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

描述（由申请人提供）：寄生线虫（PN）感染仍然是全球人类健康的主要威胁，感染人数超过10亿。儿童、孕妇和老年人特别容易因线虫感染而发病。控制策略仅限于对受感染个体进行定期除虫，这受到再感染率高和耐药蠕虫种群发展的限制。目前还没有针对人类泌尿系膜感染的疫苗。新药和疫苗的开发将需要更好地了解参与抗PN感染免疫反应的宿主因子。对特定宿主的要求和缺乏良好的动物模型限制了对动物宿主用来对抗PN攻击的机制的研究。在这里，我们建议使用一个由三种模式生物组成的系统：一种昆虫，果蝇；昆虫病原（或昆虫寄生）线虫；及其共生细菌光habduus luminesens。这个系统是独特的，因为它不仅有望揭示病原体如何进化毒力，而且还揭示了两种病原体（蠕虫和细菌）如何协同利用一个共同的宿主（昆虫）。尽管果蝇主要的NF-κB免疫信号通路已被鉴定和表征，但其他进化保守的通路可能调节宿主免疫机制。最近有研究表明，转化生长因子-β (TGF-β)超家族信号调节果蝇对损伤和细菌感染的免疫反应，我们有初步证据表明某些TGF-β通路信号分子可能参与对异虫性线虫的免疫反应。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Aim 1中，我们将分析TGF-β信号传导成员对Heterorhabditis和光habdus的果蝇组织特异性转录应答，以及TGF-β信号传导与其他先天免疫途径的相互作用。在Aim 2中，我们提出研究TGF-β分子是否调节细胞免疫功能及其与针对异habditis线虫及其光habduus细菌的体液反应的相互作用。在Aim 3中，我们计划研究这两种病原体单独或共同对TGF-β信号通路受损的果蝇的病理影响。我们期望这个项目的结果将对TGF-β信号分子的免疫作用产生新的见解，并可能揭示目前未知的先天免疫系统层。这些知识将大大有助于改进实践的发展，以控制人类PN。

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.