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PRINCE, ALICE S., M.D.
Professor of Pediatrics (Infectious Disease) in Pharmacology

Bacterial induction of cytokine signaling in epithelial cells

Office: Black Building | 4th Floor | Room 418
Telephone: 212.305.4193
Fax: 212.305.8780
Email:
asp7@columbia.edu

Prince Lab

Current Research
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.

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Selected Publications

1. Adamo, R., Soong, G., Sokol, S., Gomez, M., Saba, S., Lee, A., Prince, A. (2004) P. aeruinosa aeruginosa flagella activate airway epithelial cells through asialoGM1/TLR2 as wellas TLR5. Amer J Resp Molec Biol 30:627-634

2. Muir, A., Soong, G., Sokol, S., Reddy, B., Gomez, M., Heerckeren, A., and Prince, A. (2004) Toll-like receptors in normal and cystic fibrosis airway epithelial cells. Am J Resp Cell Mol Biol 30:777-783

3. Soong, G., Adamo, R., and Prince, A. (2004) TLR2 is mobilized into an apical lipid raft receptor complex to signal infection in airway epithelial cells. J Clin Invest 113:1482-1489

4. Gomez, M. I., Lee, A., Reddy, B., Muir, A., Soon, G., Pitt, A. Cheung, A., and Prince, A. (2004) Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1. Nat Med 10:842-846

5. Sadikot, R.T., Blackwell T.S., Christman, J.W., and Prince, A. (2005) Pathogen-host interactions in Pseudomonas aeruginosa pneumonia: the state of the art. Amer J Resp Crit Care Med 171:1209-1223

6. Gomez, M., Sokol, S., Muir, A., Soong, G., Bastien, J., and Prince, A. (2005) Bacterial induction of TACE expression and IL-6R alpha shedding regulates airway inflammation. J Immunol 175:1930-1936

7. Prince, A. (2006) Flagellar activation of epithelial signaling. Am J Resp Cell Molec Biol 34:548-551

8. Chun, J., Soong, G., Prince, A. (2006) Activation of Ca2+-dependent signaling by TLR2. J Immunol 177:1330-1337

9. Gomez, M., O'Seaghdha, S., Magargee, M., Foster, T.J., Prince, A. (2006) Staphylococcus aureus protein A activates TNFR1 signaling through conserved IgG binding domains. J Biol Chem 281:20190-20196

10. Soong, G., Muir, A., Gomez, M.I., Reddy, B., Planet, P., Singh, P., Kanetko, Y., Wolfgang, M.C., Prince, A. (2006) Bacterial neuraminidase facilatates mucosal infection by participating in biofilm production. J Clin Invest In Press