Immunosenescence, the age-related decline in immune function, is manifested by an increase in susceptibility to many infectious diseases, including serious Streptococcus pneumoniae (pneumococcus) infection. Acute pulmonary inflammation is characteristic of pneumococcal lung infection and may exacerbate tissue damage and disease progression. The elderly suffer from `Inflammaging', the age-dependent increase in basal and induced levels of proinflammatory cytokines. Further, polymorphonuclear leukocytes (PMNs) from elderly individuals display defects in several activities, such as chemotaxis, opsonophagocytic killing, and ROS production. Using a model of intratracheal challenge of wild-type mice, which recapitulates the susceptibility to pneumococcal infection among the elderly, our preliminary data suggests that PMN dysfunction may be a primary cause of the increased susceptibility to pneumococcal pneumonia. Furthermore, adoptive transfer of PMNs from young mice into aged mice conferred resistance to pneumococcal lung challenge, indicating that young PMNs possess defense functions that are lacking in aged PMNs. Comparing the gene expression of uninfected or pneumococcus-exposed PMNs from young and aged mice (by our collaborator Dr. Bou Ghanem) revealed age-dependent expression differences. However, the precise PMN dysfunction leading to age- dependent susceptibility remains unknown and is a focus of this proposal. Here we propose to identify the specific PMN functions that diminish with age and result in the susceptibility to pneumococcal lung infection, as well as systematically test the degree to which age-associated, PMN-mediated susceptibility is due to a diminished defense and/or an enhanced disease-promoting activity. By pinpointing the key host defenses that degrade with age and result in invasive pneumococcal disease, these studies will not only facilitate precisely targeted interventions against a major infectious agent, but also provide insight into the aging innate immune system that may lead to novel therapies against other infections that disproportionately afflict the elderly. In addition, taking a high-risk, high-reward approach, we seek to treat PMNs derived from HoxB8 progenitor cell lines with low levels of inflammatory cytokines found in the bloodstream of the aged host to confer on these PMNs an aged phenotypic profile with respect to PMN activities and RNA expression.
Our Aims are (1) Characterize PMN functions that diminish upon aging and recapitulation these defects in PMNs derived from immortalized myeloid progenitors. (2) Assess the degree to which aged PMNs not only fail to defend against infection but also actively promote pneumococcal disease, thus contributing to age-associated susceptibility to S. pneumoniae.
We seek to pinpoint the key age-associated PMN dysfunctions that result in invasive pneumococcal disease in order to facilitate precisely targeted interventions against this and other agents that afflict the elderly and enable the use of a broad array of genetic approaches to the study of PMN function in host defense.
