Invasive Streptococcus pneumoniae (pneumococcus) infections in the elderly, such as pneumonia, bacteremia, and meningitis, create a considerable health and economic burden in the United States. This calls for a better understanding of the underlying pathways driving immune dysregulation in aged hosts rendering them susceptible to infections. My long-term goal is to lead a research group in an academic setting exploring the age-driven changes in the extracellular adenosine (EAD) pathway, a major regulator of inflammation, and its contribution to the heightened susceptibility of aged hosts to S. pneumoniae infection. Background: An important contributor to the course of disease following S. pneumoniae lung infection is polymorphonuclear leukocytes- (PMNs-). We found that PMNs are initially required for controlling bacterial numbers, however, extended presence of inflammatory PMNs led to significant lung damage and poor control of infection. In searching for regulators of inflammation, we found that EAD, that is produced from breakdown of ATP leaking from injured cells by the ectoenzymes CD73 and CD39 and mediates its action via four adenosine receptors, targets both PMN function and pulmonary recruitment during pneumococcal infection in young mice. When we modeled age-associated susceptibility to S. pneumoniae, we found that aged mice are highly susceptible to invasive pneumococcal infection and that susceptibility was linked to impairment of pneumococcal killing by PMNs and enhancement of pulmonary PMN recruitment. This led to the Hypothesis that: dysregulation of the EAD pathway upon aging results in both impairment in PMN function and exacerbation of pulmonary PMN influx and contributes to the age-associated susceptibility to S. pneumoniae infection. I will characterize the changes in the EAD pathway during S. pneumoniae infection using an aged murine model, its effect on age-driven dysregulation in PMN responses and age-driven susceptibility to bacterial pneumonia. Significance and innovation: Elucidating the changes occurring in the EAD pathway with age has the potential to uncover novel pathways that drive immunosenescence and lead to feasible strategies using readily available adenosine-based therapies to to mitigate the age-associated decline in resistance to bacterial pneumonia. Timeline: As I am very new to the aging field, the mentored K99 phase will provide me the time and resources needed to take advantage of the unique opportunities at Tufts University including close interaction with my two mentors Drs. John Leong and Simin Meydani who are experts in immunosenescence and animal modeling of infectious diseases, involvement in the Healthy and Active Aging at Tufts initiative and courses in the biology of aging to further gain expertise in this area. I will also learn the techniques required to make this project feasible, publish more papers and transition to independence including application for the R00 phase of this award within two years and for independent faculty positions at academic institutes.
Streptococcus pneumoniae is the leading cause of bacterial pneumonia in the elderly. The experiments in this proposal are designed to uncover the role of the Extracellular Adenosine pathway in the age-driven susceptibility to infections by this bacterium. This will allow the potential use of readily available adenosine- based therapies to combat this serious infection in the elderly.
