Systematic analysis of cell death regulation in mosquitoes

蚊子细胞死亡调控的系统分析

• 批准号: 7645220
• 负责人: Lei Zhou
• 金额: $ 32.28万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645220
• 关键词: Aedes; Anopheles Genus; Anopheles gambiae; Apoptosis; Apoptotic; Baculoviruses; Binding; Bioinformatics; Caspase; Caspase Gene; Cell Death; Cells; Classification; Culex (Genus); Culicidae; Data; Development; Drosophila genus; Enzymes; Gene Family; Genes; Genetic; Genome; Infection; Insecta; Life Cycle Stages; Malaria; Mediating; Mosquito Control; Orthologous Gene; Parasites; Pathway interactions; Play; Population; Preparation; Regulation; Resources; Role; Stress; Tissues; Title; Virus; Virus Diseases; West Nile virus; Work; disorder control; genome sequencing; inhibitor-of-apoptosis protein; pathogen; response; vector; vector-induced

Title: Systematic analysis of cell death regulation in mosquitoes. Cell death (apoptosis) is an important component of the vector/host immuno-response mechanism. It has been implicated in the infectious life cycle of a variety of pathogens, such as the malaria parasite and the West Nile virus, in mosquitoes. However, our understanding of cell death regulation in mosquitoes has been hindered greatly by the lacking of a complete list of major insect cell death regulators, i.e. the *Reaper/Hid/Grim -like IAP-antagonists, in the annotated mosquito genomes. IAPs (Inhibitor of Apoptosis Proteins) are the essential ¿Brake¿ of the core cell death machinery in insects. They bind to caspases and inhibit the activity of these ¿deadly¿ enzymes. Genetic studies in Drosophila have shown that most programmed cell death during development is mediated through specific expression of IAP-antagonists such as reaper, hid, and grim (RHG) in cells destined to die. Most of these IAP-antagonists are also required for mediating cell death in response to environmental stress. The genome project for the primary malaria vector, Anopheles gambiae, revealed a significant expansion of the IAP and caspase gene families when compared to Drosophila. This was postulated to reflect the functional requirement of fine-tuning cell death regulation in response to parasite and virus infection. It also strongly implies that the IAP-antagonist ?? IAP ?? Caspases pathway, as is in Drosophila, is fundamentally important for cell death regulation in mosquitoes. However, due to extensive sequence divergence, the annotated complete An. gambiae genome sequence did not initially include any ortholog of RHG-like IAP-antagonist. Using a systematic bioinformatics approach, we identified and subsequently characterized the first RHG-like IAPantagonists, michelob_x (mx), in Anopheles and Aedes genomes. To probe the involvement of these pro-apoptotic genes in mediating vector-pathogen interaction, we identified the mx ortholog in Culex and found that it is induced by CuniNPV (a mosquito baculovirus) infection to Cx.quinauifasciatus (section 4.5; Zhou et al, in preparation). In addition, we have identified another IAP-antagonist, IBMP6, as the ortholog of Drosophila Hid. Interestingly, ibmp6 is induced by MIV infection of the Aag2 cells (section 4.6). These data indicate that like in Drosophila, multiple IAP-antagonist are required for cell death regulation in mosquito. Further more, distinct IAP-antagonists is(are) utilized against different infections or in different tissues. Since the IAP-antagonist genes play pivotal roles in insect cell death regulation and our work revealed that they are involved in pathogen-induced vector response, elucidating fully this group of genes in mosquitoes will be essential for the comprehensive understanding of cell death regulation in response to pathogen challenge as well as during normal mosquito life cycle. This proposed project aims at (1) Systematic identification and functional verification of the IAP-antagonists in major mosquito genomes. (2)Elucidating the role of these IAP-antagonists in mediating vector-pathogen interaction using CuniNPV, MIV, and B.algerae. (3) Developing public resources for systematic analysis of cell death regulation in mosquitoes. Cell death (apoptosis) is implicated in the infectious life cycle of a variety of pathogens, such as the malaria parasite and the West Nile virus, in mosquitoes. Understanding cell death response will help us to develop strategy for controlling mosquito transmitted disease and for controlling mosquito population.

标题：蚊子中细胞死亡调节的系统分析。 细胞死亡（凋亡）是载体/宿主免疫反应的重要组成部分 机制。在多种病原体的传染性生命周期中，它已被暗示，例如 疟原虫和西尼罗河病毒在蚊子中。但是，我们对细胞死亡的理解 由于缺乏完整的主要昆虫清单，蚊子中的调节受到了极大的阻碍 细胞死亡调节剂，即在注释的蚊子中 *收割机/HID/GRIM类似IAP抗逆抗激素 基因组。 IAP（凋亡蛋白的抑制剂）是核心细胞死亡机械的必需制动器 在昆虫中。它们与胱天蛋白酶结合并抑制这些致命的酶的活性。遗传研究 在果蝇中，发育过程中大多数编程的细胞死亡都是通过 在注定死亡的细胞中，诸如收割者，HID和Grim（RHG）等IAP抗逆抗突的特定表达。 这些IAP抗逆邦剂大多数也需要介导细胞死亡，以应对环境 压力。原发性疟疾载体的基因组项目，Anopheles Gambiae，揭示了一个 与果蝇相比，IAP和caspase基因家族的显着扩展。这是 发表以反映以响应微调细胞死亡调节的功能要求 寄生虫和病毒感染。这也强烈暗示了IAP抗逆转录病毒学家？ IAP ?? caspase 与果蝇一样，途径对于蚊子中的细胞死亡调节至关重要。 但是，由于序列差异很大，注释已完成。冈比亚基因组 序列最初不包括任何RHG样的IAP抗逆邦剂的直系同源物。使用系统 生物信息学方法，我们确定并随后表征了第一个RHG样的Iapantagonists， Michelob_x（MX），在肛门和艾德斯基因组中。探究这些的参与 促凋亡基因介导载体 - 病原体相互作用，我们确定了Culex中的MX直系同源物 并发现它是由cuninpv（蚊子杆菌病毒）感染引起的。 （第4.5节； Zhou等人，在准备中）。此外，我们已经确定了另一个IAP抗Antagonist， IBMP6，作为果蝇的直系同源物。有趣的是，IBMP6是由MIV感染引起的 AAG2细胞（第4.6节）。这些数据表明，与果蝇一样 蚊子中细胞死亡调节所必需的。此外，使用了独特的IAP抗逆邦大竞争者 针对不同的感染或不同组织。 由于IAP抗逆邦基因在昆虫细胞死亡调节中起关键作用，我们的工作 发现它们参与了病原体诱导的载体反应，完全阐明了这组 蚊子中的基因对于对细胞死亡调节的全面了解至关重要 对病原体挑战以及正常蚊子生命周期的反应。这个建议的项目 目的是（1）主要的IAP抗逆邦剂的系统识别和功能验证 蚊子基因组。 （2）阐明这些IAP抗逆邦剂在介导载体 - 病原体中的作用 使用CuninPV，MIV和B.Algerae相互作用。 （3）开发系统的公共资源 分析蚊子中的细胞死亡调节。 细胞死亡（细胞凋亡）在多种病原体的传染性生命周期中隐含 寄生虫和西尼罗河病毒在蚊子中。了解细胞死亡反应将有助于我们发展 控制蚊子传播疾病和控制蚊子种群的策略。