Immune interactions with commensal microbes in early life

生命早期与共生微生物的免疫相互作用

• 批准号: 10567936
• 负责人: CHYI S HSIEH
• 金额: $ 71.52万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-02 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567936
• 关键词: Address; Adult; Affect; Allergic; Antibiotics; Antigen Presentation; Antigen-Presenting Cells; Antigens; Bacteria; Bacterial Antigens; Bacterial Infections; Bacterial Translocation; Biological; Bypass; CD4 Positive T Lymphocytes; Cells; Colitis; Colon; Data; Development; Disease; Distant; Elderly; Event; Future; Generations; Genetic; Germ-Free; Goblet Cells; Growth; Helicobacter; Homeostasis; Human; Hygiene; Immune; Immune System Diseases; Immune response; Immune system; Immunologic Stimulation; In Vitro; Individual; Infection; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Knowledge; Laboratories; Lactobacillus; Lamina Propria; Life; Lymphoid Tissue; Measures; Mediating; Methods; Microbe; Mus; Nature; Outcome; Pathologic; Pathology; Pathway interactions; Pattern; Peripheral; Phase; Phenotype; Physiological; Population; Predisposition; Reagent; Regulatory T-Lymphocyte; Reporting; Reproducibility; Resistance; Risk; Risk Factors; Role; Route; Severities; Small Intestines; System; T cell response; T-Lymphocyte; T-cell receptor repertoire; Testing; Time; Transgenic Mice; Transgenic Organisms; Weaning; antigen-specific T cells; commensal bacteria; commensal microbes; feeding; gut bacteria; gut homeostasis; gut microbiota; immune function; immune health; in vivo; mesenteric lymph node; microbial; microbiota; pharmacologic; prevent; response; single-cell RNA sequencing

Project Summary/Abstract Events in early life, particularly those altering the gut microbiota and immune development, can have an important role in determining future risk of immune related disorders. For example, it has been reported that the how substances are encountered by the immune system, the timing of feeding practices, hygiene, and the use of antibiotics, in early life can modify the risk of immune driven disorders later in life. A common theme amongst many of these studies is that these risk factors likely affect the developing microbiota. However, the biologic basis for how early life microbial changes can affect the risk of immune disorders later in life is incompletely understood. Previous data from our laboratories have suggested that during this preweaning period, specific live gut bacteria are selectively delivered to the immune system and that interaction of these live bacteria with cellular immune populations locally in the colonic lamina propria or in distant lymphoid tissues establishes a durable (life- long) and balanced immune system. In preliminary studies, we observed substantial variance in the amount of bacterial translocation in this preweaning period, which was corroborated with studies of antigen-specific T cell responses to a translocating bacterial spp. We therefore hypothesize that the magnitude and quality of the immune response to these translocating bacteria species during the preweaning period is a stochastic event during normal ontogeny which represents an important variable in determining whether an individual establishes a balanced immune system and prevents immune mediated pathologies in later life. However, the nature of these translocating bacteria and methods to quantify the antigen-specific responses to these bacteria remain a gap in our knowledge. We will address this question by identifying and characterizing how the translocating bacteria are encountered by the immune system (Aim 1) and generate reagents to track bacterial antigen presentation via T cell responses in vivo (Aim 2). We will use these reagents to integrate the immune response over the preweaning period to translocating bacterial spp. during physiologic development and correlate it with intestinal immune challenges including infection and experimental colitis in later life (Aim 3). If successful, this project may reveal that preweaning translocation is an important stochastic developmental variable involved in generating intestinal immune health and homeostasis.

项目摘要/摘要 早期生命中的事件，特别是那些改变肠道微生物区系和免疫发育的事件，可能会产生 在确定未来免疫相关疾病的风险方面发挥重要作用。例如，有报道称， 免疫系统如何遇到物质，喂养的时机，卫生和使用 在抗生素中，早期生活可以改变晚年免疫驱动疾病的风险。一个共同的主题是 其中许多研究表明，这些风险因素可能会影响正在发育的微生物区系。然而，生物学上的 关于生命早期微生物变化如何影响晚年免疫紊乱风险的基础还不完全 明白了。我们实验室之前的数据表明，在这段断奶前阶段，特定的活体 肠道细菌被选择性地输送到免疫系统，这些活细菌与细胞的相互作用 结肠固有层或远处淋巴组织中的局部免疫群体建立了持久的(生命- 长)和平衡的免疫系统。在初步研究中，我们观察到在数量上的巨大差异 断奶前阶段的细菌易位，这与抗原特异性T细胞的研究相印证 对一种转位细菌的反应。因此，我们假设， 在断奶前阶段对这些移位细菌的免疫反应是一个随机事件 在正常个体发育过程中，这代表着一个重要的变量，决定一个人是否 平衡的免疫系统，并防止在以后的生活中免疫介导的病理。然而，它的性质是 这些移位细菌和量化这些细菌的抗原特异性反应的方法仍然是一种 我们知识上的鸿沟。我们将通过确定和描述移位如何解决这个问题 细菌被免疫系统遇到(目标1)，并产生追踪细菌抗原的试剂 通过体内T细胞反应呈现(目标2)。我们将使用这些试剂来整合免疫反应 在断奶前的一段时间内转移细菌。在生理发育过程中，并与 肠道免疫挑战，包括感染和晚年实验性结肠炎(目标3)。如果成功，这将是 项目可能揭示断奶前易位是一个重要的随机发育变量 产生肠道免疫健康和动态平衡。