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

摘要-项目2（PR 2） 生命早期的微生物暴露可以塑造个体的基础免疫状态，影响急性反应 感染、疫苗和对环境过敏原的反应。已知围产期微生物暴露 影响免疫个体发育，并与过敏和哮喘的发病率上升有关，但机制仍然很差 定义了微生物群在粘膜上的定植、接种疫苗和全身性感染都会改变免疫功能。 个体发育，而是对这些事件在早期生命中的组合相互作用的机械理解 当然，他们所产生的编程影响免疫发展的早期生活（理想）缺乏。项目 2（PR 2）将研究表观遗传机制，作为理解微生物介导编程的基础 的理想。越来越多的工作强调了基因组的表观遗传调控在这两个方面的重要作用。 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机制有关 受体（PRR）信号传导。因此，这些机制将微生物环境、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， 要考虑的相互作用和因素。然而，我们在临床核心的合作者（CC;铅Pichichero） 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 常规疫苗接种水平伴随低细胞免疫记忆（低疫苗应答者，LVR）， 而其它的则表现出强的保护性免疫（高疫苗应答者，HVR）。除此之外，有些孩子 易发生反复呼吸道感染（易感染，IP），而其他具有类似病原体负荷的患者， 弹性（非感染倾向，NIP）。这些表型亚组将作为潜在变量， 通过潜在类别分析反映微生物介导的免疫编程的构建。整体 努力将限定粘膜和系统的轨迹（例如，我们理想中的免疫个体发育和微生物组 Meta队列（IMC）包括与VR、IP和哮喘相关的4个不同纵向儿童队列。 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 理想.我们认为IDEAL的这些表型和亚表型有助于 儿童疾病，因此将确定与IDEAL轨迹相关的甲基化敏感基因， 预测VR、IP和哮喘的内型和亚表型。我们认为内型可能具有不同的 病理生理学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。PR 2的结果将包括 增强对早期免疫编程的机制理解，获得关于基因组的知识， 有助于VR、IP和哮喘的内型的元件/途径，预后生物标志物和新靶点 进行预防性干预。

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.