SYSTEMIC AND EPITHELIAL INSECT IMMUNITY

全身和上皮昆虫免疫

• 批准号: 6336274
• 负责人: JULES A HOFFMAN
• 金额: $ 25.66万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6336274
• 关键词: Anopheles; Drosophilidae; epithelium; gene expression; gene mutation; immunity; immunoregulation; laboratory mouse; mass spectrometry; microorganism immunology; molecular cloning; molecular genetics; protein structure function; receptor; serine proteinases; tissue /cell culture

This project focuses on the structure, regulation, and function of genes involved in insect immunity, which shows close parallels to innate immunity in mammals. Our work concentrates on two model dipteran insects, the fruitfly Drosophila melanogaster and the malaria vector mosquito Anopheles gambiae. Because of its powerful genetics, Drosophila is an excellent model system in which to isolate new genes involved in immunity, and to functionally characterize their protein products. Anopheles is a system of choice to decipher the innate response of vector insects to the medically important parasites they carry. Previous work using the Drosophila model has led to the identification of many immune inducible antimicrobial peptides. Interestingly, these peptides can be grouped according to their targets, with some being active against fungi, and other against Gram-negative and/or Gram-positive bacteria. It has recently been shown that the antimicrobial response of Drosophila is not non- specific but can discriminate among various classes of microorganisms, reflected in differential expression of genes encoding antibacterial and antifungal peptides following injection of distinct microorganisms. Similarly, different levels of induction of immune markers by different bacteria have been observed in cell lines derived from the mosquito A. gambiae. In addition, recent work has revealed that exposure of surface epithelia to microorganisms results in induction of an immune response in Anopheles and Drosophila. Taken together, these results raise the question of the nature, structure and function of the molecules involved in infectious non-self recognition in insects, elucidation of which constitutes the main goal of this proposal. Over the next few years, we plan to 1) characterize molecularly the factors involved in recognition of fungi, bacteria, and protozoan parasites in Drosophila and Anopheles; 2) examine the functional importance and roles of these molecules in insect systemic and local immunity; 3) identify the molecules mediating the transduction of recognition into an immune response. Abundant precedents exist testifying that evolutionary conservation between insects and mammals is such that comparative analysis of regulatory phenomena in these two groups of animals is very fruitful. To give but one example from an earlier collaboration that led to this Programme Project application, the demonstration that the TOLL receptor is involved in the antifungal immunity in Drosophila directly stimulated the identification and functional characterization of the TOLL homologue in humans. We are applying jointly with our colleagues for a Programme Project Grant because we are confident that the structural and functional comparison of molecules recognizing molecular patterns on thy surface of microorganisms in mammals and insects will provide better insight into the mechanisms and evolution of first line host defense. In addition, these studies will aid understanding of how insects react to infection, and can be refractory to transmission of medically important parasites.

该项目重点研究基因的结构、调控和功能 参与昆虫免疫，这与先天免疫非常相似 哺乳动物的免疫力。我们的工作集中在两种双翅目昆虫模型上， 果蝇 黑腹果蝇 和疟疾媒介蚊子 冈比亚按蚊。由于其强大的遗传学，果蝇是 优秀的模型系统，可分离涉及免疫的新基因， 并对其蛋白质产品进行功能表征。按蚊是一种 选择系统来破译媒介昆虫对昆虫的先天反应 它们携带有医学上重要的寄生虫。之前的工作使用 果蝇模型已导致许多免疫诱导因子的鉴定 抗菌肽。有趣的是，这些肽可以分为 根据他们的目标，其中一些对真菌具有活性，并且 其他针对革兰氏阴性和/或革兰氏阳性细菌。最近有 研究表明，果蝇的抗菌反应并非非 特定但可以区分不同类别的微生物， 反映在编码抗菌基因的差异表达上 注射不同微生物后的抗真菌肽。 同样，不同水平的免疫标记物的诱导水平也不同。 在源自蚊子 A 的细胞系中观察到细菌。 冈比亚。此外，最近的工作表明，表面暴露 上皮细胞对微生物的作用会导致免疫反应的诱导 按蚊和果蝇。 总而言之，这些结果提出了性质、结构的问题 参与传染性非自我识别的分子和功能 在昆虫中，阐明这一点是本研究的主要目标 提议。在接下来的几年里，我们计划 1) 进行分子表征 参与识别真菌、细菌和原生动物的因素 果蝇和按蚊中的寄生虫； 2）检查功能 这些分子在昆虫全身和局部的重要性和作用 免疫; 3) 鉴定介导转导的分子 识别进入免疫反应。 存在大量先例证明进化保守 昆虫和哺乳动物之间的比较分析 这两类动物的调节现象是非常富有成效的。到 仅举一个早期合作的例子，该合作导致了这一结果 项目申请，TOLL受体的论证 参与果蝇的抗真菌免疫，直接刺激 TOLL同源物的鉴定和功能表征 人类。我们正在与我们的同事共同申请一个计划 项目拨款，因为我们有信心结构和功能 分子比较识别表面上的分子模式 哺乳动物和昆虫体内的微生物将提供更好的了解 一线宿主防御的机制和演变。此外，这些 研究将有助于了解昆虫对感染的反应，并且可以 对医学上重要的寄生虫的传播具有抵抗力。