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.

项目总结/摘要 对细菌感染的先天免疫应答的诱导是一个复杂的过程， 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，成千上万的基因在转录水平上受到不同的调控。 过程，引发一系列生理变化，使宿主对感染做出反应。然而，在这方面， 目前，在我们对这些信息的动态进展的认识方面，存在着很大的差距 转化为功能性蛋白质。最近的证据表明，监管 负责引导和制备转录物以附着到核糖体上进行翻译的组分可以 在翻译过程中引入选择性偏见。因此，翻译起始是一个潜在的来源， 个体间存在显著的免疫学差异。特别是，在一大片分类群中， 从昆虫到哺乳动物，先前接触微生物可以给未来的先天免疫系统带来某种形式的记忆。 反应，导致随后感染时的抵抗力和生存结果增强。我们最近的数据 从引发赤拟谷盗面粉甲虫表明，在翻译起始动力学的转变的作用， 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 被训练来对抗微生物诱导剂这些平行的先天免疫记忆现象挑战了我们的经典 了解先天免疫系统和适应性免疫系统之间的功能和进化差异， 需要进一步研究翻译起始偏差在产生防御表型中的作用。 这个建议的第一个目的是研究翻译起始对转录转变的保真度 随着时间的推移，在细菌感染诱导的先天免疫应答期间观察到。康贝特人将以 翻译起始在使用核糖体分析（Ribo-Seq）促进翻译效率偏倚中的作用 在强大的模式生物T.苏云金芽孢杆菌感染的栗，利用紧密的 从酵母到人类的翻译起始机制的进化保守性。第二个目的是 该项目是利用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异中的作用。 我们的长期目标是了解先天免疫系统动态变化的潜在机制， 免疫反应，以便可以设计更有效的方法来治疗脓毒症和免疫反应， 病理条件。通过研究翻译启动的动力学在早期阶段， 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 细菌感染和免疫病理学治疗的有前途的前沿， 令人兴奋和临床相关。