Innate Immune Responses to Mucosal Pathogens
We are examining the interactions of several mucosal pathogens with both phagocytic and non-phagocytic cells. Work with N. gonorrhoeae has established that distinct proinflammatory responses are observed in different compartments of the female lower genital tract (endocervical, ectocervical and vaginal cell lines). Using these cell lines we have demonstrated that infection with N. gonorrhoeae inhibits the apoptotic response of these cells. N. gonorrhoeae may thus establish infection by inhibiting the apoptotic response to infection, thereby resisting killing from both the host cell and the innate immune response. Current studies are focused on defining the role of toll-like receptors and intracellular signaling receptors in N. gonorrhoeae induced proinflammatory responses in epithelial cells. Work with P. gingivalis has demonstrated the invasive capabilities of these organisms for endothelial cells and has defined specific cell signaling pathways involved in this response. We have shown that 2 adhesins of this organism, the major and minor fimbriae proteins bind to and signal through TLR2 for an inflammatory response in human aortic endothelial cells. Furthermore both the major and minor fimbriae proteins can signal through TLR4 if the accessory proteins MD2 and CD14 are present. Our recent studies are focused on defining intracellular signaling receptors and pathways utilized by P. gingivalis to induce IL-1ß secretion in endothelial cells.
In addition to this work, we are establishing a mouse infection model in our laboratory that can be potentially very useful in understanding the pathogenesis of gonorrhea, such as the role of different host receptors including intracellular receptors NOD1 and NOD2 and the cIAP-2 and Rip2 proteins, in the recognition and immune response to N. gonorrhoeae in the genital tract.
Figure right: Confocal microscopy was performed on endocervical cell cultures infected with N. gonorrhoeae F62-GFP and stained with a red fluorescent plasma membrane marker.
Figure left: anti-apoptotic response of live N. gonorrhoeae-stimulated endocervical cells. Mitochondrial membrane potential measured by staining with rhodamine followed by analysis by flow cytometry.