? ? Aging is associated with increased inflammation; inflammation the result of a wide range of factors including dysregulation of senescent cells, environmental exposures, and age-associated illnesses. Inflammation is also requisite for Streptococcus pneumoniae (the pneumococcus) attachment and invasion; the pneumococcus being a leading cause of death in the elderly. Pneumococcal disease in the elderly is characterized by its rapid onset, severity, and high-mortality rate; thus we hypothesize that age-associated inflammation (AAI) occurs in the lungs and predisposes the elderly for invasive pneumococcal disease (IPD). This hypothesis is based on the following observations: 1) That the elderly experience low-grade chronic inflammation characterized by elevated levels of NFkB activation in tissues and pro-inflammatory cytokines in the blood. 2) That the elderly are at risk for pneumococcal infection and that their risk increases with underlying conditions that enhance inflammation. 3) That the pneumococcal ligands polymeric immunoglobulin receptor (pIgR) and platelet activating factor receptor (PAFr) are responsive to NFkB activation and are up- regulated/expressed following exposure to pro-inflammatory cytokines. 4) That S. pneumoniae binds to pIgR and/or PAFr and uses these proteins to invade cells and translocate to the bloodstream. And finally, 5) that infection of elderly humans and aged mice with S. pneumoniae is characterized by severe infection with more tissue damage, lung consolidation, higher bacterial burden, and mortality than the young. To test our hypothesis we will:
Aim 1 : Determine if AAI occurs in the lungs of healthy aged mice. A) Measure levels of NFkB activation and pro-inflammatory cytokines in the lungs. B) Measure pIgR and PAFr levels in the lungs. C) Determine if prolonged exposure to low levels of TNF1 or IL-6 increases pIgR/PAFr expression in the lungs.
Aim 2 : Determine if aged mice challenged with S. pneumoniae experience a dysregulated immune response and if the response contributes to tissue damage. A) Measure levels of NFkB activation, cytokines, and leukocyte infiltration in infected aged mice. B) Measure ICAM-1, P-selectin, pIgR, and PAFr levels in the lungs of infected aged mice. C) Determine if prolonged exposure to TNF1 or IL-6 increases susceptibility of young mice to S. pneumoniae. -- Aging is associated with increased inflammation and susceptibility to IPD. This grant will determine if a link exists between these observed phenomena. -- ? ? ? ?
