Innate Immune Responses to Mucosal Pathogens
We are examining the interactions of several mucosal pathogens with both phagocytic and non-phagocytic cells. We are examining in vitro model systems for endothelial and epithelial cells, platelets, and macrophages / monocytes. Using defined animal models of inflammation we are characterizing the roles of innate immune pathways in inflammatory processes in vivo. We established in a mouse model for oral inflammation that P. gingivalis oral infection induced progressive inflammation and atherosclerosis in ApoE-/- mice which was prevented if mice were first immunized with a whole bacterial cell vaccine prior to oral infection. P. gingivalis acceleration of atherosclerosis was associated with increased expression of TLRs in atheromas. We also observed that mice deficient in the innate immune receptor TLR2 exhibited diminished inflammation and atherosclerosis following infection. In contrast, TLR4 deficiency exacerbated P. gingivalis induced atherosclerosis. We also established a role for TLR4 signaling in IL-1ß secretion, bacterial survival, autophagy, and inflammasome activation. We have also shown P. gingivalis mediated TLR4 evasion strategies play a critical role in chronic inflammation at sites distant from infection and that distinct pathways of immune activation are at play at local versus systemic sites of inflammation.
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. 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.
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: Pathogen-induced inflammation by Neisseria gonorrhoeae via activation of the inflammasome and NFkB signaling.