Inhibition of JNK signaling in the Asian malaria vector Anopheles stephensi extends mosquito longevity and improves resistance to Plasmodium falciparum infection.
Inhibition of JNK signaling in the Asian malaria vector Anopheles stephensi extends mosquito longevity and improves resistance to Plasmodium falciparum infection.
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DOI：
10.1371/journal.ppat.1007418
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发表时间：
2018-11
期刊：
影响因子：
6.7
通讯作者：
Luckhart S
中科院分区：
文献类型：
--
作者：
Souvannaseng L;Hun LV;Baker H;Klyver JM;Wang B;Pakpour N;Bridgewater JM;Napoli E;Giulivi C;Riehle MA;Luckhart S
疟疾是由疟原虫寄生虫感染引起的全球健康问题。随着杀虫剂和药物耐药性的上升，迫切需要制定新的控制策略，包括阻断主要蚊子媒介物种中寄生虫孢子繁殖的策略。由细胞外信号调节激酶（ERK）和应激活化蛋白激酶（SAPKs）c-Jun N-末端激酶（JNKs）和p38 MAPK调节的MAPK信号传导途径在真核生物中高度保守，包括人疟疾寄生虫恶性疟原虫的蚊子载体。蚊子中的这些途径中的一些已被详细研究，但通过JNK信号转导整合寄生虫发育和蚊子适应性的机制尚未阐明。为此，我们设计了靶向SAPKs的MAPK磷酸酶4（MKP 4）的中肠特异性过表达，并使用了两种有效且特异性的JNK小分子抑制剂（SMI）来评估JNK信号转导操作对斯氏按蚊繁殖力，寿命，中间代谢和恶性疟原虫发育的影响。MKP 4过表达和SMI处理降低了恶性疟原虫感染的蚊子的比例，并且相对于对照降低了卵囊负荷。SMI处理的蚊子与对照组相比，寿命没有差异，而基因操作的蚊子寿命延长。SMI处理的蚊子的代谢组学分析揭示了对假定的抗性机制和寿命延长背后的生理学的见解，这首次表明恶性疟原虫诱导的JNK信号传导降低了蚊子的寿命并增加了对感染的易感性，与先前发表的报告相反，可能是通过无脊椎动物宿主和寄生虫之间的关键相互作用来获得在孢子发育过程中发挥重要作用的营养物质。疟疾是由疟原虫寄生虫感染引起的全球健康问题。随着杀虫剂和药物耐药性的上升，迫切需要开发新的控制策略。一种策略是通过操纵蚊子中肠（寄生虫发育的关键组织）中的关键信号通路和过程来开发抗疟原虫蚊子。MAPK信号通路在真核生物中是高度保守的，并且调节蚊子载体中的人疟疾寄生虫恶性疟原虫的发育。在这里，我们研究了斯氏按蚊JNK信号转导的操纵如何影响恶性疟原虫的发育和关键的蚊子生活史特征。我们使用了多种互补的方法来证明疟原虫感染激活蚊子JNK信号以牺牲宿主寿命为代价。值得注意的是，这些组合效应来自与其他转导途径的网络信号传导和蚊子宿主中中间代谢的改变。
Malaria is a global health concern caused by infection with Plasmodium parasites. With rising insecticide and drug resistance, there is a critical need to develop novel control strategies, including strategies to block parasite sporogony in key mosquito vector species. MAPK signaling pathways regulated by extracellular signal-regulated kinases (ERKs) and the stress-activated protein kinases (SAPKs) c-Jun N-terminal kinases (JNKs) and p38 MAPKs are highly conserved across eukaryotes, including mosquito vectors of the human malaria parasite Plasmodium falciparum. Some of these pathways in mosquitoes have been investigated in detail, but the mechanisms of integration of parasite development and mosquito fitness by JNK signaling have not been elucidated. To this end, we engineered midgut-specific overexpression of MAPK phosphatase 4 (MKP4), which targets the SAPKs, and used two potent and specific JNK small molecule inhibitors (SMIs) to assess the effects of JNK signaling manipulations on Anopheles stephensi fecundity, lifespan, intermediary metabolism, and P. falciparum development. MKP4 overexpression and SMI treatment reduced the proportion of P. falciparum-infected mosquitoes and decreased oocyst loads relative to controls. SMI-treated mosquitoes exhibited no difference in lifespan compared to controls, whereas genetically manipulated mosquitoes exhibited extended longevity. Metabolomics analyses of SMI-treated mosquitoes revealed insights into putative resistance mechanisms and the physiology behind lifespan extension, suggesting for the first time that P. falciparum-induced JNK signaling reduces mosquito longevity and increases susceptibility to infection, in contrast to previously published reports, likely via a critical interplay between the invertebrate host and parasite for nutrients that play essential roles during sporogonic development. Malaria is a global health concern caused by infection with Plasmodium parasites. With rising insecticide and drug resistance, there is a critical need to develop novel control strategies. One strategy is to develop a Plasmodium-resistant mosquito through the manipulation of key signaling pathways and processes in the mosquito midgut, a critical tissue for parasite development. MAPK signaling pathways are highly conserved among eukaryotes and regulate development of the human malaria parasite Plasmodium falciparum in the mosquito vector. Here, we investigated how manipulation of Anopheles stephensi JNK signaling affects development of P. falciparum and key mosquito life history traits. We used multiple, complementary approaches to demonstrate that malaria parasite infection activates mosquito JNK signaling for its own benefit at a cost to host lifespan. Notably, these combined effects derive from networked signaling with other transduction pathways and alterations to intermediary metabolism in the mosquito host.
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