Neisseria gonorrhoeae Modulates Cell Death in Human Endocervical Epithelial Cells through Export of Exosome-Associated cIAP2

Abstract

Several bacterial pathogens persist and survive in the host by modulating host cell death pathways. We previously demonstrated that Neisseria gonorrhoeae, a Gram-negative pathogen responsible for the sexually transmitted infection gonorrhea, protects against exogenous induction of apoptosis in human cervical epithelial cells. However, induction of cell death by N. gonorrhoeae has also been reported in other cell types. The mechanisms by which N. gonorrhoeae modulates cell death are not clear, although a role for the inhibitor of apoptosis-2 (cIAP2) has been proposed. In this study, we confirmed that N. gonorrhoeae induces production of cIAP2 in human cervical epithelial cells. High levels of intracellular cIAP2 were detected early after N. gonorrhoeae stimulation, which was followed by a marked decrease at 24 h. At this time point, we observed increased levels of extracellular cIAP2 associated with exosomes and an overall increase in production of exosomes. Inhibition of cIAP2 in N. gonorrhoeae-stimulated epithelial cells resulted in increased cell death and interleukin-1␤ (IL-1␤) production. Collectively these results indicate that N. gonorrhoeae stimulation of human endocervical epithelial cells induces the release of cIAP2, an essential regulator of cell death and immune signaling. The induction of programmed cell death is a common host response to bacterial pathogens and typically results in clearance by phagocytic immune cells (1). Release of inflammatory mediators by dying cells further influences immune responses, tightly coupling cell death and inflammation during bacterial infection (2). While repression of cell death pathways favors host cell survival, induction of cell death can be beneficial for pathogens. Accordingly, pathogens often manipulate such cell death pathways to favor their own replication and persistence (3-5). Apoptosis, pyroptosis, and necroptosis are programmed cell death pathways with distinct inflammatory outcomes; apoptosis is noninflammatory, while pyroptosis and necroptosis are highly inflammatory (6). Each of these pathways can be initiated or repressed by different pathogens and in different cell types.Neisseria gonorrhoeae is a Gram-negative diplococcus responsible for the sexually transmitted infection gonorrhea. Infection of the female genital tract by this organism is localized at the cervix, in both endocervical and ectocervical epithelial cells (7). Epithelial cells are the first responders and orchestrators of the early innate immune response during mucosal infection (8, 9). Epithelial cells shape the tissue immune microenvironment by producing cytokines and chemokines (10, 11), releasing cellular factors such as damage-associated molecular patterns (DAMPs) (12, 13) that can further activate immune cells and via production of antimicrobial peptides that control infecting microorganisms (14, 15). Our group and others have reported that N. gonorrhoeae manipulates cell death pathways, either inducing or preventing cell death, in different cell types (16)(17)(18)(19)(20)(21)....

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