Development of human adaptive immunity to Staphylococcus aureus

金黄色葡萄球菌是一种具有侵袭性耐药的人类细菌病原体。金黄色葡萄球菌是美国传染病发病率、死亡率和医院相关感染的主要原因，也是全球范围内令人生畏的健康威胁。减轻金黄色葡萄球菌疾病的唯一持久解决方案是成功开发一种通用疫苗。尽管人类金黄色葡萄球菌感染的临床负担很大，并且从实验系统中收集了大量关于疾病发病机制的分子知识，但关于人类金黄色葡萄球菌感染的宿主免疫反应的知识却明显缺乏。这一事实仍然是以往疫苗方法的一个最重要的缺点，因为纳入疫苗抗原的科学前提并不是基于已知的人类对金黄色葡萄球菌免疫的相关因素。迄今为止，研究人员在儿科人群中的研究强烈表明，对金黄色葡萄球菌的适应性免疫反应是在生命早期初始暴露于该生物体时形成的，这增强了理解婴儿期和幼儿期人类对金黄色葡萄球菌适应性免疫反应发展的重要性。拟议的项目通过对金黄色葡萄球菌保护性免疫自然发展的多方面分析，利用对金黄色葡萄球菌α-毒素（Hla）作为抑制宿主抗原特异性T细胞反应的毒力因子的作用的新见解，解决了目前的知识空白。再加上对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的观察结果，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。为此目的，将采用一种基于队列的方法，在正常、健康的儿童发育和金黄色葡萄球菌疾病的背景下，对人类免疫进行比较分析。这种暴露的环境预计会引起保护性免疫反应或适应不良反应，我们假设将通过对健康和感染受试者的配对分析作为发育的功能来识别。这些研究将首次利用基于高维质量细胞术（CyTOF）的人类T细胞对金黄色葡萄球菌的反应分析，表征细胞分化和功能反应。与发展中的人类抗体对金黄色葡萄球菌毒力因子的多重分析相结合，通过提出的研究产生的生物库将支持对健康婴幼儿的适应性免疫进行比较分析，相对于在表现为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。拟议的多学科团队具有独特的优势，可以开展第一个高度集中的、假设驱动的方法来检查人类对金黄色葡萄球菌免疫的发展。这项研究将使我们了解宿主对金黄色葡萄球菌反应的自然发展，为能够引起人群免疫的金黄色葡萄球菌疫苗的战略设计和实施提供必要的基础。

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.