Early Life Pulmonary Infection, Microbiome and Trained Innate Immunity

生命早期肺部感染、微生物组和经过训练的先天免疫

基本信息

项目摘要

Project Summary Early life respiratory syncytial virus (RSV) pulmonary infection can lead to the development of childhood wheeze and asthma. This is an important area of concern as the overall incidence of asthma has been increasing. There is a critical need to understand how early life events can predispose an individual for immunopathology later in life such as asthma. Previous work in our laboratory using a neonatal murine model of RSV infection has demonstrated that RSV infection can alter the early life gut microbiome. We have also shown that RSV infection predisposes neonates for enhanced allergic disease in adulthood. However, the interplay between early life infections and alterations in the microbiome is not well understood. We hypothesize that a concurrent change in the microbiome with infection in early life leads to enhanced allergic responses later in life through trained innate immunity of immune cell precursors. We will test this hypothesis by assessing the respective factors in gnotobiotic experiments using both naïve and RSV-induced altered microbiomes followed by allergic modeling with cockroach allergen (CRA) to establish the differential and synergistic roles of the altered microbiome and RSV infection. Additional data collected since the initial submission further supports our hypothesis showing that conventional murine microbiome transfer into germ- free neonates reduces the airway hyperreactivity after allergen challenge when compared to germ-free neonates. This does not occur when microbiome is transferred into germ-free adults suggesting that early life is a critical window for protection possibly through epigenetic regulation of the immune system. Additional preliminary data show that immune cell precursors such as bone marrow monocytes are epigenetically altered following early life RSV infection with concurrent gut microbiome alteration further indicating trained immunity. Monocytes seed the lung environment upon inflammation and can differentiate into various other cells that reinforce inflammation within the lung during an allergic response. We plan to obtain a comprehensive understanding of the trained innate immunity after RSV infection by performing ChIP-seq experiments for activating and repressive histone modifications in bone marrow monocytes. This application has also been revised since initial submission based on reviewer’s comments to better investigate the role of microbiome alterations upon immune cell precursors by directly testing the impact of epigenetic alteration of monocytes during allergic inflammation. The results from these studies will further our understanding of how early life pulmonary infections and alterations of the early life microbiome impacts trained innate immunity. This project will also serve as excellent training for the applicant, Alexander Ethridge, to gain the research and critical thinking skills that will help him become a successful, independent scientist.
项目摘要 生命早期呼吸道合胞病毒(RSV)肺部感染可导致儿童喘息的发展 和哮喘。这是一个值得关注的重要领域,因为哮喘的总体发病率一直在增加。那里 是一个关键的需要了解如何早期生活事件可以倾向于一个人的免疫病理学以后, 生活如哮喘。我们实验室之前使用RSV感染的新生鼠模型进行的工作, 证明RSV感染可以改变早期生活肠道微生物组。我们还发现RSV感染 使新生儿在成年后易患增强的过敏性疾病。然而,早期生活和 感染和微生物组的改变还不清楚。 我们假设,在生命早期,微生物组与感染的同时变化导致过敏性疾病的增强。 通过免疫细胞前体的训练先天免疫,在以后的生活中产生反应。我们将通过以下方式检验这一假设: 评估使用幼稚和RSV诱导的改变的致菌实验中的相应因素 微生物组,然后用蟑螂过敏原(CRA)建立过敏模型,以建立差异和 改变的微生物组和RSV感染的协同作用。自初次报告以来收集的其他数据 提交的材料进一步支持了我们的假设,即常规鼠微生物组转移到生殖细胞中, 与无菌新生儿相比,无菌新生儿降低了过敏原激发后的气道高反应性。 当微生物组转移到无菌成人时,这不会发生,这表明早期生活是一个关键因素。 保护窗口可能通过免疫系统的表观遗传调节。 额外的初步数据表明,免疫细胞前体,如骨髓单核细胞, 在生命早期RSV感染后改变,同时肠道微生物组改变,进一步表明受过训练 免疫力单核细胞在炎症时在肺环境中播种,并且可以分化成各种其他细胞 在过敏反应中增强肺部的炎症。我们计划获得一个全面的 通过进行ChIP-seq实验,了解RSV感染后训练的先天免疫, 激活和抑制骨髓单核细胞中的组蛋白修饰。该应用程序也被 自首次提交以来,根据评审员的评论进行了修订,以更好地研究微生物组的作用 通过直接测试单核细胞表观遗传改变的影响, 在过敏性炎症中。 这些研究的结果将进一步加深我们对早期肺部感染和改变 影响先天免疫力的因素。该项目也将作为优秀的培训, 申请人,亚历山大埃瑟里奇,获得研究和批判性思维能力,这将有助于他成为一个 成功独立的科学家

项目成果

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Alexander Dale Ethridge的其他文献

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