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.

项目摘要 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 古老的和新近进化的蛋白质拼凑而成。先天免疫机制是如何产生的， 这些途径如何适应整合新的防御机制？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 保护免受传染病。此外，由于免疫途径在进化上是灵活的， 作为细胞信号网络如何更广泛地组装和多样化的一个很好的模型。 我们专注于细胞自主免疫的进化，它提供了关键的保护， 被感染的细胞细胞自主免疫的各个方面在真核生物中发现，包括在单细胞生物中。 在自然环境中与细菌相互作用的吞噬生物。为了了解古代免疫系统 蛋白质组装成现代哺乳动物的途径，我们使用不同的真核生物在理想的 系统发育位置，以揭示先天免疫的起源和进化。我们使用高度 易处理的Dictyosteoblasts系统发现和表征变形虫中的抗菌防御，而 利用更多的真核生物来了解免疫蛋白和途径是如何进化的。我们 实验整合了分子、生物化学、遗传、细胞、进化和基因组方法， 揭示了在不同生物体中防御细菌感染的重要功能基因。因为 细胞自主防御更容易在单倍体单细胞物种中观察和研究，这些实验 有望揭示细胞自主免疫的新机制。其中一些机制可能是 在动物的免疫防御中非常保守，这使我们能够重建这些免疫途径 出现和改变。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 解决细胞防御问题，产生实用的分子工具，如新的抗菌剂， 和免疫的新范例。