The temporal dynamics of translation efficiency during an innate immune response

先天免疫反应过程中翻译效率的时间动态

• 批准号: 10643912
• 负责人: Ann Thomas Tate
• 金额: $ 15.85万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643912
• 关键词: Acute; Adaptive Immune System; Anti-Bacterial Agents; Antifungal Agents; Bacillus thuringiensis; Bacterial Infections; Binding; Biology; Complex; Coupled; Data; Detection; Disease; Disease susceptibility; Effectiveness; Event; Exhibits; Exposure to; Feedback; Flour; Future; Gene Expression Profile; Generations; Genes; Genetic Transcription; Goals; Health; Human; Immune; Immune response; Immune system; Immunologic Memory; Immunologics; Individual; Infection; Innate Immune Response; Innate Immune System; Insecta; Investigation; Knowledge; Macrophage; Mammals; Mediating; Memory; Microbe; Molecular; Natural Source; Order Coleoptera; Outcome; Pathologic; Patient-Focused Outcomes; Pattern; Peptide Initiation Factors; Phase; Phenotype; Physiological; Population; Predisposition; Process; Production; Proteins; Proteomics; RNA; RNA Interference; Recovery; Regulation; Research; Resistance; Ribosomes; Role; Secondary to; Sepsis; Shapes; Signal Transduction; Source; Tertiary Protein Structure; Time; Training; Transcript; Translation Initiation; Translation Process; Translations; Tribolium; Up-Regulation; Variant; Yeasts; acute infection; antimicrobial; clinically relevant; cytokine; defense response; experience; fitness; frontier; immunopathology; improved; individual variation; innate immune mechanisms; knock-down; mRNA sequencing; microbial; model organism; mortality; novel; opportunity cost; pathogenic bacteria; response; ribosome profiling; secondary infection; spelling; survival outcome; therapy design

PROJECT SUMMARY/ABSTRACT The induction of an innate immune response to bacterial infection is a complex process that requires the rapid and efficient conversion of the microbial detection event into a set of functional defense responses. Thousands of genes can become differentially regulated at the transcriptional level in the early stages of this process, setting off the suite of physiological shifts that prepare the host to respond to the infection. However, there is currently a large gap in our knowledge concerning the dynamics of the progression of these messages into functional proteins during an innate immune response. Recent evidence suggests that regulatory components responsible for guiding and preparing transcripts to attach to ribosomes for translation can introduce selective bias into the translation process. Thus, translation initiation represents a potential source of substantial immunological variation from individual to individual. In particular, across a large swath of taxa from insects to mammals, previous exposure to microbes can impart a form of memory to future innate immune responses, resulting in heightened resistance and survival outcomes upon subsequent infection. Our recent data from primed Tribolium castaneum flour beetles suggests a role for shifts in translation initiation dynamics in the priming phenotype, resembling translation initiation shifts recently observed in mammalian macrophages trained against microbial elicitors. These parallel innate immune memory phenomena challenge our canonical understanding of the functional and evolutionary divide between innate and adaptive immune systems, and demand further investigation into the role of translation initiation biases in generating defense phenotypes. The first aim of this proposal is to investigate the fidelity of translation initiation to transcriptional shifts observed during the innate immune response induced by bacterial infection over time. We will determine the role of translation initiation in facilitating biases in translation efficiency using ribosomal profiling (Ribo-Seq) in the powerful model organism T. castaneum infected with Bacillus thuringiensis, taking advantage of the tight evolutionary conservation of translation initiation machinery from yeast to humans. The second aim of this project is to manipulate the expression of translation initiation factors using RNAi-mediated knockdown to investigate the role of translation efficiency in generating variation in innate defense and memory phenotypes. Our long-term goal is to understand the underlying mechanisms of variation in the dynamics of innate immune responses so that more effective approaches can be designed for the treatment of sepsis and immuno- pathological conditions. By investigating the dynamics of translation initiation during the early phase of bacterial infection and its contribution to variation in innate immune phenotypes, we will be developing a promising frontier for the treatment of bacterial infections and immunopathology that is both conceptually exciting and clinically relevant.

项目摘要/摘要 对细菌感染的先天免疫反应的诱导是一个复杂的过程，需要 将微生物检测事件的快速转化为一组功能防御反应。 在此初期，成千上万的基因可以在转录水平上受到差异调节 过程，设置生理转变套件，使宿主做好对感染的反应。然而， 目前，我们的知识差距很大 在先天免疫反应期间进入功能蛋白。最近的证据表明监管 负责指导和准备成绩单以附加到核糖体进行翻译的组件可以 将选择性偏置引入翻译过程。因此，翻译起始代表了潜在的来源 从个人到个体的实质免疫学变化。特别是，遍布大量的分类单元 从昆虫到哺乳动物，先前接触微生物可以赋予一种记忆形式到未来的先天免疫 反应，导致随后感染后的耐药性和存活率的增强。我们最近的数据 从底漆的tribolium castaneum面粉甲虫提出了转移在翻译启动动力学中的作用 启动表型，类似于翻译起始的变化，最近在哺乳动物巨噬细胞中观察到 针对微生物引起者进行了训练。这些平行的先天免疫记忆现象挑战了我们的规范 了解先天和适应性免疫系统之间的功能和进化鸿沟，以及 要求进一步研究翻译起始偏见在产生防御表型中的作用。 该提案的第一个目的是调查转录转移转换的翻译启动的保真度 随着时间的流逝，细菌感染引起的先天免疫反应期间观察到。我们将确定 翻译启动在促进偏见中使用核糖体分析（Ribo-Seq）在翻译效率中的作用 在功能强大的模型生物中，t. castaneum感染了苏云金芽孢杆菌，利用紧身 从酵母到人类的翻译起始机制的进化保护。第二个目标 项目是使用RNAi介导的敲低来操纵翻译起始因子的表达 研究翻译效率在产生先天防御和记忆表型变化中的作用。 我们的长期目标是了解先天动力学变化的潜在机制 免疫反应，因此可以设计出更有效的方法来治疗败血症和免疫 病理状况。通过研究早期翻译启动的动力学 细菌感染及其对先天免疫表型变异的贡献，我们将开发一个 有望治疗细菌感染和免疫病理学的前沿，这两者在概念上都是 令人兴奋和临床相关。