Following transmission from an infected to uninfected host, the gonococcus adheres to the apical side of the epithelial cells. This is mediated through gonococcal surface structures such as type IV pili (tfp), opacity (Opa) proteins, lipooligosaccharide (LOS) and the major OM protein porin, PorB [56]. Tfp, LOS and Opa can undergo both phase and antigenic variation during infection that minimizes recognition and elimination by the immune system [57].

Primary attachment is initiated by tfp which bind to the host cell surface receptor CD46 and/or complement receptor 3 [58,59]. In vitro studies indicate that antigenic variation of tfp influences pilus-mediated adherence to human tissue, colony morphology and DNA transformation efficiency [60,61]. To promote further intimate attachment, Opa proteins, which are phase variable [62], adhere to the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) receptors, but some variants can bind to heparan sulfate proteoglycans (HSPGs) on host cells [58,63,64,65,66]. Attachment is also mediated by gonococcal LOS, which binds specifically to the host asialoglycoprotein receptor on HepG2 cells [67], human sperm cells [68] and epithelial cells [69]. Following adhesion, N. gonorrhoeae replicates to form microcolonies and biofilms [70,71], and some bacteria can proceed to invade epithelial cells by transcytosis [72,73,74]. During infection, gonococci releases fragments of bacterial LOS, peptidoglycan (PG) and OM vesicles during cell growth that activate two pattern recognition receptors, toll-like receptor (TLR) and nucleotide-binding oligomerization domain-like receptor (NOD) on epithelial cells, macrophages and dendritic cells [75,76,77,78,79]. N. gonorrhoeae also releases heptose-1,7-bisphosphate, a precursor for the incorporation of heptose into LOS, which activates TNF receptor-associated factor-interacting protein with forkhead-associated protein A (TIFA)-dependent immunity [80,81]. Activation of these TIFA, NOD and TLR signaling pathways leads to the activation of inflammatory transcription factors and release of pro-inflammatory cytokines and chemokines (e.g., IL-6, IL-8, CXCL3, CXCL10 and TNF-α) [58,82,83]. In response to these signals, large amounts of polymorphonuclear leukocytes (PMNs) are recruited to the site of infection, where N. gonorrhoeae is recognized and phagocytosed. Since gonococci can survive and replicate within PMNs, the massive influx of PMNs forms an observable purulent exudate that facilitates transmission [84].