Induction of human macrophage cell death by Neisseria gonorrhoeae
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The obligate human pathogen Neisseria gonorrhoeae is responsible for the sexually transmitted disease, gonorrhea. This pathogen colonizes mucosal surfaces, and is most commonly found in the urogenital tract. The genital mucosa is comprised of various cells from epithelial to immune cells including the macrophage. Macrophages are abundant immune cells within the genital submucosa. Though the cytokine response of macrophages following N. gonorrhoeae infection is well characterized, survival of these cells following infection has not been well described. In this study, we examined the ability of N. gonorrhoeae strain FA1090B to modulate cell death in differentiated THP-1 cells (dTHP-1) and human monocyte-derived macrophages (MDMs) harvested from peripheral blood. N. gonorrhoeae was demonstrated to induce cell death in both macrophage types in a dose-dependent manner as measured at 6 hours post-stimulation. Cell death did not proceed via classical apoptosis but was associated with activation of immune caspases-1 and -4, required for the canonical and non-canonical pyroptotic pathways, respectively. MDM cell death was found to be dependent on immune caspase activity and associated with intracellular bacteria. Furthermore, caspase-4-associated MDM cell death was also observed with cytosolic N. gonorrhoeae-purified lipooligosaccharide (LOS). We did not however observe differences in the induction of pyroptosis by a penta-acylated non-immune stimulating LOS mutant strain, 1291ΔmsbB, as compared to the isogenic wild type strain 1291, or strain FA1090B. Activation of pyroptosis correlated with increased production of the pro-inflammatory mediators IL-1β, IL-6 and TNF-α. Pre-treatment of dTHP-1 cells with conditioned media from bacterial stimulated samples had little effect on N. gonorrhoeae induced cell death. Collectively, our results demonstrate that N. gonorrhoeae induces pyroptosis in human macrophages due, in part, to LOS. We postulate that N. gonorrhoeae induced pyroptosis of macrophages may partially contribute to lack of immunological memory and continual neutrophil recruitment, a hallmark of N. gonorrhoeae infection.