David H. Walker, M.D.2011-12-202014-02-192010-09-282011-12-202014-02-192009-03-182007-06-26etd-03182009-181446http://hdl.handle.net/2152.3/55Identifying the role(s) dendritic cells play in rickettsial infection is important in determining the characteristics which elicit protective immunity. Previous data imply that Th1 responses are essential for immunity to rickettsiae; however, they do not address mechanisms important in initiating early immunity, particularly those involving dendritic cells. Dendritic cells are instrumental in initiation and control of a strong Th1 response towards invading pathogens. I hypothesize that cutaneous dendritic cells comprise an important initial target for rickettsial infection. Additionally, activation and migration of rickettsiae-infected dendritic cells to draining lymph nodes may be critical to activation of NK and CD8 T-cells. Lastly, preliminary data suggest that rickettsiae act as TLR4 agonists on dendritic cells, resulting in their activation. To elucidate the significance of dendritic cells in rickettsioses, I developed a model of dermal infection to demonstrate that cutaneous dendritic cells comprise an important initial target cell. Furthermore, I demonstrated that rickettsiae-infected dendritic cells were capable of inducing protective immunity in naïve mice to an ordinarily lethal challenge. This protection was correlated with significantly elevated levels of IFN-γ producing CD4 and CD8 T-cells as well as NK cells, indicating that rickettsiae-infected dendritic cells are capable of inducing protective Th1 responses and NK cell mobilization. Lastly, we demonstrated that mice defective in TLR4 signaling were more susceptible to lethal rickettsial infection. This susceptibility was correlated with a significant decrease in Th1 immune responses. Additionally, TLR4 was shown to be critical towards the generation of Th17 responses. TLR4 ligation in dendritic cells also appears important in augmenting NK cell activation in vivo.electronicengCopyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.toll-like receptor 4Rickettsiaenatural killer cellsdendritic cellsdissertation