Development of human adaptive immunity to Staphylococcus aureus

人类对金黄色葡萄球菌适应性免疫的发展

基本信息

批准号：
10366018
负责人：
Juliane Bubeck Wardenburg
金额：
$ 62.85万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-05 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366018
关键词：
Active Immunization Address Adult Age Animals Antibiotic Resistance Antibodies Antibody Response Antigens Antimicrobial Resistance B-Lymphocytes Cessation of life Child Childhood Clinical Clinical Trials Communicable Diseases Complex Coupled Critical Illness Cytometry Data Development Disease Drug resistance Economic Burden Economics Epidemic Epidemiology Evaluation Exotoxins Exposure to Failure Foundations Generations Genus staphylococcus Glean Health Hospitals Human Immune response Immunity Individual Infant Infection Infection prevention Investments Knowledge Life Light Maternally-Acquired Immunity Measures Mediating Medical Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Multi-Drug Resistance Nosocomial Infections Operative Surgical Procedures Organism Pathogenesis Patients Pharmacology Phase III Clinical Trials Phenotype Pneumonia Population Positioning Attribute Preparation Public Health Recording of previous events Recurrence Research Research Personnel Role Sepsis Serology Specificity Staphylococcus aureus Staphylococcus aureus infection System T cell response T-Cell Development T-Lymphocyte T-cell diversity Therapeutic Toxin Vaccination Vaccine Antigen Vaccine Design Vaccines Virulence Factors adaptive immune response adaptive immunity alpha Toxin antigen-specific T cells antimicrobial base biobank burden of illness cohort comparative design drug development early childhood high dimensionality high risk population infancy insight interest mortality multidisciplinary novel novel strategies novel therapeutics pathogenic bacteria patient population preservation prevent receptor resistant strain response success universal vaccine vaccine development

项目摘要

Staphylococcus aureus is an aggressive antibiotic-resistant human bacterial pathogen. S. aureus is a leading cause of infectious disease morbidity, mortality, and hospital-associated infection in the U.S., and a formidable health threat worldwide. The only durable solution to mitigate S. aureus disease is the successful development of a universal vaccine. In spite of the clinical burden of human S. aureus infection, and considerable molecular knowledge of disease pathogenesis gleaned from experimental systems, there is a striking paucity of knowledge regarding the host immune response in human S. aureus infection. This fact has remained the single most significant shortcoming of prior vaccine approaches, as the scientific premise for the inclusion of vaccine antigens has not been based on known correlates of human immunity to S. aureus. The investigators’ studies to date in the pediatric population strongly suggest that the adaptive immune response to S. aureus is templated early in life when initial exposure to the organism occurs, amplifying the importance of understanding the development of the human adaptive immune response to S. aureus during infancy and early childhood. The proposed project addresses current knowledge gaps through a multifaceted analysis of the natural development of protective immunity to S. aureus, leveraging novel insight on the role of S. aureus α-toxin (Hla) as a virulence factor that dampens the antigen-specific T cell response in the host. Coupled with the observation that the serologic response to Hla is a correlate of long-term protective immunity to S. aureus in children, these findings suggest that neutralizing Hla may simultaneously afford disease protection and preclude modulation of host immunity by S. aureus. To this end, a cohort-based approach for comparative analysis of human immunity in the context of normal, healthy childhood development, as well as in the setting of S. aureus disease, will be performed. The context of this exposure is expected to elicit protective immunologic responses or maladaptive responses, which we hypothesize will be discernable through paired analyses of healthy and infected subjects as a function of development. These studies will be the first to leverage high-dimensionality mass cytometry (CyTOF)-based analysis of the human T cell response to S. aureus, characterizing both cellular differentiation and the functional response. Paired with multiplex analysis of the developing human antibody response to S. aureus virulence factors, the biorepository generated through the proposed study will support a comparative analysis of adaptive immunity in healthy infants and young children relative to that observed in patients who manifest both local and invasive S. aureus infection. The proposed multi-disciplinary team is uniquely positioned to conduct the first highly-focused, hypothesis-driven approach to examination of the development of human immunity to S. aureus. This research will inform our understanding of the natural development of the host response to S. aureus, providing an essential foundation for the strategic design and implementation of a S. aureus vaccine capable of eliciting population-level immunity.

金黄色葡萄球菌是一种对抗生素具有耐药性的人类细菌病原体，是美国传染病发病率、死亡率和医院相关感染的主要原因，也是全球范围内严重的健康威胁。金黄色葡萄球菌病是一种通用疫苗的成功开发，尽管人类金黄色葡萄球菌感染的临床负担，并且从实验系统中收集到了大量关于疾病发病机制的分子知识，但知识仍然严重缺乏。关于人类金黄色葡萄球菌感染中的宿主免疫反应，这一事实仍然是先前疫苗方法的一个最显着的缺点，因为包含疫苗抗原的科学前提并不是基于人类对金黄色葡萄球菌免疫的已知相关性。研究人员迄今为止在儿科人群中进行的研究强烈表明，对金黄色葡萄球菌的适应性免疫反应是在生命早期当最初接触该生物体时形成的，这增强了了解人类对金黄色葡萄球菌适应性免疫反应发展的重要性。金黄色葡萄球菌期间拟议的项目通过对金黄色葡萄球菌保护性免疫的自然发展进行多方面分析，利用对金黄色葡萄球菌 α-毒素 (Hla) 作为抑制毒力因子的作用的新见解，解决了当前的知识差距。结合观察到 Hla 的血清学反应与儿童对金黄色葡萄球菌的长期保护性免疫相关，这些发现表明中和 Hla 可能。同时提供疾病保护并排除金黄色葡萄球菌对宿主免疫的调节为此，我们采用基于队列的方法对正常、健康的儿童发育以及金黄色葡萄球菌环境中的人类免疫进行比较分析。这种暴露的背景预计会引起保护性免疫反应或适应不良反应，我们将通过对健康受试者和感染受试者的配对分析来辨别这些反应作为发育的函数。 -维数质量基于细胞计数 (CyTOF) 的人类 T 细胞对金黄色葡萄球菌反应的分析，表征细胞分化和功能反应，并结合对金黄色葡萄球菌毒力因子的发展中的人类抗体反应的多重分析，通过提议生成的生物库。该研究将支持对健康婴儿和幼儿的适应性免疫与在表现出局部和侵袭性金黄色葡萄球菌感染的患者中观察到的适应性免疫进行比较分析。拟议的多学科团队具有独特的优势来进行首次研究。这项研究将帮助我们了解宿主对金黄色葡萄球菌反应的自然发展，为战略设计和实施提供重要基础。能够引发人群水平免疫的金黄色葡萄球菌疫苗。