**1.1 Pathogenesis of** *N. gonorrhoeae*

In order to establish infection, *N. gonorrhea* first establishes colonization of the mucosal epithelium by adherence and attachment to various epithelial surfaces. This is the first step in pathogenesis, which is mediated by specific bacterial surface structures, including pili type IV (retraction) and opacity (Opa) proteins. The pili type IV retraction brings the gonococci to the cell surface and enable interactions with other surface structures [4].

The next step following adherence is replication of *N. gonorrhoeae,* colonies formation and possibly biofilms. An invasion and transcytosis occur with possible competition with the resident microbiota. During these initial stages in gonococcal infection, *N. gonorrhoeae* produces or sheds lipopolysaccharides, fragments of peptidoglycan, and outer membrane vesicles. The latter could activate Toll-like receptors signaling in epithelial cells, dendritic cells, and macrophages, leading to the release of cytokines and chemokines and then activation of the inflammatory transcription factor. These innate immune signaling pathways allow the recruitment a large number of polymorphonuclear leukocytes to the site of infection where they interact with and phagocytose *N. gonorrhoeae*. The gonococcal colonization could result in symptomatic or asymptomatic infection. In case of sufficient neutrophil influx into the site of infection, a symptomatic infection may occur [4].

Furthermore, *N. gonorrhoeae* avoids clearance by the host immune system in a process known as antigenic variation, due to pili type IV. During this process, gonorrhea alters its cell surface antigens by replacing portions of the expressed pilin gene (*pilE*) with segments of the silent pilin gene (*pilS*) through homologous recombination [5]. *N. gonorrhoeae* could also modulate the host iron innate immune defenses to survive intracellularly under limited bioavailability of iron. This bacterium can survive in association with monocytes and macrophages. Gonococcal stimulation of macrophages influences the pro-inflammatory response, leading to damage during natural infection [6].
