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侵略性抗生素抗生素的人类细菌病原体。金黄色葡萄球菌是美国传染病发病率，死亡率和与医院相关的感染的主要原因，以及全世界的强大健康威胁。减轻金黄色葡萄球菌疾病的唯一耐用解决方案是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燃烧以及从实验系统收集的疾病发病机理的大量分子知识，但关于人链球菌感染中宿主免疫响应的知识仍然存在明显的知识。这一事实仍然是先前疫苗方法的最重要的缺点，因为包括疫苗抗原的科学前提并未基于人类免疫与金黄色葡萄球菌的已知相关性。迄今为止，研究者在小儿种群中的研究强烈表明，当初步暴露于生物体时，对金黄色葡萄球菌的适应性免疫响应是在生命的早期模板，从而扩大了了解人类适应性免疫激发在婴儿期和儿童期间对金黄色葡萄球菌的发展的重要性。所提出的项目通过对保护免疫学向金黄色葡萄球菌的自然发展进行多方面的分析来解决当前知识，从而利用了对金黄色葡萄球菌α-Toxin（HLA）的作用的新颖见解，作为一种病毒因素，该病毒是该死的，该病毒使抗原特异性T细胞与corlelagy se corelelagions。中和HLA可能简单地提供了疾病的保护，并排除了金黄色葡萄球菌对宿主免疫学的调节。为此，将进行基于队列的方法，用于在正常，健康的儿童发展以及在金黄色葡萄球菌疾病的情况下对人类免疫学进行比较分析。预计这种暴露的背景会引起受保护的免疫反应或适应不良的反应，我们假设这将通过对健康和感染受试者的配对分析作为发育的函数进行分析。这些研究将是第一个利用对金黄色葡萄球菌的人体T细胞反应的基于高维性质量细胞仪（CYTOF）的分析，表征了细胞分化和功能反应。与对金黄色葡萄球菌病毒因子的发展的人类抗体反应的多重分析，通过拟议的研究产生的生物膜将支持健康婴儿和幼儿适应性免疫学的比较分析相对于表现出局部和侵入性金黄色葡萄球菌感染的患者的比较。拟议的多学科团队的独特位置是进行第一种高度关注的，假设驱动的方法，以检查对金黄色葡萄球菌的人类免疫学的发展。这项研究将为我们了解宿主对金黄色葡萄球菌的自然发展的理解，为战略设计和实施能够引发人群水平免疫学的链球菌疫苗的实施为基础。