Chlamydia trachomatis infection remains a major cause of pelvic inflammatory disease, and often leads to fallopian tube injury and infertility in humans. While effective antibiotics are available, asymptomatic infection may ascend to the upper genital tract (GT) and cause irreversible tissue damage before it is discovered. One strategy for avoiding injury to the upper GT is through preventative vaccination. However, the anti-chlamydial CD4 T-helper type 1 (Th1) response that develops to eradicate infection is also thought to participate in upper GT injury. The goal of this project is to identify mechanisms that regulate chlamydial immunity in the upper GT to better understand the basis of upper GT injury. We recently reported that CD4 cells are primarily recruited to the upper but not the lower GT and that Th1 attractant chemokines are produced primarily in the upper GT during infection. Based on those findings we hypothesize that the ability to recruit T cells differs between the upper and lower GT. We have also found that Th1 cells are not the only subset recruited to the GT. Anti-Chlamydia-specific T cells that produce IL-10 are also recruited to the GT during infection. T cells that secrete IL-10 may interfere with a Th1 response and enhance upper GT injury. Therefore, it will be important in validating the hypothesis to determine whether the IL-10 producing T cells that are recruited to the GT can modulate the Th1 response against Chlamydia. To test this hypothesis we will 1) Identify mechanism(s) that control the enhanced recruitment of Th1 CD4 cells to the upper GT, 2) Determine if altering Th1 CD4 cell recruitment improves immunity against Chlamydia infection. 3) Determine if IL-10 producing T cells subsets (Th2, Tr1) impede anti-chlamydial Th1 immunity. To achieve these goals, we will focus on identifying chemokine and chemokine receptor ligands that mediate Th1 cell recruitment to the GT. In addition, we will attempt to boost immunity in the lower GT by the delivery of these Th1-attractant chemokines to the vaginal region using adenoviruses that secrete Th1-atrractant chemokines. Also, using IL-10 knockout and transgenic mice we will determine whether IL-10 producing T cell subsets influence anti-Chlamydia immunity and the development of upper GT injury.
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