Host epithelium integrity in the female reproductive tract during Neisseria gonorrhoeae infection

Abstract: Neisseria gonorrhoeae infections are asymptomatic in approximately fifty percent of the affected women. Left untreated, this can develop into a long-term inflammatory state with detrimental secondary complications such as ectopic pregnancy and sterility. Furthermore, studies have shown that N. gonorrhoeae infection may be a contributing factor to urogenital cancers.We found that gonococcal infections induce DNA damage in human vaginal and cervical cells. As a consequence of the DNA damage the cell cycle progression is altered. Mitotic checkpoint genes and proteins important in regulation of metaphase were distorted. Partly because of this, the progression of mitosis was hampered. An additional contributing cause of the DNA damage and dysfunctional mitosis is the release of endogenous gonococcal restriction endonucleases.Most N. gonorrhoeae infection studies are performed on cultured monolayers of cells derived from tumors.  In order to create a system which more resembled in vivo conditions and study N. gonorrhoeae infections, we developed a polarized epithelium of human non-tumorigenic vaginal VK2/E6E7 cells. In the search for an animal model for the human-restricted pathogen we evaluated the CD46 transgenic mouse model in the study of gonococcal infections.In summary, this thesis aims to increase the understanding of the basic molecular function of how invasive gonococcal infections affect host cell cycle regulation, DNA integrity and potential predisposition to cellular malignancies in the epithelium of the female reproductive tract. Since the female reproductive tract is colonized with Lactobacillus, the impact of lactobacilli to the host cell cycle has also been investigated.