Project 2: Epigenetic ontogeny of vaccine response, susceptibility to respiratory infectious disease and asthma

项目2：疫苗反应、呼吸道传染病和哮喘易感性的表观遗传个体发育

• 批准号: 10435042
• 负责人: Tobias R. Kollmann
• 金额: $ 15.58万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-10 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10435042
• 关键词: Acute; Address; Age; Antibodies; Asthma; Benchmarking; Biological Markers; Birth; Blood specimen; Cells; Characteristics; Child; Childhood; Clinical; Communicable Diseases; Complex; DNA Methylation; DNA methylation profiling; Data; Data Set; Development; Disease; Early Diagnosis; Elements; Enhancers; Environment; Epigenetic Process; Event; Exhibits; Functional disorder; Genes; Genome; Genomics; Growth; Hypersensitivity; Immune; Immune response; Immunity; Immunologic Memory; Immunologics; Individual; Infection; Intervention; Knowledge; Lead; Life; Life Cycle Stages; Link; Machine Learning; Measures; Mediating; Methylation; Modeling; Modification; Molecular; Molecular Target; Mucous Membrane; Outcome; Participant; Pathologic; Pathway interactions; Performance; Perinatal; Peripheral; Phenotype; Predisposition; Production; Prognostic Marker; Receptor Signaling; Recurrence; Regression Analysis; Reproducibility; Respiratory Tract Infections; Role; Shapes; Subgroup; Systemic infection; Testing; Time; Training; Vaccination; Vaccines; base; biomarker signature; catalyst; cohort; combinatorial; disorder risk; environmental allergen; epigenetic marker; epigenetic profiling; epigenetic regulation; epigenome-wide association studies; genetic signature; genome-wide; immunoregulation; insight; learning algorithm; microbial; microbiome; microbiota; mucosal microbiota; novel; pathogen; personalized intervention; potential biomarker; predictive marker; preventive intervention; prognostic model; promoter; prospective; respiratory; response; statistical learning; vaccination outcome; vaccine response

SUMMARY – Project 2 (PR2) Early life microbial exposures can shape an individual’s basal immune state influencing acute responses to infections, vaccines and responses to environmental allergens. Perinatal microbial exposures are known to influence immune ontogeny and are linked to rising rates of allergy and asthma, yet mechanisms remain poorly defined. Colonisation of the mucosae by microbiota, vaccinations and systemic infections all modify immune ontogeny, but a mechanistic understanding of the combinatorial interactions of these events in the early life course, and their resulting programming effects on immune development in early life (IDEAL) are lacking. Project 2 (PR2) will investigate epigenetic mechanisms as a basis for understanding microbially-mediated programming of IDEAL. A growing body of work highlights an important role for epigenetic regulation of the genome in both central and peripheral immune cells following vaccination and infection. Dynamic changes in epigenetic modifications at gene enhancers and promoters in innate cells are mechanistically linked to pathogen recognition receptor (PRR) signalling. These mechanisms therefore bridge the microbial environment, host genome and immune ontogeny. Early life microbial exposures are a complex construct considering the broad scope of interactions and factors to consider. Yet our collaborators in the Clinical Core (CC; Lead Pichichero) have demonstrated reproducibly that some children display a phenotype of low production of protective antibody (Ab) levels to routine vaccinations with concomitant low cellular immune memory (low vaccine responders, LVR), whilst others exhibit robust protective immunity (high vaccine responders, HVR). In addition to this, some children are prone to recurrent respiratory infections (infection prone, IP) whilst others with similar pathogen burden are resilient (non-infection prone, NIP). These phenotypic subgroups will be capitalized upon as latent variables that reflect the construct of microbially-mediated immune programming through a latent class analysis. The overall effort will define trajectories of mucosal and systemic (e.g., immune ontogeny and microbiome across our IDEAL Meta Cohort (IMC) comprised of four diverse longitudinal childhood cohorts in relation to VR, IP and asthma. Epigenome-wide association analysis will identify methylation-sensitive genes that characterize trajectories of IDEAL. We posit that these phenotypes and sub-phenotypes of IDEAL contribute to the development of childhood illness and will therefore identify methylation-sensitive genes associated with IDEAL trajectories that predict endotypes and sub-phenotypes of VR, IP and asthma. We consider endotypes are likely to have distinct pathophysiology mechanisms and that epigenetic biomarkers of microbially-mediated immune programming can provide early detection as well as novel targets for precision interventions. Outcomes from PR2 will include enhanced mechanistic understanding of early immune programming, knowledge gains regarding genomic elements/pathways contributing to endotypes of VR, IP and asthma, prognostic biomarkers, and novel targets for preventive interventions.

摘要-项目2(PR2) 生命早期接触微生物会影响个体的基本免疫状态，影响急性反应 对感染、疫苗和对环境过敏原的反应。围产期接触微生物已知 影响免疫个体发育，并与过敏和哮喘发病率上升有关，但机制仍不清楚 已定义。微生物区系对粘膜的定植、疫苗接种和全身感染都会改变免疫功能。 个体发生学，而是对早期生命中这些事件的组合相互作用的机械理解 当然，它们对早期生命免疫发育的编程效果(理想)是缺乏的。项目 2(PR2)将研究表观遗传机制，作为理解微生物介导的编程的基础 理想化。越来越多的工作突显了表观遗传调控在这两种疾病中的重要作用 接种疫苗和感染后的中枢和外周免疫细胞。表观遗传学的动态变化 先天细胞中基因增强子和启动子的修饰与病原体识别有机械联系 受体(PRR)信令。因此，这些机制在微生物环境、宿主基因组和 免疫个体发育。早期生命微生物暴露是一个复杂的结构，考虑到 相互作用和需要考虑的因素。然而，我们在临床核心(CC；Lead Pichiccho)的合作者已经 可重复地证明，一些儿童表现出保护性抗体(Ab)产量低的表型 与常规疫苗水平相比，伴随着低细胞免疫记忆(低疫苗响应者，LVR)， 而另一些则表现出强大的保护性免疫力(高疫苗应答率，HVR)。除此之外，一些孩子 容易反复呼吸道感染(易感染，IP)，而其他有类似病原体负担的人 有弹性(不容易感染，NIP)。这些表型亚群将被作为潜在变量加以利用 通过潜在类别分析反映微生物介导的免疫程序的构建。整体而言 努力将定义粘膜和系统的轨迹(例如，跨越我们理想的免疫个体发生和微生物组 Meta Cohort(IMC)由四个与VR、IP和哮喘相关的不同纵向童年队列组成。 表观基因组关联分析将识别甲基化敏感基因，这些基因表征了 非常理想。我们认为，这些理想的表型和亚表型有助于 儿童疾病，因此将识别与理想轨迹相关的甲基化敏感基因 预测VR、IP和哮喘的内型和亚型。我们认为内型很可能有不同的 微生物介导的免疫程序的病理生理机制和表观遗传生物标记物可以 提供早期检测以及精确干预的新目标。PR2的成果将包括 增强了对早期免疫编程的机制理解，关于基因组的知识获得 影响VR、IP和哮喘内型的因素/途径、预后生物标志物和新靶点 进行预防性干预。