The origins and evolution of eukaryotic antibacterial defenses

真核生物抗菌防御的起源和进化

• 批准号: 10711117
• 负责人: Tera Catherine Levin
• 金额: $ 37.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711117
• 关键词: Amoeba genus; Animals; Anti-Bacterial Agents; Antibacterial Response; Bacteria; Bacterial Infections; Biochemical; Cell model; Cells; Communicable Diseases; Dictyostelium; Environment; Eukaryota; Evolution; Genes; Genetic; Genomic approach; Haploidy; Immune; Immune system; Immunity; Infection; Innate Immune System; Life; Modernization; Molecular; Natural Immunity; Organism; Pathway interactions; Phagocytes; Phylogenetic Analysis; Positioning Attribute; Proteins; Shapes; Signal Transduction; System; Time; Trees; antimicrobial; emerging pathogen; experimental study; flexibility; innate immune pathways; microbial; novel; tool

PROJECT SUMMARY Molecular mechanisms of innate immunity are constantly changing as organisms evolve to defend against the threats of newly emerged pathogens. As a consequence, our innate immune pathways are a patchwork of both ancient and recently evolved proteins. How did mechanisms of innate immunity arise, and how have these pathways adapted to integrate new defenses? The answers to these questions are important because these dynamics have shaped the functions of modern-day immunity, determining how hosts are protected from infectious diseases. Moreover, because immune pathways are evolutionarily flexible, they can serve as an excellent model for how cellular signaling networks assemble and diversify more broadly. We focus on the evolution of cell-autonomous immunity, which provides critical protections within infected cells. Aspects of cell-autonomous immunity are found across eukaryotes, including in unicellular phagocytic organisms that interact with bacteria in natural environments. To understand how ancient immune proteins have assembled into modern mammalian pathways, we use diverse eukaryotes at ideal phylogenetic positions to uncover the origins and evolution of innate immunity. We use the highly tractable Dictyostelium system to discover and characterize antibacterial defenses in amoebae, while leveraging additional eukaryotes to understand how immune proteins and pathways have evolved. Our experiments integrate molecular, biochemical, genetic, cellular, evolutionary, and genomic approaches to reveal genes functionally important for defending against bacterial infections in diverse organisms. Because cell-autonomous defenses are easier to observe and study in haploid, unicellular species, these experiments promise to uncover new mechanisms of cell-autonomous immunity. Some of these mechanisms may be deeply conserved with immune defenses in animals, allowing us to reconstruct how these immune pathways arise and change. Other immune mechanisms in these diverged eukaryotes may represent novel evolutionary solutions to the problem of cellular defense, yielding both practical molecular tools such as new antimicrobials and novel paradigms of immunity.

项目总结 先天免疫的分子机制随着生物体的进化而不断变化 抵御新出现的病原体的威胁。因此，我们的先天免疫途径是一种 由古老的和最近进化的蛋白质拼凑而成。先天免疫机制是如何产生的，以及 这些途径是如何适应整合新的防御系统的？这些问题的答案很重要 因为这些动态塑造了现代免疫的功能，决定了宿主如何 免受传染病侵袭。此外，由于免疫途径在进化上是灵活的，它们可以 为蜂窝信令网络如何更广泛地组装和多样化提供了一个极好的模型。 我们关注的是细胞自主免疫的进化，它在体内提供关键的保护 被感染的细胞。细胞自主免疫的某些方面在真核生物中被发现，包括在单细胞中。 在自然环境中与细菌相互作用的吞噬有机体。为了了解古代免疫是如何 蛋白质已经组装成现代哺乳动物的途径，我们在理想中使用不同的真核生物 以揭示先天免疫的起源和进化。我们使用的是高度的 发现和表征阿米巴中抗菌防御的易驯化的Dictyostelius系统，而 利用更多的真核生物来了解免疫蛋白质和免疫途径是如何进化的。我们的 实验结合了分子、生化、遗传、细胞、进化和基因组方法来 揭示在不同生物体中对抵御细菌感染具有重要功能的基因。因为 在单倍体、单细胞物种中，细胞自主防御更容易观察和研究，这些实验 承诺发现细胞自主免疫的新机制。其中一些机制可能是 与动物的免疫防御深度保守，使我们能够重建这些免疫途径 站起来，改变吧。这些分化的真核生物中的其他免疫机制可能代表了新的进化 细胞防御问题的解决方案，产生了实用的分子工具，如新的抗菌剂 以及新的免疫模式。