Development of human adaptive immunity to Staphylococcus aureus

金黄色葡萄球菌是一种侵袭性的耐药性人类细菌病原体。S.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，也是全球范围内一个可怕的健康威胁。缓解S.金黄色葡萄球菌病是一种通用疫苗的成功开发。尽管人类S.金黄色葡萄球菌感染，以及从实验系统中收集到的疾病发病机制的大量分子知识，但关于人类S.金黄色葡萄球菌感染这一事实仍然是现有疫苗方法的唯一最显著的缺点，因为包含疫苗抗原的科学前提不是基于已知的人对S.金黄色。迄今为止，研究人员在儿科人群中的研究强烈表明，对S。金黄色葡萄球菌在生命早期初始暴露于该生物体时是模板化的，这放大了理解人类对金黄色葡萄球菌的适应性免疫应答的发展的重要性。金黄色葡萄球菌在婴儿期和幼儿期。拟议的项目通过对S.金黄色葡萄球菌，利用新的见解的作用，金黄色葡萄球菌α毒素（Hla）作为一种毒力因子，抑制宿主中抗原特异性T细胞应答。结合对Hla的血清学应答与对S.金黄色葡萄球菌在儿童中的作用，这些发现表明中和Hla可以同时提供疾病保护并阻止S.金黄色。为此，一个基于队列的方法比较分析人类免疫的背景下，正常，健康的儿童发展，以及在设置S。金黄色葡萄球菌病，将进行。这种暴露的背景下，预计会引起保护性免疫反应或适应不良反应，我们假设这将是可辨别的，通过配对分析健康和感染的受试者作为一个功能的发展。这些研究将是第一个利用基于高维质量细胞术（CyTOF）的人类T细胞对S.金黄色葡萄球菌，表征细胞分化和功能反应。与发展中的人对S.金黄色葡萄球菌毒力因子，通过拟议的研究产生的生物库将支持健康婴儿和幼儿的适应性免疫的比较分析，相对于在表现出局部和侵袭性的S.金黄色葡萄球菌感染拟议的多学科小组具有独特的地位，可以进行第一个高度集中的、假设驱动的方法来检查人类对S。金黄色。这项研究将为我们了解宿主对S.金黄色葡萄球菌，提供了一个重要的战略设计和实施的基础。金黄色葡萄球菌疫苗，其能够引发群体水平的免疫。

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.