Role of TGF-Beta signaling in the Drosophila immune response against nematode-bac

TGF-β信号在果蝇针对线虫-bac的免疫反应中的作用

基本信息

批准号：
8891791
负责人：
Ioannis Eleftherianos
金额：
$ 22.88万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8891791
关键词：
Adult Affect Animal Model Animals Anti-Bacterial Agents Antigen Targeting Antiparasitic Agents Bacteria Bacterial Infections Biological Assay Biological Process Child Defense Mechanisms Development Drosophila genus Drosophila melanogaster Drug Targeting Drug resistance Elderly Genetic Transcription Health Hemocytes Host Defense Human Immune Immune response Immune system Individual Infection Insecta Integration Host Factors Investigation Knowledge Label Lead Location Metabolic Microbe Modeling Monitor Monophenol Monooxygenase Morbidity - disease rate Natural Immunity Nematoda Nematode infections Parasites Parasitic nematode Pathologic Pathology Pathway interactions Pharmaceutical Preparations Photorhabdus Physiological Plague Population Pregnant Women Reaction Regulation Role Signal Pathway Signal Transduction Signaling Molecule Staining method Stains Study models System Techniques Testing Tissues Transcriptional Regulation Transforming Growth Factor beta Vaccine Antigen Vaccines Virulence Wound Infection Xenorhabdus luminescens antimicrobial peptide fly immune activation immune function improved insect genetics insight member mutant novel pathogen response

项目摘要

DESCRIPTION (provided by applicant): Parasitic nematode (PN) infections remain a major threat to human health worldwide, with more than 1 billion people infected. Children, pregnant women, and the elderly are particularly susceptible to morbidity from nematode infection. Control strategies are restricted to periodic de-worming of infected individuals, which is limited by rapid re-infection rates and the development of drug resistant worm populations. There are no vaccines available for PN infections in humans. Development of new drugs and vaccines will require a better understanding of host factors that participate in the immune response against PN infection. The requirement of an obligate host and the lack of good animal models have limited investigations into mechanisms that animal hosts employ to oppose PN attacks. Here we propose to use a system consisting of three model organisms: an insect, Drosophila melanogaster; the entomopathogenic (or insect parasitic) nematode Heterorhabditis bacteriophora; and its symbiotic bacteria Photorhabdus luminescens. This system is unique because it promises to reveal not only how pathogens evolve virulence but also how two pathogens (worm and bacteria) can synergize to exploit a common host (insect). Despite the identification and characterization of the main NF-κB immune signaling pathways in Drosophila, other evolutionary conserved pathways might regulate host immune mechanisms. It was recently shown that Transforming Growth Factor-beta (TGF-β) superfamily signals modulate the Drosophila immune response to wounding and bacterial infection and we have preliminary evidence that certain TGF-β pathway signaling molecules are potentially involved in the response against Heterorhabditis nematodes. We will use this information to investigate the exact role of TGF-β signaling components in Drosophila anti-nematode and antibacterial defense mechanisms. In Aim 1, we will analyze the Drosophila tissue-specific transcriptional response of TGF-β signaling members to Heterorhabditis and Photorhabdus, and the interaction between TGF-β signaling and other innate immune pathways. In Aim 2, we propose to examine whether TGF-β molecules modulate cellular immune functions and their interaction with humoral reactions against Heterorhabditis nematodes and their Photorhabdus bacteria. In Aim 3, we plan to study the pathologic effects caused by the two pathogens, separately or together, to Drosophila flies with compromised TGF-β signaling. We expect that the results from this project will generate novel insights into the immune role of TGF-β signaling molecules and may expose a currently unknown layer of the innate immune system. Such knowledge will contribute significantly to the development of improved practices to control PN in humans.

描述（由申请人提供）：寄生线虫 (PN) 感染仍然是全世界人类健康的主要威胁，有超过 10 亿人感染。儿童、孕妇和老年人特别容易受到线虫感染的影响。仅限于对感染个体进行定期驱虫，这受到快速再感染率和耐药蠕虫种群发展的限制。目前还没有针对人类 PN 感染的疫苗和新药物的开发。疫苗需要更好地了解参与针对 PN 感染的免疫反应的宿主因素。对专性宿主的要求和良好动物模型的缺乏限制了对动物宿主抵抗 PN 攻击的机制的研究。使用由三种模式生物组成的系统：昆虫，黑腹果蝇；昆虫病原性（或昆虫寄生）线虫异杆菌；及其共生细菌发光杆菌；该系统是独特的，因为它不仅揭示了病原体如何进化毒力，而且揭示了两种病原体（蠕虫和细菌）如何协同利用共同宿主（昆虫），尽管主要的 NF-κB 免疫已被识别和表征。除了果蝇中的信号通路外，其他进化保守的通路也可能调节宿主免疫机制。最近研究表明，转化生长因子-β (TGF-β) 超家族信号可调节果蝇对伤害和伤害的免疫反应。细菌感染，我们有初步证据表明某些 TGF-β 通路信号分子可能参与针对异杆线虫的反应，我们将利用这些信息来研究 TGF-β 信号成分在果蝇抗线虫和抗菌防御机制中的确切作用。在目标 1 中，我们将分析 TGF-β 信号成员对异杆菌属和发光杆菌属的果蝇组织特异性转录反应，以及它们之间的相互作用在目标 2 中，我们建议检查 TGF-β 分子是否调节细胞免疫功能及其与异杆线虫及其发光杆菌细菌的体液反应的相互作用。两种病原体单独或共同对 TGF-β 信号传导受损的果蝇造成的病理影响，我们预计该项目的结果将为了解 TGF-β 信号传导的免疫作用提供新的见解。 TGF-β 信号分子可能会暴露先天免疫系统中目前未知的一层，这些知识将极大地促进人类 PN 控制改进实践的发展。