Innate Immunity and Inflammation

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.

Pathogen Induced Chronic Inflammatory Disorders
Chronic inflammation culminates in devastating events, results in significant host pathology, and is associated with a number of human diseases including autoimmune diseases, infectious diseases, neoplastic diseases, and inflammatory atherosclerosis. Our studies focus on two pathogens associated with chronic inflammation, Chlamydia pneumoniae and Porphyromonas gingivalis. C. pneumoniae  is a respiratory pathogen that causes a mild, usually asymptomatic pneumonia. P. gingivalis induces a local host inflammatory response that results in inflammatory bone destruction, which is manifested as periodontal disease. Normally, the acute inflammatory response is self-limited, working to contain these infections until the adaptive immune response is activated.  However, under some circumstances, a chronic inflammatory state can ensue, resulting in additional host pathology. Recently, both C. pneumoniae and P. gingivalis have been implicated in the pathogenesis of chronic inflammatory plaque formation although how these pathogens induce and maintain chronic inflammation is not well defined. Our laboratory has defined the role of specific innate immune signaling pathways in immune cells that contribute collectively to pathogen-induced chronic inflammation. We are examining in vitro model systems for platelets, endothelial cells, and macrophages. Using defined animal models of inflammation we are characterizing the roles of innate immune pathways in inflammatory processes in vivo. Enhanced understanding of the roles of specific innate immune signaling pathways, which participate in proinflammatory mediator expression and functional immune responses will provide a promising avenue for novel therapies for chronic inflammatory disorders.

Faculty involved in this research are: