Immunometabolic signatures of BCG-induced neonatal trained immunity

BCG 诱导的新生儿训练免疫力的免疫代谢特征

• 批准号: 10664100
• 负责人: Asimenia Angelidou
• 金额: $ 17.75万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-06 至 2028-06-01
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664100
• 关键词: Acetyl Coenzyme A; Adult; Advisory Committees; Age; Attenuated; Award; BCG Live; BCG Vaccine; Bioenergetics; Biological Assay; Birth; Blood specimen; Boston; Cause of Death; Childhood; Communicable Diseases; Complement; Data; Development; Disease; Enzyme Inhibitor Drugs; Enzymes; Epigenetic Process; Exposure to; Funding; Future; Glycolysis; Goals; Health; Health Benefit; Human; Immune; Immune Tolerance; Immune system; Immunity; Immunization; Immunize; Immunologic Memory; Immunology; Impairment; In Vitro; Infant; Infection; Infection prevention; Intervention; Israel; Leukocytes; Life; Link; Lipids; Mass Spectrum Analysis; Mediating; Mediator; Medical center; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Molecular; Molecular Profiling; Morbidity - disease rate; Mycobacterium bovis; National Institute of Allergy and Infectious Disease; Neonatal; Neonatal Mortality; Neonatology; Newborn Infant; Participant; Pathway interactions; Pediatric Hospitals; Pediatrics; Peripheral; Phenotype; Plasma; Program Development; Publishing; Research; Respiratory Tract Infections; Scientist; Sepsis; Shapes; Small Interfering RNA; Stimulus; Succinates; Systems Biology; Techniques; Training; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccines; Vulnerable Populations; Whole Blood; Work; World Health Organization; adaptive immunity; alpha ketoglutarate; career; career development; chemokine; clinical training; cofactor; cohort; cytokine; epidemiology study; experience; experimental study; human model; immune activation; immunoregulation; in vitro Assay; in vitro Model; in vivo; innate immune mechanisms; insight; instructor; medical schools; metabolome; metabolomics; monocyte; mortality; multidisciplinary; neonatal human; neonatal immunity; neonatal morbidity; neonate; novel; pathogen; prevent; programs; randomized trial; receptor; response; skills; vaccine development; vaccine formulation; vaccine response; vaccinology

Project Summary/Abstract This proposal presents a 5-year research career development program focused on the study of Bacille Calmette- Guérin (BCG) vaccine and the mechanisms of innate immune memory, otherwise known as trained immunity, underlying its observed, pathogen-agnostic, protective health effects in early life. The candidate is currently an Instructor of Pediatrics at Harvard Medical School in the Department of Neonatology at Beth Israel Deaconess Medical Center, and Associate Scientist at the Precision Vaccines Program in Boston Children’s Hospital (BCH). The outlined proposal builds on the candidate’s previous research on in vitro modeling of human leukocyte responses to BCG vaccine formulations and complements her clinical training as a Neonatologist. Under the mentorship of Dr. Ofer Levy, a human immunology and vaccinology expert at BCH, and complementary guidance by an Advisory Committee, the candidate will characterize novel immunometabolic mechanisms of BCG vaccine- induced trained immunity in newborns. The proposed experiments and didactic work will provide the candidate with a unique intellectual framework and skill set at the intersection of newborn immunology, trained immunity and systems biology that will facilitate her transition to independence as a translational pediatric vaccinologist. Infectious diseases are leading causes of neonatal morbidity and mortality, due in part to a distinct immune system at this developmental stage. The live attenuated Mycobacterium bovis vaccine BCG is given at birth to millions of newborns worldwide to prevent severe forms of tuberculosis (TB). Epidemiologic studies demonstrate that BCG confers a mortality benefit to immunized newborns when administered early in life, attributed to protection vs. non-TB respiratory infections and sepsis. The mechanisms underlying BCG beneficial health effects in early life are incompletely characterized, while in adults epigenetic and metabolic reprogramming of monocytes have been implicated. This proposal will investigate the immunometabolic signatures of BCG-induced trained immunity in human newborns, who manifest distinct immunity and bioenergetic demands. The proposed study is based on preliminary data demonstrating distinct immunometabolic rewiring in human newborns and their leukocytes after BCG immunization producing key age-specific signatures of BCG-induced trained immunity. More specifically, the aims of this proposal are to: 1) Characterize BCG-induced immunometabolic pathways of trained immunity in human newborn monocytes using a novel in vitro platform established by the candidate; 2) Leverage an in vivo cohort to identify and validate metabolic pathways that may drive trained immunity in BCG-immunized human neonates; and 3) Mechanistically probe age-specific metabolic pathways of BCG-induced trained immunity in vitro. The proposed project, linking expertise in neonatology, immunology, metabolism, vaccinology and systems biology will dissect cellular and molecular mechanisms of BCG-induced trained immunity in early life, thereby providing fresh insights to inform future early life vaccine development.

项目摘要/摘要 这项建议提出了一个为期5年的研究生涯发展计划，重点是研究巴克利·卡尔梅特- Guérin(卡介苗)疫苗和先天免疫记忆的机制，也称为训练免疫， 其潜在的观察到的，病原体不可知的，保护性的健康影响在生命早期。候选人目前是一名 贝丝·伊斯雷尔女执事哈佛医学院新生儿科儿科讲师 他是波士顿儿童医院(BCH)精密疫苗项目的副科学家。 概述的提案建立在候选人之前对人类白细胞体外建模的研究基础上 对卡介苗制剂的反应，并补充了她作为一名新生儿专家的临床培训。在.之下 BCH人类免疫学和疫苗专家Ofer Levy博士的指导和补充指导 通过一个咨询委员会，候选人将描述卡介苗的新免疫代谢机制- 在新生儿中诱导训练性免疫。建议的实验和教学工作将为候选人提供 以独特的智力框架和技能集于新生儿免疫学、训练有素的免疫学 和系统生物学，这将有助于她过渡到独立的翻译儿科疫苗专家。 感染性疾病是新生儿发病率和死亡率的主要原因，部分原因是一种独特的免疫系统。 系统处于这个发展阶段。牛分枝杆菌减毒活疫苗卡介苗出生时接种 全球数百万新生儿用于预防严重形式的结核病(TB)。流行病学研究表明 卡介苗在生命早期给予免疫新生儿死亡率方面的好处，归因于 预防与非结核病呼吸道感染和败血症的对比。卡介苗有益健康的机制 早期生命的影响并不完全表征，而在成年人中，表观遗传和代谢重新编程 单核细胞也有牵连。这项建议将研究卡介苗诱导的免疫代谢特征 在人类新生儿中训练免疫，他们表现出明显的免疫力和生物能量需求。建议数 这项研究是基于初步数据显示，在人类新生儿和 卡介苗免疫后的白细胞产生关键的卡介苗诱导训练的年龄特异性特征 豁免权。更具体地说，这项提议的目的是：1)表征卡介苗诱导的免疫代谢 利用一种新的体外培养平台研究人类新生儿单核细胞的免疫训练途径 候选人；2)利用体内队列来识别和验证可能驱动受过训练的代谢途径 卡介苗免疫的人新生儿的免疫；3)机械地探索年龄特异的代谢途径 卡介苗诱导的体外训练性免疫。 拟议的项目，将新生儿学、免疫学、新陈代谢、疫苗学和系统方面的专门知识联系起来 生物学将剖析卡介苗诱导早期训练性免疫的细胞和分子机制，从而 提供新的见解，为未来的早期疫苗开发提供信息。