BBSRC-NSF/BIO: Regulatory control of the system-wide innate immune response in marine invertebrates

动物生活在不断变化的环境中，这些环境富含微生物。免疫系统的作用是首先识别这些微生物，然后通过保护宿主或允许微生物生长来做出适当的反应，作为精心调节的互利关系的一部分。然而，尽管经过数十年的研究，免疫系统只在少数物种（人类和小鼠）中进行了详细研究。 拟议的工作将通过调查棘皮动物的免疫反应，特别是海胆和海星的幼虫阶段，来解决这一知识空白。这些幼虫是形态简单，透明的动物，在变形前几个月在海洋中游泳和进食。 在这个项目中，这是奥本大学（美国）和伦敦大学学院（英国）研究人员之间的合作。幼虫将暴露于特定的海洋细菌，引发免疫反应。 将感染的幼虫解离成单细胞，其将用于测量基因表达的变化。 这些实验将确定动物免疫系统的基本方面，并确定治疗疾病的新策略。这些科学研究结果将辅之以更多的战略，以使更广泛的社会各阶层参与进来。这包括为小学生举办海洋讲习班，并参加奥本大学为当地资源不足学校的初中和高中学生举办的互动式开放日。本文提出的这项工作采用了一种协作方法，将最近可用的基因组序列与以单细胞分辨率定量基因表达的新技术相结合。这种系统水平的方法将定义控制不同棘皮动物物种免疫反应的调控机制，以确定动物免疫的基本特性以及物种特异性适应。通过保护宿主免受有害病原体的侵害并培养有益的微生物群，免疫系统在动物进化的最前沿发挥作用。为了应对快速进化的微生物，动物依靠复杂的机制来检测和消除病原体。这些机制与维持细胞内稳态和解决应激的宿主机制交织在一起。该提案的目的是了解进化压力如何塑造介导免疫反应的细胞。这项工作建立在紫海胆（Strongylocentrotus purpuratus）幼虫的免疫反应的基础上，通过将这些发现扩展到不同系统发育距离的其他棘皮动物物种。 暴露于细菌和病毒病原体的棘皮动物幼虫的细胞免疫应答将使用显微镜和通过使用单细胞RNA-Seq分析基因表达的全系统变化来表征。网络建模方法将用于预测控制免疫反应的调节联系。 将使用体内扰动测定法来确认候选连接。这种创新的分析将揭示免疫反应的进化保守原则以及物种特异性适应。这个美国/英国合作项目由美国国家科学基金会和英国生物技术和生物科学研究理事会支持。这个奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Animals live in constantly changing environments that are rich in microbial life. The role of immune systems is to first recognize these microbes and then respond appropriately by either protecting the host or allowing the microbes to grow as part of a carefully regulated, mutually beneficial relationship. However, despite decades of research, the immune systems have been investigated in detail in only a few species (humans and mice). The proposed work will address this gap in knowledge by investigating immune responses in echinoderms, specifically the larval stages of sea urchins and sea stars. These larvae are morphologically simple, transparent animals that swim and feed in the ocean for several months prior to metamorphosis. In this project, which is a collaboration between researchers at Auburn University (US) and University College London (UK). Larvae will be exposed to specific marine bacteria that elicit immune responses. Infected larvae will be dissociated to single cells which will be used to measure changes in gene expression. These experiments will identify fundamental aspects of animal immune systems and identify novel strategies for treating disease. These scientific findings will be complemented with additional strategies to engage various segments of the broader community. This includes the development of marine-based workshops for elementary school students and participation in an interactive open house for middle- and high-school students from local under- resourced schools hosted at Auburn University. This work proposed here employs a collaborative approach that integrates recently available genome sequences with new technology for quantifying gene expression at single-cell resolution. This systems-level approach will define the regulatory mechanisms that control immune responses across different echinoderm species to identify fundamental properties of animal immunity as well as species-specific adaptations. By protecting the host from harmful pathogens and cultivating a beneficial microbiota, immune systems operate at the forefront of animal evolution. In response to rapidly evolving microbes, animals rely on sophisticated mechanisms for detecting and eliminating pathogens. These mechanisms are intertwined with host mechanisms for maintaining cellular homeostasis and resolving stress. The aim of this proposal is to understand how evolutionary pressures shape the cells that mediate immune response. This work builds on the well-characterized immune responses in purple sea urchin (Strongylocentrotus purpuratus) larvae by extending these findings to additional echinoderm species at varying phylogenetic distances. Cellular immune responses of echinoderm larvae exposed to bacterial and viral pathogens will be characterized using microscopy and by profiling system-wide changes in gene expression using single-cell RNA-Seq. Network modeling approaches will be used to predict regulatory linkages that control immune responses. Candidate linkages will be confirmed using in vivo perturbation assays. This innovative analysis will reveal evolutionarily conserved principles of immune response as well as species-specific adaptations. This collaborative US/UK project is supported by the US National Science Foundation and the UK Biotechnology and Biological Sciences Research Council.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.