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

 描述（由申请方提供）：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。目前尚无针对人类PN感染的疫苗。开发新的药物和疫苗将需要更好地了解参与针对PN感染的免疫应答的宿主因素。需要一个合适的主机和缺乏良好的动物模型，限制了调查的机制，动物宿主采用反对PN攻击。在这里，我们建议使用一个系统，包括三个模式生物：昆虫，果蝇;昆虫和人类PN异小杆线虫gerrardi;和它的互利共生细菌Photorhabdus asybiotica。该系统是独一无二的，因为它不仅有望揭示病原体如何进化毒力，而且还揭示两种病原体（蠕虫和细菌）如何协同利用共同的宿主（昆虫）。尽管在果蝇中主要的NF-κB免疫信号通路已被鉴定和表征，但其他进化上保守的通路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）超家族信号调节果蝇对创伤和细菌感染的免疫应答，我们有初步证据表明某些TGF-β途径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TGF-β信号组分在果蝇抗线虫和抗菌防御机制中的确切作用。目的1：分析果蝇TGF-β信号转导的组织特异性转录调控 在感染异小杆菌属和光小杆菌属后，TGF-β信号传导对其他先天免疫途径的潜在干扰。在目的2中，我们建议检查TGF-β分子是否调节细胞免疫功能，以及后者是否与应答病原体的体液反应相互作用。在目标3中，我们将探索TGF-β信号转导在果蝇感染异小杆线虫或共生线虫或光杆菌单独感染的酚氧化酶/黑化反应中的参与。我们期望该项目的结果将对TGF-β信号分子在宿主抗线虫/抗菌免疫应答中的潜在作用产生新的见解，从而可能揭示先天免疫系统的当前未知层。这些知识将大大有助于开发更好的实践来控制人类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 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.