The long-term goal of this research is to elucidate the immune mechanisms of endothelial cells lining the vascular system that either impair or elicit effective immune responses against endothelium-target infectious agents such us rickettsiae. These obligately intracellular bacteria include agents of potential use for bioterrorism such as Rickettsia rickettsii (the cause of Rocky Mountain spotted fever) and R. prowazekii (the cause of epidemic typhus). In adequate mouse models, the effective anti-rickettsial immune response involves NK cells, CD8+ T cells, and the activation of rickettsicidal mechanisms of endothelial cells; however, C57BL/6 mice are significantly more resistant to rickettsial infection than C3H/HeN mice despite the fact that CD8+ T cells are necessary for the complete clearance of rickettsiae in both strains. Given that endothelial cells respond to rickettsial infection by expressing multiple immune response genes, we hypothesize that the inflammatory phenotype of rickettsia-infected endothelial cells influences the development of the innate and/or adaptive immunity against rickettsiae. Thus, the objective of this application is to understand the role of the endothelium in the production of effective or ineffective anti- rickettsial immune responses. I will approach this objective through the following specific aims: 1) Determine the role of the rickettsia-induced endothelial inflammatory phenotype in the effector functions of endothelial cells, NK cells and CD8+ T cells; and 2) Determine the in vivo role of rickettsia-infected endothelial cells in the activation or tolerization of naive CD8+ T lymphocytes. I will carry out these aims by 1) comparing the rickettsicidal activity and expression of MHC-class I, T cell costimulatory molecules, and NK cell ligands of rickettsia-infected primary endothelial cell cultures and tissues from susceptible and resistant mice; 2) measuring the differences in effector functions of NK cells and CD8+ T cells stimulated by rickettsia-infected endothelial cells of either mouse strain; and 3) comparing the priming or tolerization of naive CD8+ T cells in mouse chimeras of either strain in which MHC class I molecules are expressed by endothelial cells but not by cells of bone marrow origin. The health impact of this research is that it will broaden the knowledge necessary for the rational design of effective vaccines against rickettsial diseases; this information will be applicable to other endothelial-target infectious agents as well as diseases in which endothelial cells might play an important role such as atherosclerosis, cancer, and vasculitides. ? ? ?
| Valbuena, Gustavo; Walker, David H (2009) Infection of the endothelium by members of the order Rickettsiales. Thromb Haemost 102:1071-9 |
