ABSTRACT The work proposed in this study seeks to investigate the role of macrophages colonization by Neisseria gonorrhoeae (Ng) during infection and the impact on gonorrhea development. Because Ng is a highly human- adapted pathogen, it has developed numerous mechanisms to avoid and actively suppress innate and adaptive immune responses. We uncovered that Ng colonizes and establishes topologically distinct colonies in macrophages. During colonization, Ng manipulates the actin cytoskeleton to invade and create an intracellular niche supportive of bacterial replication. This new model of Ng persistence in macrophages is significant for gonorrhea symptomatology and outcome since the relevant cellular reservoir of bacteria during in vivo infections has yet to be identified. Here we will uncover (1) the host receptors required for macrophages colonization by Ng; (2) bacterial adhesins involved in macrophages colonization; and (3) the role of macrophages colonization by Ng in the context of mucosal immunity in gonorrhea human samples.