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: 9915885
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915885
• 关键词: Address; Africa; African; 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; Phagocytosis; Plasmodium; Plasmodium berghei; Population; Predisposition; Proteins; Proteomics; RNA Interference; Reaction; Regulation; Reporting; Resistance; Specificity; Speed; Structure; Surface; TEP1 gene; Testing; Tissues; Travel; Work; base; complement pathway; complement system; disease transmission; disorder control; experimental study; feeding; fitness; health economics; immunoregulation; 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.

概括 疟疾是一种毁灭性的疾病，每年导致约 429,000 人死亡，并威胁到一半的人口 世界人口。疟疾是由原生动物疟原虫寄生虫引起的，这些寄生虫在 人类和蚊子的宿主。鉴于其对人类健康和经济发展的影响， 为了控制疟疾，已经做出了相当大的努力，采用了针对疟疾和疟疾两个方面的寄生虫的策略。 主机。最近有人推动将我们的重点从控制疟疾转向消灭疟疾。这个努力 加上抗​​药性寄生虫和蚊子杀虫剂抗药性等新出现的问题 需要紧急制定新策略来控制疾病传播。 非洲疟疾的主要传播媒介是冈比亚按蚊。为了发生疟疾传播， 载体必须首先被感染。蚊子拥有复杂的免疫库，提供多种 当寄生虫穿过不同的组织时，会产生多层保护。最有力的障碍之一是 由蚊子补体样途径形成，这是最大的补体途径之一 疟原虫在其整个生命周期中面临的瓶颈。我们的工作旨在剖析分子 蚊子补体系统的机制。 鉴于其在杀死疟原虫方面的重要性，我们和其他人已经集中了相当多的注意力 冈比亚按蚊补体成分及其作用机制的鉴定，主要 非洲疟疾媒介。我们开发了一种新的尖端蛋白质组学方法来直接识别 该途径的组成部分。我们的方法利用了补充组件这一事实 定位于微生物表面。这种蛋白质组学方法将识别蚊子所需的因素 互补，当与基因沉默结合时，将描绘出层次组装 补体激活所需的因子。我们最近发现了两种 C 型凝集素的复合物 (CTL4/CTLMA2) 作为蚊子补体的新成分。有趣的是，当 CTL 复合物 沉默后，寄生虫杀灭能力急剧增加，这表明 CTL 复合物是一种负面的 蚊子补体调节剂。沉默 CTL 复合物也会使蚊子更加敏感 到细菌感染。我们将了解这个综合体及其合作伙伴如何选择 通过针对特定的免疫效应途径来防御疟原虫和细菌。 我们的工作将极大地增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，因此也有可能改变对 病媒疾病传播。