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.

项目概要生命早期呼吸道合胞病毒 (RSV) 肺部感染可导致儿童喘息和哮喘。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。至关重要的是要了解早期生活事件如何使个体在以后容易发生免疫病理学我们实验室之前使用 RSV 感染的新生儿模型进行了研究。 RSV 感染可以改变早期肠道微生物组我们还证明了 RSV 感染。新生儿在成年后易患过敏性疾病。然而，早期生活之间的相互作用。感染和微生物组的改变尚不清楚。我们发现，生命早期感染引起的微生物群的同时变化会导致过敏症状增强通过训练免疫细胞前体的先天免疫来在以后的生活中做出反应，我们将通过以下方式检验这一假设。使用天然和 RSV 诱导的改变来评估无菌实验中的各个因素微生物组，然后使用蟑螂过敏原 (CRA) 进行过敏建模，以建立差异和自最初以来收集的微生物组改变和 RSV 感染的协同作用。提交的材料进一步支持了我们的假设，即传统的小鼠微生物组转移到细菌中与无菌新生儿相比，游离新生儿可降低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体内时，这种情况不会发生，这表明早期生命是至关重要的可能通过免疫系统的表观遗传调节来提供保护的窗口。其他初步数据表明，骨髓单核细胞等免疫细胞前体是表观遗传的生命早期 RSV 感染后，肠道微生物群发生同时变化，进一步表明单核细胞在炎症时在肺部环境中播种，并可以分化成各种其他细胞。我们计划获得全面的过敏反应期间肺部炎症的信息。通过进行 ChIP-seq 实验了解 RSV 感染后经过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也已被应用。自初次提交以来根据审稿人的意见进行了修订，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来改变免疫细胞前体过敏性炎症期间。这些研究的结果将进一步加深我们对生命早期肺部感染和改变如何发生的理解。该项目也将作为对早期生命微生物组影响训练的先天免疫的良好培训。申请人 Alexander Ethridge 获得研究和批判性思维技能，这将帮助他成为一名成功的、独立的科学家。