Host-pathogen interactions controlling Chlamydia developmental cycle

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SUMMARY Chlamydia trachomatis is the leading cause of sexually transmitted infections of bacterial origin. No vaccine is available. Infections are often asymptomatic, leading to long-term damage of the reproductive organs and deleterious effects on human health ranging from pelvic inflammatory disease to infertility. Pathogenesis is linked to a host inflammatory response triggered by the invasion of the genital tract epithelium with this obligate intracellular pathogen. A hallmark and critical aspect of Chlamydia intracellular life style is its bi-phasic developmental cycle, during which the bacteria alternate between infectious (EB) and replicative (RB) forms within the lumen of a membrane-bound compartment called the inclusion. The mechanisms that govern progression through the developmental cycle are poorly understood. Here we describe a Chlamydia conditional mutant in an inclusion membrane protein. The mutant displays a severe, yet complementable, developmental defect in the early stages of the developmental cycle, most likely during EB to RB conversion. Moreover, this Inc protein interacts with a host factor involved in the late stages of the developmental cycle, when the bacteria exit the cell via extrusion. We propose to test the hypothesis that this Inc protein plays a dual role early (Aim 1) and late (Aim2) during the developmental cycle and to determine its contribution to pathogenesis (Aim 3). Through the use of cell biology, bacterial genetics, transcriptomics, proteomics and in vivo approaches, our studies will further our understanding of the molecular mechanisms governing the host-Chlamydia interactions that control the developmental cycle. Altogether our work has the potential to identify therapeutic targets to block transmission of and pathogenesis associated with this important sexually transmitted pathogen.