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 诱导对细菌感染的先天免疫反应是一个复杂的过程，需要 快速有效地将微生物检测事件转化为一组功能性防御反应。 在这一过程的早期阶段，数以千计的基因可以在转录水平上变得不同的调节 这一过程引发了一系列生理变化，使宿主做好应对感染的准备。然而， 目前，我们对这些消息的进程动态的了解存在很大差距 在先天免疫反应过程中转化为功能性蛋白质。最近的证据表明，监管部门 负责引导和准备转录本附着到核糖体进行翻译的组件可以 在翻译过程中引入选择性偏见。因此，翻译的启动是一个潜在的来源 个体间的免疫学差异很大。尤其是在一大片分类群上 从昆虫到哺乳动物，以前接触微生物可以赋予未来某种形式的记忆，使其产生先天免疫。 在后续感染时，会导致更高的抵抗力和生存结果。我们最近的数据 来自启动的赤拟谷盗粉甲的研究表明，翻译启动动力学的转变在 启动表型，类似于最近在哺乳动物巨噬细胞中观察到的翻译起始转变 针对微生物激发子进行了训练。这些平行的先天免疫记忆现象挑战了我们的规范 了解天然免疫系统和获得性免疫系统之间的功能和进化差异，以及 需要进一步研究翻译起始偏差在产生防御表型中的作用。 这一建议的第一个目的是调查翻译起始对转录转换的保真度 在细菌感染引起的先天免疫反应过程中观察一段时间。我们将确定 翻译起始在利用核糖体图谱促进翻译效率偏差中的作用(Ribo-Seq) 在感染苏云金芽孢杆菌的强大模式生物卡氏杆菌中，利用紧凑型 从酵母到人类的翻译起始机制的进化保守。这样做的第二个目的是 项目是使用RNAi介导的敲除来操纵翻译启动因子的表达，以 研究翻译效率在产生先天防御和记忆表型变异中的作用。 我们的长期目标是了解先天动态变化的潜在机制。 免疫应答，以便设计更有效的方法来治疗脓毒症和免疫。 病理情况。通过对翻译启动的早期阶段的动态研究 细菌感染及其对先天免疫表型变异的贡献，我们将开发一种 治疗细菌感染和免疫病理学的有希望的前沿领域 令人兴奋的和临床相关的。