Development of human adaptive immunity to Staphylococcus aureus

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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.