Inhibitors of Eicosanoid Biosynthesis Reveal that Multiple Lipid Signaling Pathways Influence Malaria Parasite Survival in Anopheles gambiae
Inhibitors of Eicosanoid Biosynthesis Reveal that Multiple Lipid Signaling Pathways Influence Malaria Parasite Survival in Anopheles gambiae
复制标题
DOI：
10.3390/insects10100307
复制
发表时间：
2019-10-01
期刊：
影响因子：
3
通讯作者：
Smith, Ryan C.
中科院分区：
文献类型：
--
作者：
Kwon, Hyeogsun;Smith, Ryan C.
类二十烷酸是由脂肪酸氧化产生的生物活性信号脂质，作为免疫稳态和炎症的重要调节剂。因此，有效的抗炎药物已被广泛用于减轻疼痛和炎症，其靶向关键的类花生酸生物合成酶。从脊椎动物到昆虫，这些类花生酸途径抑制剂的使用提供了评估类花生酸在特征较少的昆虫系统中的作用的机会。在这项研究中，我们研究了类花生酸对冈比亚按蚊体内疟原虫生存的潜在作用。使用疟原虫卵囊数量来评估寄生虫感染，评估类花生酸生物合成途径的一般或特异性抑制剂。地塞米松和吲哚美辛，磷脂A2（PLA 2）和环氧合酶（考克斯）的抑制剂，各自的管理后，卵囊数不受影响。然而，通过使用escuaoke抑制脂氧合酶（LOX）活性显著增加卵囊存活。相反，12-[[（三环[3.3.1.13，7]癸-1-基氨基）羰基]氨基]-十二烷酸（AUDA），一种环氧化物羟化酶（EH）的抑制剂，减少卵囊数量。这些实验通过RNAi实验进一步验证，以沉默与An中EH同源的候选基因。冈比亚确认他们的贡献疟原虫的发展。与AUDA处理的结果类似，EH的沉默显著减少了卵囊数量。这些结果表明，特定的类花生酸在An。冈比亚对疟原虫在蚊子宿主中的存活具有激动剂或拮抗剂作用。
Eicosanoids are bioactive signaling lipids derived from the oxidation of fatty acids that act as important regulators of immune homeostasis and inflammation. As a result, effective anti-inflammatory drugs have been widely used to reduce pain and inflammation which target key eicosanoid biosynthesis enzymes. Conserved from vertebrates to insects, the use of these eicosanoid pathway inhibitors offer opportunities to evaluate the roles of eicosanoids in less-characterized insect systems. In this study, we examine the potential roles of eicosanoids on malaria parasite survival in the mosquito Anopheles gambiae. Using Plasmodium oocyst numbers to evaluate parasite infection, general or specific inhibitors of eicosanoid biosynthesis pathways were evaluated. Following the administration of dexamethasone and indomethacin, respective inhibitors of phospholipid A2 (PLA2) and cyclooxygenase (COX), oocyst numbers were unaffected. However, inhibition of lipoxygenase (LOX) activity through the use of esculetin significantly increased oocyst survival. In contrast, 12-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]-dodecanoic acid (AUDA), an inhibitor of epoxide hydroxylase (EH), decreased oocyst numbers. These experiments were further validated through RNAi experiments to silence candidate genes homologous to EH in An. gambiae to confirm their contributions to Plasmodium development. Similar to the results of AUDA treatment, the silencing of EH significantly reduced oocyst numbers. These results imply that specific eicosanoids in An. gambiae can have either agonist or antagonistic roles on malaria parasite survival in the mosquito host.