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neutrophil chemotactic factors, including leukotriene B4 (LTB4), KC, and macrophage inflammatory protein (MIP) 2 (unpublished observations) [28, 29].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.)