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

针对蚊子补体来改变先天免疫反应的特异性

• 批准号: 10376038
• 负责人: Michael Joseph Povelones
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-04 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376038
• 关键词: Address; Africa; African; Anopheles Genus; Anopheles gambiae; Anti-Bacterial Agents; Antifungal Agents; Attention; Bacteria; Bacterial Infections; Biochemical; Biological; Biological Assay; Biological Response Modifiers; Blood; C-Type Lectins; Cells; Complement; Complement Activation; Complex; Culicidae; Cytolysis; Data; Development; Disease; Disease Vectors; Drug resistance; Economic Development; Engineering; Equilibrium; Event; Face; Gene Silencing; Hemolymph; Human; Immune; Immune response; Immune system; Immunity; Infection; Innate Immune Response; Insecticide Resistance; Knowledge; Lead; Life Cycle Stages; Malaria; Mass Spectrum Analysis; Measures; Methods; Modeling; Molecular; Mosquito Control; Mus; Parasite resistance; Parasites; Pathway interactions; Persons; Phagocytosis; Plasmodium; Plasmodium berghei; Population; Predisposition; Proteins; Proteomics; RNA Interference; Reaction; Regulation; Reporting; Resistance; Specificity; Speed; Surface; TEP1 gene; Testing; Tissues; Travel; Work; base; complement pathway; complement system; disease transmission; disorder control; experimental study; feeding; fitness; health economics; in vivo; insight; malaria transmission; microbial; novel; pathogen; protein function; response; restoration; vector

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.

摘要 疟疾是一种毁灭性的疾病，每年约有42.9万人死亡，威胁着 全世界的人口。疟疾是由原生动物疟原虫引起的，这种寄生虫在 人类和蚊子的宿主。鉴于其对人类健康和经济发展的影响， 已经做出了相当大的努力来控制疟疾，使用的战略是针对这两个地区的寄生虫 主持人。最近推动将我们的重点从控制疟疾转向根除疟疾。这一努力 结合抗药性寄生虫和蚊子抗药性等新出现的问题 要求迫切制定控制疾病传播的新战略。 非洲疟疾的主要媒介是冈比亚按蚊。要发生疟疾传播， 病媒首先必须被感染。这种蚊子有一个复杂的免疫库，可以提供多种 当寄生虫穿过不同的组织时，保护层就会出现。最大的障碍之一是 由蚊子补体形成的类途径，这是负责最大的 疟疾在其整个生命周期中都面临着瓶颈。我们的工作目的是解剖分子 蚊子补体系统的机制。 鉴于它在杀死疟原虫中的重要性，我们和其他人的相当大的关注已经集中在 冈比亚按蚊补体成分的鉴定及其作用机制的研究 非洲疟疾病媒。我们开发了一种新的尖端蛋白质组学方法来直接鉴定 这条路径的组成部分。我们的方法利用了补足成分的事实 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。 互补，当与基因沉默结合时，将描绘出 补体激活所需的因子。我们最近发现了两个C型凝集素的复合体 (CTL4/CTLMA2)作为蚊虫补体的新成分。有趣的是，当CTL复合体 沉默后，寄生虫的杀伤率急剧增加，这表明CTL复合体是一个负面的 蚊虫补体调节剂。使CTL复合体沉默也会使蚊子更敏感 细菌感染。我们将了解该综合体及其合作伙伴如何在 通过靶向特定免疫效应途径的疟原虫和细菌防御。 我们的工作将极大地促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 媒介疾病传播。