Initiation and Regulation of Immune Protease Pathways

免疫蛋白酶途径的启动和调节

基本信息

批准号：
8322661
负责人：
HAOBO JIANG
金额：
$ 22.11万
依托单位：
OKLAHOMA STATE UNIVERSITY STILLWATER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-03-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8322661
关键词：
Arthropod Vectors Arthropods Bacteria Binding Biochemical Biological Assay Biological Models Blood coagulation Cessation of life Cleaved cell Cloning Collection Complement Activation Complementary DNA Complex Culicidae Detergents Drosophila genus Enzymes Evolution Feedback Filariasis Goals Gram-Negative Bacteria Gram-Negative Bacterial Infections Gram-Positive Bacteria Health Hemolymph Homologous Gene Immune Immune response Infection Insect Vectors Insecta Invaded Investigation Knowledge Lead Malaria Mammals Manduca sexta Mediating Melanins Microbe Molecular Molecular Probes Monophenol Monooxygenase Mycoses Natural Immunity Orthologous Gene Parasites Pathway interactions Peptide Hydrolases Plasma Plasmodium Positioning Attribute Principal Investigator Process Production Proteins Proteolytic Processing Quinones Reaction Regulation Research Roentgen Rays Role Serine Protease Source Structure Surface Sushi Domain System Testing Tissues antimicrobial peptide base biochemical model cofactor defense response disease transmission experience extracellular fungus genetic analysis grasp human disease in vivo insight killings microbial pathogen positional cloning pro-phenoloxidase programs protein complex protein purification public health relevance receptor receptor binding reconstitution resistance mechanism response transmission process vector

项目摘要

DESCRIPTION (provided by applicant): An extracellular serine protease network coordinates key mechanisms of insect defense against microbial infection. Proteolytic activation of prophenoloxidase (PPO) generates phenoloxidase that catalyzes the production of reactive compounds to sequester and kill invading pathogens and parasites. Proteolytic processing of sp¿tzle precursor triggers the Toll pathway, which induces the synthesis of antimicrobial peptides and other defense proteins. In insect vectors of human diseases, initiation and regulation of these protease systems may be disrupted by proteins from the intruders. Knowledge of such protein interactions from biochemical model insects such as Manduca sexta will be useful for understanding and manipulating similar systems in arthropod vectors to interfere with disease transmission. We have discovered a branch of the M. sexta protease network that detects Gram-positive bacteria and fungi and mediates PPO activation. In this network, pathogen recognition receptors bind to microbes and initiate protease pathways for PPO and Toll activation. We have identified a new Sushi-domain protease that may participate in a branch of the pathway responsive to Gram-negative bacterial infection. A positive feedback loop in the protease system controls locality and potency of the defense responses. We plan to extend our research on the PPO activation reaction by examining the initiation and regulation of immune protease pathways. The specific aims of this project are: 1) Characterization of the pathway initiation by Gram-negative bacteria; 2) Elucidation of the positive regulatory mechanisms in the protease system; 3) Investigation of the structure, function, and activation of M. sexta PPO. PUBLIC HEALTH RELEVANCE This research will continue to elucidate the function and regulation of a serine protease network during innate immune responses, which produces phenoloxidase and antimicrobial peptides to entrap and kill parasites that cause malaria and filariasis. The acquired knowledge will be useful for disrupting the transmission of human diseases in vector species.

描述（由申请人提供）：细胞外丝氨酸蛋白酶网络协调昆虫防御微生物感染的关键机制，原酚氧化酶（PPO）的蛋白水解激活产生酚氧化酶，该酶催化反应性化合物的产生，以隔离和杀死入侵的病原体和寄生虫。斯普tzle 前体触发 Toll 途径，诱导人类疾病的昆虫载体合成抗菌肽和其他防御蛋白，这些蛋白酶系统的启动和调节可能会被来自入侵者的蛋白质破坏。像 Manduca sexta 这样的昆虫将有助于理解和操纵节肢动物载体中的类似系统以干扰疾病传播。检测革兰氏阳性细菌和真菌并介导 PPO 激活在该网络中，病原体识别受体与微生物结合并启动 PPO 和 Toll 激活的蛋白酶途径。蛋白酶系统中的正反馈回路控制着防御反应的局部性和效力，我们计划通过检查免疫蛋白酶的启动和调节来扩展我们对 PPO 激活反应的研究。该项目的具体目标是：1）表征革兰氏阴性细菌的途径启动；2）阐明蛋白酶系统中的正向调节机制；3）研究支原体的结构、功能和激活。公共健康相关性这项研究将继续阐明先天免疫反应过程中丝氨酸蛋白酶网络的功能和调节，该网络产生酚氧化酶和抗菌肽诱捕并杀死引起疟疾和丝虫病的寄生虫。所获得的知识将有助于阻断人类疾病在媒介物种中的传播。