The Pathobiology of Neisseria gonorrhoeae Lower Female Genital Tract Infection

Abstract

Infection and disease associated with Neisseria gonorrhoeae, the gonococcus, continue to be a global health problem. Asymptomatic and subclinical gonococcal infections occur at a high frequency in females; thus, the true incidence of N. gonorrhoeae infections are presumed to be severely underestimated. Inherent to this asymptomatic/subclinical diseased state is the continued prevalence of this organism within the general population, as well as the medical, economic, and social burden equated with the observed chronic, disease sequelae. As infections of the lower female genital tract (i.e., the uterine cervix) commonly result in subclinical disease, it follows that the pathobiology of cervical gonorrhea would differ from that observed for other sites of infection. In this regard, the potential responses to infection that are generated by the female reproductive tract mucosa are unique in that they are governed, in part, by cyclic fluctuations in steroid hormone levels. The lower female genital tract has the further distinction of being able to functionally discriminate between resident commensal microbiota and transient pathogens. The expression of functionally active complement receptor 3 by the lower, but not the upper, female genital tract mucosa; together with data indicating that gonococcal adherence to and invasion of primary cervical epithelial cells and tissue are predominately aided by this surface-expressed host molecule; provide one explanation for asymptomatic/subclinical gonococcal cervicitis. However, co-evolution of the gonococcus with its sole human host has endowed this organism with variable survival strategies that not only aid these bacteria in successfully evasion of immune detection and function but also enhance cervical colonization and cellular invasion. To this end, we herein summarize current knowledge pertaining to the pathobiology of gonococcal infection of the human cervix.

Keywords: Akt; Neisseria gonorrhoeae; bacterial adherence and invasion; complement receptor 3; integrin signaling; nitric oxide; phospholipase; uterine cervix.

Figure 1

A working model of cervical infection by gonococci. Based on published, as well as unpublished data, a putative, working model of the dynamic interactions mediating gonococcal disease of cervical epithelia is presented in context of the menstrual cycle. Estrogen (E2), predominant in the follicular phase is depicted by the blue line. Progesterone (Pg) is predominant in the luteal phase following ovulation (occurring around day 14) and is depicted in green. Menses occurs when both E2 and Pg levels are low. The actions of E2 and Pg are mediated by their cognate steroid hormone receptors (SHRs, shown as purple crosses). Upon stimulation, SHRs function as transcription factors mediating the expression of select cellular products (e.g., complement (C′) protein C3) or as signaling mediators (e.g., in the Akt-dependent induction of nitric oxide, NO). Cervical epithelial cells produce and secret all of the proteins comprising the alternative pathway of the C′ system. During the luteal phase and during menses, C3 is release to the extracellular milieu where it is activated to form C3b upon gonococcal infection. C3b binds to the gonococcus surface where it is rapidly cleaved to form inactive, iC3b, a necessary ligand for complement receptor 3 (CR3)-mediated cervical cell invasion. Deposition of C3b upon the gonococcus surface in conjunction with CR3 engagement promote the sustained release of secreted gonococcal products, including a phospholipase D (PLD) that aid colonization, invasion, and survival of gonococci during their residence within the lower female genital tract. As estrogen concentrations begin to rise, CR3 presence on the surface of pex cells is increased. More CR3 available to bind iC3b-opsonized gonococci correlates with the increased association of gonococci with pex cells. Engagement of CR3 triggers the recruitment of SHRs to the cytoplasmic domain of CR3 where they likely participate in the cervical cell signaling pathways triggered with gonococcal infection. The direct interaction of (Ng)PLD with (host) Akt, triggers ruffle formation and the internalization of gonococci within macropinosomes. Levels of CR3 on the surface of both uninfected and infected pex cells decrease with increasing E2. This might indicate that the internalization of gonococci is augmented by E2 in the mid-follicular phase. Gonococcus-containing vacuoles coalesce near the apical surface within pex cells, and CR3 is disengaged. Protein secretion by intracellular gonococci residing within the macropinosome under conditions of low Pg is likely down-regulated as a consequence of rapid C3 depletion. However, as progesterone levels begin to rise, C3 levels also would again increase because of transcription factor activity exerted upon the C3 gene by SHRs. It is then expected that Akt activity would be increasingly maintained as more PLD is released by gonococci in the presence of increased C3(b). The ability of Pg to promote the intracellular survival of gonococci occurs in part by augmenting Akt activity, which triggers nitric oxide (NO) production. NO supports (micro)aerobic respiration by intracellular (and extracellular) gonococci. Late in the luteal phase, Akt activity decreases with progressively decreasing Pg. Decreasing Akt, which also plays a role in cellular trafficking, in conjunction with other host and bacterial constituents, may modulate the release of C3 and gonococci from pex cells to the extracellular cell surface where ever increasing numbers of bacteria colonize the cell surface, eventually leading to the formation of a biofilm.