Role of TGF-beta signaling in the Drosophila immune response against nematode-bacteria complexes

 描述(申请人提供)：寄生性线虫(PN)感染仍然是全球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。控制策略仅限于对感染者进行定期驱虫，这受到快速再感染率和抗药性蠕虫种群发展的限制。目前还没有针对人类PN感染的疫苗。新药和疫苗的开发将需要更好地了解参与对PN感染的免疫反应的宿主因素。对合适宿主的要求和良好动物模型的缺乏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个模式生物组成的系统：昆虫，黑腹果蝇；昆虫和人类的Pn Heterorhabditis Gerrardi；以及它的互生细菌--共生光杆菌。这个系统是独一无二的，因为它不仅可以揭示病原体如何进化毒力，而且还可以揭示两种病原体(蠕虫和细菌)如何协同利用共同的宿主(昆虫)。尽管果蝇体内主要的NF-κB免疫信号通路已被鉴定和鉴定，但其他进化保守的通路可能调节宿主的免疫机制。最近发现转化生长因子-β(转化生长因子-β)超家族信号调节果蝇对创伤和细菌感染的免疫应答，初步证据表明转化生长因子-β(β-β)通路的某些信号分子可能参与果蝇对线虫及其相关细菌的免疫应答。我们将利用这些信息来阐明转化生长因子-β信号成分在果蝇抗线虫病中的确切作用和抗菌防御机制。在目标1中，我们将分析果蝇组织中转化生长因子-β信号的特异性转录调控 成员感染异形虫病和杆状杆菌，以及转化生长因子-β信号与其他先天免疫途径的潜在干扰。在目标2中，我们建议研究转化生长因子-β分子是否调节细胞免疫功能，以及后者是否与病原体的体液反应相互作用。在目标3中，我们将探讨转化生长因子-β信号转导通路在果蝇感染无菌异弯杆菌或共生线虫或光杆菌感染果蝇的酚氧化酶/黑化反应中的作用。我们期望这一项目的结果将对转化生长因子-β信号分子在宿主抗线虫/抗细菌免疫反应中的潜在作用产生新的见解，从而可能揭示目前未知的先天免疫系统的一层。这些知识将大大有助于开发改进的做法，以控制人类的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 a suitable 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 insect and human PN Heterorhabditis gerrardi; and its mutualistic bacteria Photorhabdus asymbiotica. 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 suggesting that certain TGF-β pathway signaling molecules are potentially involved in the fly immune response against the nematodes and their associated bacteria. We will use this information to elucidate the exact role of TGF-β signaling components in Drosophila antinematode and antibacterial defense mechanisms. In Aim 1, we will analyze the Drosophila tissuespecific transcriptional regulation of TGF-β signaling members upon infection with Heterorhabditis and Photorhabdus, and the potential interference of TGF-β signaling with other innate immune pathways. In Aim 2, we propose to examine whether TGF-β molecules modulate cellular immune functions and whether the latter interact with humoral reactions in response to the pathogens. In Aim 3, we will explore the involvement of TGF-β signaling in the phenoloxidase/melanization response of Drosophila flies infected with Heterorhabditis axenic or symbiotic nematodes or Photorhabdus bacteria alone. We expect that the results from this project will generate novel insights into the potential role of TGF-β signalng molecules in the host anti-nematode/antibacterial immune response and thus 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.