INTERACTIONS OF NEISSERIA GONORRHOEAE WITH EPITHELIAL CELLS
Stein, Daniel C
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Neisseria gonorrhoeae (GC) infects epithelial cells lining the female reproductive tract. The majority of GC infections in women are asymptomatic, which can lead to chronic inflammation and serious complications, including pelvic inflammatory disease, disseminated gonococcal infection, and infertility. GC is known to induce signaling in epithelial cells, including the activation of epidermal growth factor receptor (EGFR) and Ca2+ flux; however, the mechanism by which the signaling leads to GC infection is unknown. Using human cervical tissue explants and epithelial cell lines, my thesis research reveals that GC interactions with polarized epithelial cells induce EGFR-dependent Ca2+ flux, which activates and mobilizes the actin motor protein non-muscle myosin II (NMII). The Ca2+ flux and NMII activation are required for GC-induced disassembling of the apical junction and GC transmigration across epithelial cells, but not GC adherence and invasion. In addition, Opa proteins expressed on GC interfere with GC-induced NMII activation and apical junction disruption, and alter GC interactions with the apical surface of the epithelium, consequently inhibiting GC transmigration. Thus, GC causes disruption of the epithelial barrier by inducing Ca2+-dependent activation of NMII, and Opa phase variation modifies infection mechanisms by regulating perijunctional actomyosin remodeling. To understand how GC establishes infection in the female reproductive track, I examined GC infection in human cervical tissue explants as well as non- polarized and polarized epithelial cells in culture to mimic the non-polarized squamous ectocervical epithelial cells and the polarized columnar endocervical epithelial cells. My results show that GC interaction induces differential remodeling of the actin cytoskeleton in non-polarized and polarized epithelial cells of human ecto- and endo-cervical tissue explants and in culture. This differential actin remodeling is dependent on the activation and redistribution of NMII and leads to different changes in the morphology and functionality of epithelial cells. These results suggest that the polarity of epithelial cells at different anatomic locations of the female reproductive tract alters the mechanisms by which GC establishes the infection.