Age-Associated Inflammation and Toll-Like Receptor Dysfunction Prime the Lungs for Pneumococcal Pneumonia

Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
The Journal of Infectious Diseases (Impact Factor: 5.78). 09/2009; 200(4):546-54. DOI: 10.1086/600870
Source: PubMed

ABSTRACT Aging is associated with increased inflammation and risk of community-acquired pneumonia. Streptococcus pneumoniae co-opts the nuclear factor kappa B (NFkB)-regulated proteins polymeric immunoglobulin receptor (pIgR) and platelet-activating factor receptor (PAFr) to attach and invade cells. We sought to determine whether aging and chronic inflammation were associated with increased pIgR and PAFr levels in the lungs and increased susceptibility to S. pneumoniae infection.
Lung protein and messenger RNA levels were quantitated using Western blot and quantitative polymerase chain reaction. NFkB activation was measured by electrophoretic mobility shift assay. Cytokine levels were measured by cytometric bead analysis. To model chronic inflammation, mice were implanted with osmotic pumps that delivered tumor necrosis factor-alpha.
Aged mice and those infused with tumor necrosis factor-alpha had increased levels of pIgR and PAFr in their lungs and were more susceptible to S. pneumoniae infection. During pneumonia, aged mice had reduced levels of pIgR and PAFr and less NFkB activation, despite greater bacterial burden. We determined that aged mice had decreased amounts of lung Toll-like receptors 1, 2, and 4 and reduced capacity to respond to S. pneumoniae with proinflammatory cytokine production.
Aged mice and, potentially, elderly humans are more susceptible to pneumonia because of a priming effect of chronic inflammation and Toll-like receptor dysfunction.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Older age has long been associated with altered inflammation and hemostasis regulation. Emerging evidence suggests that age-related differences in inflammation and hemostasis abnormalities may play a role in the development of and long-term outcomes after critical illness. A better understanding of underlying mechanisms may provide new possibilities for therapeutic interventions. In this review, we will examine how age-related differences in inflammatory and coagulation responses are affected through the continuum of healthy state, before infection occurs, to severe sepsis and recovery.
    12/2011; 2(6):501-11.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cellular senescence is an age-associated phenomenon that promotes tumor invasiveness owing to the secretion of proinflammatory cytokines, proteases, and growth factors. Herein we demonstrate that cellular senescence also potentially increases susceptibility to bacterial pneumonia caused by Streptococcus pneumoniae (the pneumococcus), the leading cause of infectious death in the elderly. Aged mice had increased lung inflammation as determined by cytokine analysis and histopathology of lung sections. Immunoblotting for p16, pRb, and mH2A showed that elderly humans and aged mice had increased levels of these senescence markers in their lungs vs. young controls. Keratin 10 (K10), laminin receptor (LR), and platelet-activating factor receptor (PAFr), host proteins known to be co-opted for bacterial adhesion, were also increased. Aged mice were found to be highly susceptible to pneumococcal challenge in a PsrP, the pneumococcal adhesin that binds K10, dependent manner. In vitro senescent A549 lung epithelial cells had elevated K10 and LR protein levels and were up to 5-fold more permissive for bacterial adhesion. Additionally, exposure of normal cells to conditioned media from senescent cells doubled PAFr levels and pneumococcal adherence. Genotoxic stress induced by bleomycin and oxidative stress enhanced susceptibility of young mice to pneumonia and was positively correlated with enhanced p16, inflammation, and LR levels. These findings suggest that cellular senescence facilitates bacterial adhesion to cells in the lungs and provides an additional molecular mechanism for the increased incidence of community-acquired pneumonia in the elderly. This study is the first to suggest a second negative consequence for the senescence-associated secretory phenotype.
    Aging cell 05/2011; 10(5):798-806. DOI:10.1111/j.1474-9726.2011.00720.x · 5.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Elderly individuals display increased susceptibility to chronic inflammatory diseases and microbial infections, such as periodontitis and oral aspiration pneumonia. The resurgent interest in innate immunity in the 2000s has been accompanied by parallel studies to understand the impact of aging on the function of the innate immune system, which not only provides first-line defense but is essential for the development of adaptive immunity. This review summarizes and discusses our current understanding of age-associated molecular alterations in neutrophils and macrophages, key inflammatory phagocytes implicated in both protective and destructive host responses. The analysis of recent literature suggests that, in advanced age, phagocytes undergo significant changes in signal transduction pathways that may affect their ability to perform antimicrobial functions or regulate the inflammatory response. These abnormalities are expected to contribute to the pathology of oral infection-driven inflammatory diseases in the elderly. Moreover, the elucidation of age-associated defects in the innate immune system will facilitate the development of intervention therapeutic strategies to promote or restore innate immune function and improve the quality of health in old age.
    02/2010; 25(1):25-37. DOI:10.1111/j.2041-1014.2009.00562.x


Available from