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

批准号：
10677304
负责人：
Alexander Dale Ethridge
金额：
$ 4.02万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677304
关键词：
Address Adult Affect Age Airway Disease Allergens Allergic Allergic Disease Allergic inflammation Antigen-Presenting Cells Area Asthma Bacterial DNA Bioinformatics Bone Marrow Bronchiolitis Cell Differentiation process Cell physiology Cells ChIP-seq Child Childhood Childhood Asthma Chromatin Chromatin Structure Circulation Climacteric Clinical Critical Thinking Data Dendritic Cells Development Emigrations Environment Epigenetic Process Event Germ-Free Gnotobiotic Goals Goblet Cells Hematopoiesis Hospitalization Hypersensitivity Hypertrophy Immune Immune response Immune system Immunity Immunology Incidence Individual Infant Infection Inflammation Inflammatory Innate Immune Response Innate Immune System Laboratories Life Link Literature Location Lung Lung diseases Lung infections Macrophage Metabolism Modeling Modification Monitor Mucosal Immune System Mucous body substance Mus Myelogenous Myeloid Cells Natural Immunity Nature Neonatal Onset of illness Pathogenicity Pathologic Population Predisposition Production Published Comment Publishing Relative Risks Research Respiratory Syncytial Virus Infections Respiratory syncytial virus Role Scientist Sentinel Shapes Stimulus Structure Testing Tissues Training Wheezing Work airway hyperresponsiveness allergic response chromatin modification cockroach allergen cytokine dietary disease phenotype epidemiology study epigenetic regulation experimental study gut microbiome gut microbiota histone modification immunopathology immunoregulation infant infection innate immune mechanisms insight microbial microbiome microbiome alteration microbiome signature microbiota migration monocyte mouse model mucosal site neonatal mice neonate novel pre-doctoral precursor cell pulmonary function skills transcriptomics

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.

项目摘要早期生命呼吸道合胞病毒（RSV）肺部感染会导致儿童时期的发展和哮喘。这是一个重要的关注领域，因为哮喘的总体事件一直在增加。那里是迫切需要了解早期生活事件如何使人倾向于以后的免疫病理学生活，例如哮喘。使用RSV感染的新生儿鼠模型在我们实验室中的先前工作已有证明RSV感染可以改变早期肠道微生物组。我们还表明RSV感染在成年后，新生儿倾向于增强过敏性疾病。但是，早期生活之间的相互作用微生物组的感染和改变尚不清楚。我们假设微生物组随着早期感染的同时变化导致过敏性增强通过训练有素的免疫细胞前体的先天免疫学，生活后期的反应。我们将通过使用幼稚和RSV诱导的变化来评估Gnotobiotic实验中的相对因子微生物组，然后用蟑螂过敏原（CRA）过敏，以建立差异和改变的微生物组和RSV感染的协同作用。自初始数据收集的其他数据提交进一步支持我们的假设，表明常规的鼠微生物组转移到生殖与无菌新生儿相比，自由新生儿在过敏原挑战后降低了气道高反应性。当微生物组转移到无菌成年人中时，这不会发生这种情况，这表明早期生命至关重要通过对免疫系统的表观遗传调节进行保护的窗口。其他初步数据表明，诸如骨髓单核细胞之类的免疫细胞前体是表观遗传的早期生命后，RSV感染随着并发肠道微生物组的改变而改变，进一步表明训练有素免疫。注射时单核细胞在肺部环境中种子，并可以分化为其他各种细胞这加剧了在过敏反应期间肺部炎症。我们计划获得全面的通过执行CHIP-SEQ实验，了解RSV感染后训练有素的先天免疫力在骨髓单核细胞中激活和反射性组蛋白修饰。这个应用程序也是根据审稿人的评论，自初次提交以来修订以更好地调查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，对免疫细胞前体进行改变在过敏性炎症期间。这些研究的结果将进一步了解早期肺部感染和改变早期微生物组影响训练有素的先天免疫。该项目还将成为出色的培训申请人亚历山大·埃特里奇（Alexander Ethridge），以获得研究和批判性思维能力，以帮助他成为一个成功的独立科学家。