Prostaglandin E2 regulates the host response to a genital infection with Chlamydia trachomatis.

摘要

Chlamydia trachomatis is a leading bacterial cause of sexually transmitted disease (STD) in humans, causing severe consequences if not treated. The pathogenesis of and immunity to chlamydial genital infection can be regulated by factors secreted during the immune response including cytokines, chemokines and molecules such as Prostaglandin E2 (PGE2). This dissertation addresses the mechanism whereby PGE2 modulates the host response to the chlamydial genital infection.; PGE2, a well-known modulator for cell survival, is induced in the reproductive tract epithelial cells following chlamydial infection. Deficiency in cyclooxygenase 2 (COX-2), the rate-limiting enzyme of PGE 2 synthesis, caused significant reduction in the bacterial load during a secondary infection in vitro. Following chlamydial infection in vivo, a decreased early bacterial burden within the genital tract (GT) was consistently observed in the mice deficient in COX-2 activity. Increased apoptosis in the Chlamydia infected epithelial cells with COX-2 ablation suggests that COX-2 might protect intracellular Chlamydia from death by suppressing the machinery of host cell apoptosis.; PGE2 has also been recognized as an immune-regulator. It potentiates interleukin 10 (IL-10) production in the draining lymph node iliac node (ILN) during chlamydial genital infection. Mice deficient in IL-10 gene had an increase of Th1 cytokine IFN-gamma synthesis in the ILN, with a shortened infection course, and less upper GT damage. Further investigation showed Chlamydia-infected mice with PGE2 treatment had increased recruitment of conventional dendritic cells (cDC), to the infected GT and ILN, mediated through the up-regulation of a chemokine receptor CCR7. PGE 2 also alters aspects of the adaptive response by boosting a stronger mRNA expression of molecules involved in the maturation and activation of bone marrow derived DC (BMDC), primarily cDC, upon live chlamydial stimulation. In addition, PGE2 skewed cDC toward non-Th1 polarizing direction by strikingly enhancing the expression of IL-10.; Taken together, these data support a model of induction of an inflammatory molecule PGE2 within GT that modulates both host cell growth and immunity during chlamydial genital infection. These findings provide further understanding of how IL-10 production is regulated during Chlamydia infection, broadening the view for vaccine development against Chlamydia infection.