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

寄生性线虫感染是世界范围内对人类健康的主要威胁。目前，还没有针对人体寄生性线虫感染的疫苗。开发新的药物和疫苗将需要更好地了解参与对寄生线虫感染分子的免疫反应的宿主因素。对合适宿主的要求，以及缺乏良好的动物模型，限制了对动物为抵御寄生线虫攻击而激活的防御机制的研究。该项目将使用一个由两种模式生物组成的系统：一种昆虫，果蝇和昆虫寄生线虫异形线虫，以提供对寄生感染过程及其对宿主免疫的影响的机械性洞察。我们将重点关注异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关于寄主成分在协调对寄生线虫的有效反应中的作用的新信息。预计这些发现将大大有助于开发限制人类寄生性线虫感染的创新策略。来自托马斯·杰斐逊科技高中(TJHSST；弗吉尼亚州亚历山大市)的高中生将接受动手实验室培训，他们将积极参与研究。尽管在天然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仍未得到充分研究。果蝇和昆虫病原线虫异形线虫是阐明寄主天然抗线虫免疫的一个重要系统。转化生长因子-β(TGFR-β)信号转导参与多种重要的生物学过程。该方案的假设是宿主转化生长因子β信号活性调节组织特异性免疫和代谢机制，以对抗寄生线虫感染因子。本课题的目的是探讨异杆菌丝氨酸肽酶(SP)对果蝇转化生长因子-β信号调节和免疫代谢功能的影响。我们将分析异形藻重组丝氨酸肽酶对果蝇体内激活素信号的组织特异性转录调控，以及转化生长因子-β信号与核因子-κB天然免疫信号之间的相互关系。此外，我们还将研究果蝇体内的激活素信号是否调节细胞免疫，以及后者是否与体液免疫相互作用，以响应异形杆虫病RSP。最后，我们将研究激活素信号与果蝇脂代谢之间的相互作用。这项研究的结果将产生关于激活素在宿主对昆虫病原线虫的免疫代谢反应中所起作用的新信息。这些发现可能会揭示寄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害虫的创新方法。来自托马斯·杰斐逊科技高中(TJHSST；弗吉尼亚州亚历山大市)的高中生将在实验室接受参与所有方面研究的培训。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.