The protease network that regulates innate immunity in mosquitoes

调节蚊子先天免疫的蛋白酶网络

• 批准号: 10232089
• 负责人: Kristin Michel
• 金额: $ 55.18万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-13 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10232089
• 关键词: Africa South of the Sahara; Anopheles Genus; Anopheles gambiae; Antiparasitic Agents; Basic Science; Binding Proteins; Biochemical; Biocontrols; Chemicals; Clip; Communicable Diseases; Culicidae; Data; Deposition; Development; Equilibrium; Future; Genetic; Genetic Screening; Genetic Transcription; Goals; Health; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunology; Individual; Infection; Innate Immune System; Insecta; Knowledge; Laboratories; Life Table Analyses; Link; Malaria; Measures; Methodology; Mission; Modeling; Molecular; Monitor; Monophenol Monooxygenase; Mosquito Control; National Institute of Allergy and Infectious Disease; Natural Immunity; Network-based; Outcome; Parasites; Pathway Analysis; Pathway interactions; Pattern; Peptide Hydrolases; Plasmodium; Populations at Risk; Predisposition; Process; Production; Proteins; Public Health; Regulation; Research; Resistance; Science; Serine Protease; Surface; System; TEP1 gene; Testing; Time; Tweens; United States National Institutes of Health; Vector-transmitted infectious disease; antimicrobial peptide; cohesion; complement pathway; disorder control; eumelanin; extracellular; fitness; genetic manipulation; immunoreaction; immunoregulation; innovation; insight; malaria transmission; microbial; novel; pathogen; pathogenic microbe; prevent; thioester; transmission process; vector; vector competence; vector control; vector mosquito

PROJECT SUMMARY The innate immune system of mosquitoes is a critical determinant of their vector competence. This includes the ability to support development and transmission of the protozoan parasite species in the genus Plasmodium by Anopheles mosquitoes, the principal vectors of human malaria world-wide. Insight into the regulation of innate immune effector mechanisms remains incomplete, but is vitally important to our fundamental understanding of host-pathogen interactions in this most important human vector-borne disease. The long-term goal is to understand immune system regulation in An. gambiae to inform current and future vector control strategies. The objective of this application is to globally identify mechanisms of immune system regulation by determining the interactions within the extracellular protease network that activate and link opsonization to melanization in the context of distinct microbial infections. The rationale for the proposed research is that detailed information on the protease network that regulate mosquito immunity could be employed to predict long-term efficacy of novel vector control strategies that employ microbial agents, and manipulate infection outcome. Guided by our preliminary data, the following three specific aims will be pursued: (1) Determine the interactions of proteases and their homologs that are critical for mosquito immunity; (2) Assess the impact of the protease network on immunity and mosquito fitness; and (3) Visualize the immunoregulatory network in mosquitoes using network science. Under the first aim, we will test the hypothesis that clip-serine proteinases and their homologs form functional modules that are required for optimal immune responses by defining their cleavage patterns, genetic interactions, and precise biochemi-cal function. Under the second aim, the potential effect of the protease network on pathogen resistance and tolerance as well as mosquito fitness will be assessed using common microbial challenge models and life table analyses. Under the third aim standard network science approaches will be used to visualize all protease interactions in the system as a static multilayered network and to analyze this network to infer proteolytic flow through that links opsonization and melanization and to identify the key molecules that control immunity. The proposed research is innovative, as it will for the first time evaluate protease cascades as a single, integrated network that controls mosquito humoral immunity during diverse immune challenges. Additionally, this project will use network science as a highly innovative approach to the study of mosquito innate immunity, which if successful will be transformative to the field of insect immunology. This project is significant as it will provide comprehensive understanding of the contribution of the protease network to mosquito health as well as the limitations of the system in overcoming infection. Ultimately, this knowledge could be employed to manipulate infection outcome and thus inform the development of new disease control strategies that aim at disrupting malaria parasite development in its vector.

项目摘要 蚊子的先天免疫系统是其向量能力的关键决定因素。这包括 支持原生动物寄生虫种类的发展和传播的能力 全球人类疟疾的主要媒介Anopheles蚊子的疟原虫。深入了解 先天免疫效应机制的调节仍然不完整，但对我们的 在这种最重要的人类媒介传播中，对宿主 - 病原体相互作用的基本了解 疾病。长期目标是了解An中的免疫系统调节。冈比亚通知当前 以及未来的向量控制策略。该应用的目的是在全球范围内确定 通过确定细胞外蛋白酶网络中的相互作用，免疫系统调节 在不同的微生物感染的背景下，激活并将调子化与黑素化。理由 拟议的研究是，调节蚊子免疫力的蛋白酶网络上的详细信息 可以用来预测采用微生物的新型向量控制策略的长期疗效 药物，操纵感染结果。在我们的初步数据的指导下，以下三个特定目标 将被追捕：（1）确定蛋白酶及其同源物的相互作用对蚊子至关重要 免疫; （2）评估蛋白酶网络对免疫和蚊子健身的影响； （3） 使用网络科学可视化蚊子中的免疫调节网络。在第一个目标下，我们将 检验夹子丝氨酸蛋白酶及其同源物形成功能模块的假设 最佳免疫反应所必需的，通过定义其切割模式，遗传相互作用和精确 生物化学函数。在第二个目标下，蛋白酶网络对病原体的潜在影响 耐药性和耐受性以及蚊子适应性将使用常见的微生物挑战评估 模型和生命表分析。根据第三个目标，标准网络科学方法将用于 将系统中的所有蛋白酶相互作用可视化为静态多层网络，并分析该网络 推断蛋白水解通过将调子化和黑色化化连接并识别关键分子的流动流动 控制免疫力。拟议的研究具有创新性，因为它将首次评估蛋白酶 级联作为一个单一的集成网络，该网络控制多种免疫期间蚊子的体液免疫力 挑战。此外，该项目将使用网络科学作为研究的一种高度创新的方法 蚊子先天免疫，如果成功的话，它将转化为昆虫免疫学领域。这 项目很重要，因为它将对蛋白酶的贡献进行全面的了解 网络与蚊子健康以及系统的局限性在克服感染中的局限性。最终，这个 知识可以用于操纵感染结果，从而告知新的发展 旨在破坏其媒介中疟疾寄生虫发育的疾病控制策略。