Role of Chlamydia trachomatis inclusion membrane proteins for early and late developmental cycle progression

Chlamydia is the most frequently reported sexually transmitted disease of bacterial origin. Vaccines are not available, and infections are often asymptomatic, resulting in untreated inflammation causing pelvic inflammatory disease, ectopic pregnancy, and infertility. The etiological agent, Chlamydia trachomatis, is an obligate intracellular bacterium that infects epithelial cells of the reproductive tract. Upon entry into host cells, the bacteria are contained within a membrane-bound vacuole known as the inclusion and undergo a unique developmental cycle, alternating between infectious (elementary body, EB) and replicative (reticulate body, RB) forms. Despite being vital for pathogenesis, little is known about the molecular mechanisms governing progression through the developmental cycle, in particular EB to RB transition and bacterial exit from host cells. Chlamydia interacts with its host cell through bacterially-encoded inclusion membrane (Inc) proteins, which are embedded within the inclusion membrane. Although progress has been made to uncover the role of Inc proteins in specific aspects of the developmental cycle, the function of most Inc proteins is still unknown. My work has focused on elucidating the roles of two Inc proteins, IncS and CTL0390, in early and late stages of the developmental cycle, respectively. Using novel genetic tools and in vivo methodologies, we showed that IncS is critical for EB to RB transition in vitro and early inclusion development in vivo. Additionally, we demonstrated that CTL0390 functions in induction of lysis at the end of the developmental cycle through activation of the DNA-sensing adaptor molecule STING. Finally, we developed a novel murine endometrial organoid model system to study Chlamydia infection which can be used to study developmental cycle progression and Inc protein expression in a relevant cellular environment. Overall, my work contributes new knowledge of Chlamydia infection and can be used for future development of novel therapeutics to treat or prevent Chlamydia infection.