Immunometabolic signatures of BCG-induced neonatal trained immunity

项目总结/摘要 该提案提出了一个为期5年的研究职业发展计划，重点是研究Bacille Calmette， Guérin（BCG）疫苗和先天免疫记忆机制，也称为训练免疫， 在生命早期观察到的病原体不可知的保护性健康作用的基础。候选人目前是一名 哈佛医学院新生儿科系儿科讲师贝斯以色列女执事 医学中心和波士顿儿童医院（BCH）精确疫苗项目的副科学家。 概述的提案建立在候选人以前对人类白细胞体外建模的研究基础上 对BCG疫苗制剂的反应，并补充她作为新生儿学家的临床培训。下 BCH的人类免疫学和疫苗学专家Ofer Levy博士的指导和补充指导 通过咨询委员会，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免疫力。拟议的实验和教学工作将提供候选人 具有独特的知识框架和技能，在新生儿免疫学的交叉点， 和系统生物学，这将有助于她过渡到独立作为一个翻译儿科疫苗学家。 传染病是新生儿发病和死亡的主要原因，部分原因是由于不同的免疫系统， 系统在这个发展阶段。牛分枝杆菌减毒活疫苗BCG在出生时给予， 全球数百万新生儿的肺结核，以预防严重的结核病（TB）。流行病学研究表明 卡介苗在生命早期接种时对免疫新生儿的死亡率有好处，这归因于 与非结核呼吸道感染和败血症相比具有保护作用。BCG有益健康的机制 在生命早期的影响是不完全的特点，而在成年后的表观遗传和代谢重编程， 单核细胞也有牵连。该提案将研究BCG诱导的免疫代谢特征， 在人类新生儿中训练免疫力，他们表现出不同的免疫力和生物能量需求。拟议 这项研究是基于初步数据，证明了人类新生儿中不同的免疫代谢重新连接， BCG免疫后的白细胞产生BCG诱导的训练的关键年龄特异性特征， 免疫力更具体地说，这项建议的目的是：1）表征BCG诱导的免疫代谢 在人类新生儿单核细胞中训练免疫的途径，使用由 2）利用体内队列来识别和验证可能驱动训练的代谢途径 BCG免疫人类新生儿的免疫力;和3）机械地探测年龄特异性代谢途径， BCG诱导的体外训练免疫。 拟议的项目，结合专业知识，在泌尿学，免疫学，新陈代谢，疫苗学和系统 生物学将剖析早期生命中BCG诱导训练免疫的细胞和分子机制，从而 为未来的早期疫苗开发提供了新的见解。

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.