Targeting mosquito complement to alter the specificity of the innate immune response

总结 疟疾是一种毁灭性的疾病，每年造成约429 000人死亡， 世界人口。疟疾是由原生动物疟原虫寄生虫引起的， 人类和蚊子宿主。鉴于其对人类健康和经济发展的影响， 已经做出相当大的努力来控制疟疾，使用针对其两个区域中的寄生虫的策略。 hosts.最近有人推动将我们的重点从控制疟疾转向消灭疟疾。这一努力 加上新出现的问题，如抗药性寄生虫和蚊子杀虫剂抗药性， 迫切需要制定新的战略来控制疾病传播。 非洲疟疾的主要媒介是冈比亚按蚊。要发生疟疾传播， 病毒必须首先被感染。蚊子有一个复杂的免疫武器库， 寄生虫通过不同的组织传播时会形成层层保护。其中一个最有力的障碍是 由蚊子补体样途径形成，这是负责一个最大的 疟原虫在其整个生命周期中都面临瓶颈。我们的工作旨在剖析 蚊子补体系统的机制。 鉴于它在杀灭疟原虫方面的重要性，我们和其他人已经集中了相当大的注意力， 在确定冈比亚按蚊的补体成分及其作用机制方面， 非洲疟疾媒介。我们开发了一种新的尖端蛋白质组学方法， 这条路的组成部分。我们的方法利用了互补成分 定位于微生物表面。这种蛋白质组学方法将确定蚊子所需的因子， 当与基因沉默结合时，将描绘出基因沉默的分级组装。 补体激活所需的因子。我们最近发现了一种由两种C型凝集素组成的复合物 (CTL4/CTLMA 2）作为蚊子补体的新组分。有趣的是，当CTL复合物 沉默后，杀寄生虫的能力显著增加，表明CTL复合物是阴性的。 蚊子补体调节因子。沉默CTL复合物也使蚊子更敏感 细菌感染。我们将了解这个综合体及其合作伙伴如何在 疟原虫和细菌通过靶向特异性免疫效应途径进行防御。 我们的工作将极大地推进对补体如何控制疟疾寄生虫负担的理解 而且，由于这种方法可以应用于其他模型，也有可能改变对 病媒传播。

SUMMARY Malaria is a devastating disease that kills approximately 429,000 people annually and threatens half of the world's population. Malaria is caused by protozoan Plasmodium parasites that alternate between human and mosquito hosts. Given its impacts on human health and economic development, a considerable effort has been made to control malaria using strategies that target parasites in both of its hosts. There has been a recent push to shift our focus from malaria control to eradication. This effort combined with emerging problems such as drug resistant parasites and mosquito insecticide resistance require the urgent development of new strategies to control disease transmission. The main vector for malaria in Africa is Anopheles gambiae. For malaria transmission to occur, the vector must first be infected. The mosquito has a sophisticated immune arsenal providing multiple layers of protection as parasites travel through different tissues. One of the most potent barriers is formed by the mosquito complement-like pathway, which is responsible for one of the biggest bottlenecks Plasmodium faces across its entire life cycle. Our work is aimed at dissecting the molecular mechanisms of the mosquito complement system. Given its importance in Plasmodium killing, considerable attention by us and others has been focused on identifying complement components and their mechanism of action in Anopheles gambiae, the main African malaria vector. We have developed a new cutting-edge proteomics approach to directly identify components of this pathway. Our method takes advantage of the fact that complement components localize to microbial surfaces. This proteomic approach will identify factors required for mosquito complement and, when combined with gene silencing, will delineate the hierarchical assembly of factors required for complement activation. We have recently identified a complex of two C-type lectins (CTL4/CTLMA2) as a new component of mosquito complement. Interestingly, when the CTL complex is silenced, there is a dramatic increase in parasite killing, suggesting that the CTL complex is a negative regulator of mosquito complement. Silencing the CTL complex also renders mosquitoes more sensitive to bacterial infections. We will understand how this complex and its partners select between Plasmodium and bacterial defense by targeting specific immune effector pathways. Our work will greatly advance the understanding of how complement controls malaria parasite burden and, as this approach can be applied to other models, also has the potential to transform the study of vector disease transmission.