Role of TGF-B signaling molecules as regulators of host immune and metabolic response to parasitic nematode infection factors

寄生线虫感染是全世界人类健康的主要威胁。目前，没有疫苗可用于人类寄生线虫感染。开发新的药物和疫苗将需要更好地了解参与寄生线虫感染分子免疫反应的宿主因素。由于缺乏合适的宿主和良好的动物模型，限制了对动物抵抗寄生线虫攻击的防御机制的研究。该项目将采用由两种模式生物组成的系统：昆虫果蝇和昆虫寄生线虫异小杆线虫，以提供寄生虫感染过程及其对宿主免疫力影响的机理见解。我们将把我们的注意力集中在异小杆线虫在感染过程中产生的致病因子的活性，以研究其与宿主抗线虫免疫功能的相互作用。这项研究的结果将产生新的信息，主机组件的作用，在编排一个有效的反应，对寄生线虫。这些发现有望大大有助于开发限制人类寄生线虫感染的创新策略。来自托马斯杰斐逊科学技术高中（TJHSST;亚历山大，弗吉尼亚州）的高中生将接受动手实验室培训，他们将积极参与研究。 尽管在先天免疫领域取得了重要进展，但宿主对寄生线虫感染的免疫反应目前研究不足。果蝇和昆虫病原线虫异小杆线虫形成了一个杰出的系统，以阐明宿主的先天抗线虫免疫。转化生长因子-β（TGF-β）信号传导参与几个重要的生物学过程。该提议的假设是宿主TGF-β信号传导活性调节针对寄生线虫感染因子的组织特异性免疫和代谢机制。本课题旨在研究异小杆线虫丝氨酸肽酶（Heterorhabditis serine peptidase，SP）对果蝇TGF-β信号转导和免疫代谢功能的影响。我们将分析异小杆线虫重组丝氨酸肽酶（Heterorhabditis recombinant serine peptidase，rSP）对果蝇组织特异性激活素信号的转录调控，以及TGF-β信号与NF-κB天然免疫信号之间的相互关系。此外，我们将研究激活素信号是否在果蝇调节细胞免疫，以及后者是否与体液免疫反应异小杆线虫rSP相互作用。最后，我们将研究激活素信号转导和脂质代谢之间的相互作用，在果蝇的挑战与异小杆线虫rSP。这项研究的结果将产生新的信息激活素在宿主免疫代谢反应对昆虫病原线虫的作用。这些发现可能揭示了宿主先天抗线虫免疫系统的一种以前未知的调节因子，因此有望有助于开发控制有害昆虫害虫的创新方法。来自托马斯杰斐逊科技高中（TJHSST;亚历山大，弗吉尼亚州）的高中生将在实验室接受培训，参与研究的各个方面。该奖项反映了NSF的法定使命，并被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

Parasitic nematode infections represent a major threat to human health worldwide. Currently, there are no vaccines available for parasitic nematode infections in humans. Development of new drugs and vaccines will require a better understanding of host factors that participate in the immune response to parasitic nematode infection molecules. The requirement of a suitable host and the lack of good animal models have limited investigations into the defense mechanisms that animals activate to oppose parasitic nematode attacks. This project will employ a system consisting of two model organisms: an insect, Drosophila and the insect parasitic nematode Heterorhabditis to provide mechanistic insight into parasitic infection processes and their effect on host immunity. We will focus our attention to the activity of a pathogenicity factor that is produced in Heterorhabditis nematodes during infection to investigate its interaction with host anti-nematode immune functions. Results from this research will generate novel information on the role of host components in orchestrating an effective response against parasitic nematodes. Such findings are expected to contribute considerably to the development of innovative tactics to restrict parasitic nematode infections in humans. High school students from Thomas Jefferson High School for Science and Technology (TJHSST; Alexandria, VA) will receive hands-on lab training and they will be actively involved in the research. Despite important progress in the innate immunity field, host immune responses to parasitic nematode infection are currently understudied. Drosophila and the entomopathogenic nematode Heterorhabditis form an outstanding system to elucidate host innate anti-nematode immunity. Transforming Growth Factor-beta (TGF-β) signaling participates in several important biological processes. The hypothesis of this proposal is that host TGF-β signaling activity regulates tissue-specific immune and metabolic mechanisms against parasitic nematode infection factors. The goal of this project is to explore the effect of Heterorhabditis serine peptidase (SP) on TGF-β signaling regulation and immunometabolic function in Drosophila. We will analyze the Drosophila tissue-specific transcriptional regulation of Activin signaling upon injection with Heterorhabditis recombinant serine peptidase (rSP) and the interrelationship between TGF-β signaling and NF-κB innate immune signaling. Also, we will examine whether Activin signaling in Drosophila modulates cellular immunity and whether the latter interacts with humoral immunity in response to Heterorhabditis rSP. Finally, we will investigate the interaction between Activin signaling and lipid metabolism in Drosophila upon challenge with Heterorhabditis rSP. Results from this research will generate novel information on the role of Activin in the host immunometabolic response against entomopathogenic nematodes. Such findings may expose a previously unknown regulator of the host innate anti-nematode immune system and therefore are expected to contribute to the development of innovative approaches for controlling harmful insect pests. High school students from Thomas Jefferson High School for Science and Technology (TJHSST; Alexandria, VA) will be trained in the lab to participate in all aspects of the research.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.