Bacterial Pathogenesis; Immunology; Infectious Disease; Microbial Pathogenesis
Research in my laboratory focuses on age-associated changes in innate immune responses that render the elderly more susceptible to infections. As the number of individuals above 65 years old is projected to reach 2 billion by 2050, infections in this population poses a serious health and economic burden. A major area of our work is on infections caused by Streptococcus pneumoniae (pneumococcus) that despite the availability of vaccines, remain the leading cause of community-acquired pneumonia in the elderly. Immunosenescence, the age-related decline in immune-cell function, and inflammaging, the age-related increase in basal inflammation, may both contribute to the increased susceptibility of the elderly to life-threatening S. pneumoniae infections such as pneumonia, bacteremia and meningitis.
Of particular interest are polymorphonuclear leukocytes (PMN) or neutrophil responses. PMNs are innate immune cells that are key determinants of disease following infection because their initial presence is required to control bacterial numbers, but their persistence in the lungs is detrimental to the host. PMN responses are dysregulated in aging; however, the pathways driving this are not well elucidated. We found that in young hosts, resistance to infection, PMN antibacterial function as well as pulmonary recruitment and resolution following pneumococcal pneumonia is controlled by the extracellular adenosine (EAD) pathway. EAD is produced by the sequential action of two exonucleosidases, CD39 and CD73, and can signal via four known adenosine receptors, that can be pro- or anti-inflammatory. Interestingly, we found that pneumococci can modulate host inflammatory responses by targeting the expression of EAD pathway components.
We are using a variety of approaches including in vitro modeling of PMN responses from human donors, mouse models of infection as well as genetic manipulation of bacteria to elucidate the following: 1) How the EAD pathway shapes PMN responses during infection; 2) The role of the EAD pathway in age-driven immune dysregulation; 3) The role of PMNs and the EAD pathway in mounting protective memory responses following vaccination in young and aged hosts; 4) The S. pneumoniae virulence factors required to manipulate the EAD pathway. Elucidating what drives the dysregulated immune responses during aging has the potential of using novel therapies to combat infections in the elderly.