Mechanism of mosquito complement-like immunity

蚊子补体样免疫机制

• 批准号: 9036411
• 负责人: Richard H. G. Baxter
• 金额: $ 30.64万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036411
• 关键词: Address; Affect; Affinity; Africa South of the Sahara; Alleles; Anaphylatoxins; Anopheles gambiae; Arthropods; Bacteria; Binding; Biochemical; Biology; Body cavities; Chemicals; Cleaved cell; Co-Immunoprecipitations; Collaborations; Complement; Complement 3a; Complement component C1; Complex; Crystallography; Culicidae; Deposition; Development; Disease; Electron Microscopy; Evolution; Family; Genes; Genome; Health; Homologous Gene; Human; Hydrolysis; Hydroxyl Radical; Immune response; Immune system; Immunity; Infection; Injection of therapeutic agent; Insect Control; Insecta; Intervention; Investigation; Knowledge; Label; Length; Light; Malaria; Mass Spectrum Analysis; Mediating; Methods; Molecular; Mosquito-borne infectious disease; Natural Immunity; Outcome Study; Parasites; Parasitic Diseases; Peptide Hydrolases; Phenotype; Plasmodium berghei; Plasmodium falciparum; Play; Population; Predisposition; Proteins; Recruitment Activity; Regulation; Rodent; Role; Serine Protease; Specificity; Structure; Structure-Activity Relationship; Surface; System; Validation; Vector-transmitted infectious disease; Vertebrates; base; biophysical techniques; body cavity; complement system; crosslink; in vivo; inhibitor/antagonist; leucine-rich repeat protein; malaria infection; novel; pathogen; prevent; thioester; three dimensional structure; transmission process; vector

 DESCRIPTION (provided by applicant): Anopheline mosquitoes transmit malaria, the world's most devastating parasitic disease, of which Anopheles gambiae is the principal vector for malaria in Sub-Saharan Africa. Different populations of mosquitoes vary widely in how readily they become infected with malaria parasites, while some strains do not transmit malaria at all. The mosquitoes' innate immune system is a significant factor that may influence the level of malaria infection; in particular the thioester-containing protein 1 (TEP1) targets malaria parasite for destruction during their initial invasion of the body cavity. The TEP1 gene varies significantl across mosquito populations with two major classes of alleles, TEP1*S and TEP1*R, that have been shown to directly influence the susceptibility to P. falciparum. In this project we will study the structure-function relationship between TEP1 alleles and their interaction with a mosquito-specific family of leucine-rich repeat proteins, the LRIM1/APL1 family. We will also study the diversity of structure and function associated with three closely-related LRR proteins APL1A, APL1B and APL1C, that influence the specificity of the TEP1 immune response. Finally, we will study the structure and function of three CLIP domain serine protease homologs (SPHs) that regulate downstream effects of TEP1 deposition, specifically melanization. The results of this project will shed light on the mechanism of mosquitoes' natural immunity to malaria infection and support the development of new vector-based transmission-blocking strategies.

 描述（由申请人提供）：按蚊传播疟疾，这是世界上最具破坏性的寄生虫病，其中冈比亚按蚊是撒哈拉以南非洲疟疾的主要媒介。不同种群的蚊子在感染疟原虫的容易程度上差异很大，而有些菌株根本不会传播疟疾。蚊子的先天免疫系统是可能影响疟疾感染水平的重要因素;特别是含硫酯蛋白1（TEP 1）在疟疾寄生虫最初入侵体腔期间靶向其进行破坏。TEP 1基因在蚊子种群中变化显著，具有两类主要的等位基因，TEP 1 *S和TEP 1 *R，其已被证明直接影响对恶性疟原虫的易感性。在这个项目中，我们将研究 TEP 1等位基因之间的结构-功能关系及其与蚊子特异性富含亮氨酸重复蛋白家族LRIM 1/APL 1家族的相互作用。我们还将研究与三种密切相关的LRR蛋白APL 1A，APL 1B和APL 1C相关的结构和功能的多样性，这些蛋白影响TEP 1免疫反应的特异性。最后，我们将研究三个CLIP结构域丝氨酸蛋白酶同源物（SPH）的结构和功能，调节TEP 1沉积的下游效应，特别是黑化。该项目的结果将揭示蚊子对疟疾感染的天然免疫机制，并支持开发新的基于媒介的传播阻断策略。