Gonococcal Pelvic Inflammatory Disease: Placing Mechanistic Insights Into the Context of Clinical and Epidemiological Observations

Abstract

While infection by Neisseria gonorrhoeae is often asymptomatic in women, undetected infections can ascend into the upper genital tract to elicit an inflammatory response that manifests as pelvic inflammatory disease, with the outcomes depending on the intensity and duration of inflammation and whether it is localized to the endometrial, fallopian tube, ovarian, and/or other tissues. This review examines the contribution of N. gonorrhoeae versus other potential causes of pelvic inflammatory disease by considering new insights gained through molecular, immunological, and microbiome-based analyses, and the current epidemiological burden of infection, with an aim to highlighting key areas for future study.

Keywords: Neisseria gonorrhoeae; cervicitis; endometrial infection; endometritis; gonorrhea; neutrophil; oophoritis; pelvic inflammatory disease (PID); salpingitis.

Figure 1.

Ascending infection and mechanisms of inflammatory damage leading to pelvic inflammatory disease after endocervical infection by Neisseria gonorrhoeae. Endocervical infection by N. gonorrhoeae may or may not manifest as cervicitis. After infection is established, host physiological and physical factors, including hormone-controlled loss of the mucus plug, uterine contractions, sexual intercourse, and retrograde menstruation, can lead to ascent of bacteria into the endometrium [2, 26]. N. gonorrhoeae–specific virulence factors may also be involved, although their actual role during ascent have yet to be demonstrated in an appropriate model. Infection and subsequent inflammation of the endometrium (endometritis), fallopian tubes (FTs) (salpingitis), or ovaries (oophoritis) can occur. Inset (bottom), Endometrial damage occurs when N. gonorrhoeae interacts with the epithelial lining, leading to bacterial transcytosis and epithelial responses including release of proinflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor (TNF); neutrophil chemokine interleukin 8 (IL-8), and the eicosanoid hepoxilin A3 (HXA3) [27, 28]. On recruitment to the site of infection, neutrophils enter a positive feedback loop by producing additional neutrophil chemotactic factors, including leukotriene B4 (LTB4), KC, and macrophage inflammatory protein (MIP) 2 (unpublished observations) [28, 29]. This results in a secondary wave of neutrophil migration into the uterine lumen, resulting in tissue damage [30]. Abbreviations: KC, keratinocyte-derived chemokine; MCP, monocyte chemoattractant protein. Inset (top), N. gonorrhoeae binding to nonciliated secretory cells and release of peptidoglycan and lipo-oligosaccharide fragments stimulate a potent inflammatory response from the epithelia of the FTs [31, 32]. The TNF produced leads to death and sloughing of ciliated cells [33], which can lead to irreversible scarring, deciliation and impaired fertility. (Illustration created using BioRender.com.)