, we determined that phospholipid reconfiguration was required for viral genome replication but not for the other steps of the virus cellular cycle. Overall, we now propose that DENV reconfigures phospholipids through the remodeling cycle to modify the endomembrane and facilitate formation of the replication complex. Furthermore, our study identified de novo phospholipid precursor as a blood determinant of DENV human-to-mosquito transmission.
登革热病毒（DENV）通过在人类和蚊子中重新配置磷脂来抑制细胞膜以进行其细胞周期。在这里，我们确定了 DENV 如何以及为何在蚊子载体中重新配置磷脂。通过抑制和激活从头合成磷脂的生物合成，我们证明了从头合成的磷脂具有抗病毒作用。与病毒为自身利益劫持脂质一致，代谢组学分析表明 DENV 积极抑制从头合成的磷脂途径，而是触发磷脂重塑。我们通过在蚊子细胞中使用同位素示踪来证明感染过程中的早期重塑诱导。然后，我们通过在感染性血液餐中补充从头合成的磷脂前体来证实蚊子中从头合成的磷脂的抗病毒作用。最终，我们确定了磷脂的重新配置对于病毒基因组复制是必需的，但对于病毒细胞周期的其他步骤则不是必需的。总的来说，我们现在提出 DENV 通过重塑循环来重新配置磷脂，以改变内膜并促进复制复合物的形成。此外，我们的研究还确定了从头合成的磷脂前体是 DENV 从人传播到蚊子的血液决定因素。
