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） 早期的生命微生物暴露会影响个人的基本免疫回报 感染，疫苗和对环境过敏原的反应。已知围产期微生物暴露是 影响免疫本体发育，与过敏和哮喘的速度上升有关，但机制仍然很差 定义。通过微生物群，疫苗接种和全身感染对粘膜的定殖均修饰免疫 个体发育，但对这些事件早期这些事件的组合相互作用的机械理解 当前缺乏对早期生命（理想）免疫发育的产生的编程影响。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。越来越多的工作突出了基因组表观遗传调节的重要作用 疫苗和感染后中央和周围免疫细胞。表观遗传学的动态变化 基因增强子和先天细胞中启动子的修饰与病原体识别有关 受体（PRR）信号传导。因此，这些机制弥合微生物环境，宿主基因组和 免疫个体发育。考虑到广泛的范围，早期生命微生物暴露是一种复杂的结构 相互作用和要考虑的因素。然而，我们的临床核心合作者（CC;铅Pichichero）拥有 可重复地证明，有些孩子表现出低产量的受保护抗体（AB）的表型 与伴随低细胞免疫记忆（低疫苗反应者，LVR）的常规疫苗接种水平， 而其他人则暴露了强大的保护性免疫（高疫苗反应者，HVR）。除此之外，有些孩子 容易发生复发性呼吸道感染（感染，IP），而其他病原体伯宁则是 弹性（无感染，nip）。这些表型亚组将被大写为潜在变量 通过潜在类别分析反映微生物介导的免疫编程的构建。总体 精力将定义粘膜和系统性的轨迹（例如，在我们的理想中，免疫个体发育和微生物组 Meta队列（IMC）完成了与VR，IP和哮喘有关的四个潜水员纵向儿童同类群。 全基因组范围的关联分析将确定甲基化敏感基因，这些基因是表征的轨迹 理想的。我们指出，理想的这些表型和子表型有助于发展 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和哮喘的内型和子表型。我们认为内型可能具有独特的 病理生理机制和微生物介导的免疫编程的表观遗传生物标志物可以 提供早期检测以及精确干预的新目标。 PR2的结果将包括 增强对早期免疫编程的机械理解，有关基因组的知识收益 导致VR，IP和哮喘，预后生物标志物以及新目标的元素/途径 用于预防性干预措施。