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.

项目摘要/摘要该提案提出了一项为期5年的研究职业发展计划，重点是研究巴奇·塞莱特（Bacille Calmette） Guérin（BCG）疫苗和先天免疫记忆的机制，也称为受过训练的免疫，在早期生命中，其观察到的，病原体敏锐的，受保护的健康影响。候选人当前是哈佛医学院的儿科讲师在贝丝·以色列执事部的新生儿学系医疗中心，以及波士顿儿童医院（BCH）精密疫苗计划的副科学家。概述的提案基于候选人先前关于人类白细胞体外建模的研究对BCG疫苗配方的反应，并补充了她作为新生儿医生的临床培训。在 BCH的人类免疫学和疫苗学专家Ofer Levy博士和互补指导由咨询委员会委员会，候选人将表征BCG疫苗的新型免疫代谢机制 - 诱导新生儿训练有素的免疫力。拟议的实验和教学工作将为候选人提供在新生儿免疫学的交汇处，具有独特的智力框架和技能，训练有素的免疫学和系统的生物学，可以促进她过渡到独立为转化小儿疫苗科医生的独立性。传染病是新生儿发病率和死亡率的主要原因，部分是由于独特的免疫力在这个发展阶段的系统。活体减弱的牛分枝杆菌bcg在出生时给予全世界数百万新生儿，以防止严重的结核病（TB）。流行病学研究表明 BCG承认生命早期管理时免疫新生儿的死亡率受益保护与非TB呼吸道感染和败血症。 BCG有益健康的基础机制早期的影响未完全表征，而在成年人中，表观遗传和代谢重编程已暗示单核细胞。该建议将研究BCG诱导的免疫代谢特征在人类新生儿中受过训练的免疫学，他们表现出明显的免疫学和生物能量需求。提议研究基于初步数据，证明了人类新生儿中明显的免疫代谢重新定位和 BCG免疫后，其白细胞产生了BCG诱导的训练有素的特定年龄特异性签名免疫。更具体地说，该提案的目的是：1）表征BCG诱导的免疫代谢人类新生单核细胞中受过训练的免疫力的途径，使用由小说的体外平台建立候选人; 2）利用体内队列来识别和验证可能驾驶训练的代谢途径 BCG免疫的人类新生儿的免疫力； 3）机械探测器特异性的代谢途径 BCG诱导的体外训练有素的免疫力。拟议的项目将新生儿学，免疫学，代谢，疫苗学和系统的专业知识联系起来生物学将剖析BCG诱导的早期训练的免疫的细胞和分子机制，从而提供新的见解，以告知未来的早期生命疫苗开发。