ABSTRACTNeisseria gonorrhoeaecauses gonorrhea, a sexually transmitted infection characterized by inflammation of the cervix or urethra. However, a significant subset of patients withN. gonorrhoeaeremain asymptomatic, without evidence of localized inflammation. Inflammatory responses toN. gonorrhoeaeare generated by host innate immune recognition ofN. gonorrhoeaeby several innate immune signaling pathways, including lipooligosaccharide (LOS) and other pathogen-derived molecules through activation of innate immune signaling systems, including toll-like receptor 4 (TLR4) and the interleukin-1β (IL-1β) processing complex known as the inflammasome. The lipooligosaccharide ofN. gonorrhoeaehas a hexa-acylated lipid A.N. gonorrhoeaestrains that carry an inactivatedmsbB(also known aslpxL1) gene produce a penta-acylated lipid A and exhibit reduced biofilm formation, survival in epithelial cells, and induction of epithelial cell inflammatory signaling. We now show thatmsbB-deficientN. gonorrhoeaeinduces less inflammatory signaling in human monocytic cell lines and murine macrophages than the parent organism. The penta-acylated LOS exhibits reduced toll-like receptor 4 signaling but does not affectN. gonorrhoeae-mediated activation of the inflammasome. We demonstrate thatN. gonorrhoeaemsbBis dispensable for initiating and maintaining infection in a murine model of gonorrhea. Interestingly, infection withmsbB-deficientN. gonorrhoeaeis associated with less localized inflammation. Combined, these data suggest that TLR4-mediated recognition ofN. gonorrhoeaeLOS plays an important role in the pathogenesis of symptomatic gonorrhea infection and that alterations in lipid A biosynthesis may play a role in determining symptomatic and asymptomatic infections.
Innate immune signaling by Toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors