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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要该提案提出了一个为期 5 年的研究职业发展计划，重点关注卡介苗的研究 - 盖林 (BCG) 疫苗和先天免疫记忆机制，也称为训练免疫，该候选者目前是一种在生命早期观察到的、与病原体无关的保护性健康效应。哈佛医学院贝斯以色列女执事新生儿科儿科讲师波士顿儿童医院 (BCH) 医疗中心和精准疫苗项目副科学家。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的基础上对 BCG 疫苗配方的反应并补充了她作为新生儿科医生的临床培训。 BCH 人类免疫学和疫苗学专家 Ofer Levy 博士的指导和补充指导由咨询委员会提出，候选人将描述 BCG 疫苗的新型免疫代谢机制 - 拟议的实验和教学工作将为候选人提供诱导训练的免疫力。拥有在新生儿免疫学、免疫学交叉领域接受过培训的独特知识框架和技能和系统生物学，这将有助于她过渡为独立的转化儿科疫苗学家。传染病是新生儿发病和死亡的主要原因，部分原因是独特的免疫系统处于该发育阶段的减毒活牛分枝杆菌疫苗 BCG 是在出生时产生的。流行病学研究表明，全球有数以百万计的新生儿可以预防严重的结核病 (TB)。 BCG 在生命早期给予免疫新生儿可降低死亡率，原因是卡介苗有益健康的机制。早期生命的影响尚未完全表征，而在成人中，表观遗传和代谢重编程该提案将研究 BCG 诱导的免疫代谢特征。人类新生儿的免疫力经过训练，表现出独特的免疫力和生物能量需求。研究基于初步数据，这些数据明显证明了人类新生儿的免疫代谢重新布线和 BCG 免疫后，他们的白细胞产生了 BCG 诱导训练的关键年龄特异性特征更具体地说，该提案的目的是： 1) 表征 BCG 诱导的免疫代谢。使用由该研究所建立的新型体外平台对人类新生儿单核细胞进行训练的免疫途径 2）利用体内队列来识别和验证可能驱动训练的代谢途径接种 BCG 的人类新生儿的免疫力；以及 3) 从机制上探讨年龄特异性的代谢途径 BCG 诱导的体外训练免疫力。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业知识联系起来生物学将剖析卡介苗在生命早期诱导的训练免疫的细胞和分子机制，从而为未来早期生命疫苗的开发提供新的见解。