We have been studying the interactions of bacteria and respiratory epithelial cells to understand the pathogenesis of bacterial infection in cystic fibrosis (CF). As airway inflammation is a major component of CF lung disease, our studies have focused on the molecular mechanisms involved in bacteria activation of epithelial proinflammatory cytokine expression. Our approach has been to use bacterial genetic systems to identify virulence genes and adhesins important in the pathogenesis of infection and to delineate the cytokine signaling systems in normal and CF epithelial cells that are activated by these bacterial components.

Pseudomonas aeruginosa is the major bacterial pathogen in CF. We demonstrated that this organism recognizes asialylated glycolipid receptors on the surface of airway epithelial cells, and that these asialylated receptors are increased in cells with CFTR mutations. Ligation of these receptors by piliated P. aeruginosa, and other pulmonary pathogens including Staphylococcus aureus activates IL-8 expression by airway epithelial cells. The pathway appears to involve recognition of these glycolipid receptors expressed within caveolae on the cell surface, the release of Ca2+ from intracellular stores and the activation of p38 and Erk1/2 mitogen activated protein kinases. This results in the translocation of NF-kB and IL-8 transcription.

As IL-8 functions as the major polymorphonuclear leukocyte chemokine in the lung, this pathway is responsible for the induction of airway inflammation in response to adherent bacteria, or their gene products. Cells with CFTR mutations appear to have increased activation of this pathway, both in response to bacterial pathogens, as well as under unstimulated conditions. In ongoing studies we are identifying the cell components which make up the asialoGM1 receptor-complex as well as the key signaling moieties involved in this pathway. Using a murine model of acute pulmonary infection, we can test the efficacy of therapeutic strategies designed to either prevent infection, or to modulate the inflammatory response mediated by the epithelial cells. Visit the Prince Lab website: http://www.columbia.edu/cu/hs/princelab