Gonococcal infections remain a challenging public health issue due, in part, to a lack of a vaccine. A major obstacle in vaccine development and for understanding gonococcal infections in women is the lack of tractable models mimicking in vivo infection in the female reproductive tract. We used human tissue-explants and isogenic gonococci (GC) to examine by quantitative imaging analysis the impact of the heterogeneity of cervical and bacterial surfaces on infection. We found that GC preferentially colonize the ectocervix and squamocolumnar junction (transformation-zone, TZ) but only penetrate into TZ and endocervical epithelia. Colonization of any region required the expression of pili. GC expressing Opacity-associated proteins (Opas) that bind the host carcinoembryonic antigen-related cell adhesion molecule (CEACAMs) (Opa_CEA) increase ecto/endocervical colonization and reduce endocervical penetration. GC expressing Opas that bind heparan sulfate proteoglycans (HSPGs) (Opa_HSPG) did not promote colonization or tissuer penetrationin any region of the cervix. Opa_CEA inhibited GC-induced disruption of epithelial-epithelial adhesions and epithelial exfoliation, enhancing GC colonization and reducing penetration, through engaging CEACAMs.We propose the following model to explain GC pathogenesis of the female reproductive tract (FRT). GC establish colonization through pili-medieated adhesion. Opa_{CEA e}xpression promotes colonization, leading to asymptomatic local infections. Low expression of Opa_CEA allows GC to effectively penetrate into the endocervical epithelium, causing symptomatic infection. Because GC with low levels of Opa_CEA expression are rare, as most 11 Opa proteins are Opa_CEA, this model provides an explanation as to why most infections of the FRT are asymptomatic and why invasive disease is rare.

Disclosure No significant relationships.