Chlamydia trachomatis is the most prevalent sexually transmitted bacterial infection in the US and the primary cause of preventable blindness worldwide. The organisms are obligate intracellular bacteria which, in women, infect epithelial cells of the cervix causing inflammation as infection ascends towards the fallopian tubes. Reproductive tract infection with C. trachomatis often results in chronic inflammation as the immune system repeatedly fails to clear infection. Moreover, prior infection of humans with C. trachomatis followed by treatment fails to provide significant protection against re-infection. Chronic infection and/or re-infection with C. trachomatis poses serious health risks to women including ectopic pregnancy, pelvic inflammatory disease (PID), and infertility. In this proposal, we seek to understand why protective memory to Chlamydia fails to develop and whether there are interventions that may allow for successful vaccination against this pathogen. Protective immunity against C. trachomatis requires production of IFN-g by cells of the innate and adaptive immune response. It is also known that expression of IFN-g by CD4+ T cells, CD8+ T cells, NK cells, and dendritic cells is partially controlled by the transcription factor T-bet. Based on preliminary data, here we consider that T-bet as a key regulator of both CD4 mediated immunity and memory development to intracellular pathogen. We propose two aims. First, we will examine the impact of T-bet on primary immunity to two different pathogens with differential dependency on T-bet for clearance of infection, C. trachomatis (T-bet dependant) and L. monocytogenes (T-bet independent). Next, we will use gene arrays and phenotypic profiling to characterize how T-bet influences Chlamydia-specific CD4+ T cell memory development. These data will clarify how T-bet transcritionally controls CD4+ immunity and memory development to pathogens in the reproductive tract. We anticipate these results will influence how vaccines will be designed to protect against C. trachomatis and other sexually transmitted infections.
| Gondek, David C; Roan, Nadia R; Starnbach, Michael N (2009) T cell responses in the absence of IFN-gamma exacerbate uterine infection with Chlamydia trachomatis. J Immunol 183:1313-9 |
