The role of A1 adenosine receptor signaling in the decline of S. pneumoniae killing by neutrophils in vaccinated aged hosts

Streptococcus pneumoniae (pneumococcus) are Gram-positive bacteria responsible for 1.6 million deaths globally each year. Available pneumococcal vaccines have reduced efficacy in the elderly, and despite vaccination, S. pneumoniae remain the leading cause of bacterial community-acquired pneumonia in adults over the age of 65. This decline in vaccine efficacy is driven by immunosenescence, the age-associated decline in immune function. Polymorphonuclear leukocytes (PMNs) are cells of the innate immune system and are required for host defense against S. pneumoniae infection. PMNs isolated from aged hosts display a significant reduction in pneumococcal killing when compared to PMNs from young hosts. This reduction in killing persists despite opsonization of bacteria with specific anti-pneumococcal antibodies, however, the signaling pathways driving this decline in PMN function and the role of PMNs in the age-related reduction in vaccine efficacy remain unclear. One pathway that controls PMN antibacterial responses is the extracellular adenosine pathway but the role of this pathway in vaccinated hosts and how it changes with age remain unexplored. This led to the hypothesis that with age, there is a decline in intracellular bacterial killing following antibody mediated uptake of S. pneumoniae, which is driven by changes in adenosine receptor signaling. This hypothesis will be tested using two specific aims: 1) Identify why intracellular killing of S. pneumoniae is defective in PMNs from old mice and 2) Identify the role of adenosine receptor signaling in the age-driven decline in intracellular killing of S. pneumoniae by PMNs. This project is significant as it will identify the mechanism of the age-related changes in PMN function following antibody mediated uptake of S. pneumoniae. Additionally, PMNs are involved in host defense against multiple pathogens, therefore this work may provide a potential therapeutic target to boost overall vaccine protectiveness in aged hosts. The overall goal of this research training plan is to strengthen the candidate’s knowledge in host-pathogen interactions, immunology, and immunosenescence. As well as to advance technical skills in microscopy, signaling, and cell biology techniques. These aims and goals will be accomplished with the guidance of the qualified mentoring team assembled by the candidate and will be aided by the opportunities offered by the training environment at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences. These resources will provide the necessary training and support to complete the proposed research and guide the candidate’s future career in academia.