Consistent with these observations, humans with gonorrhea have elevated serum IL-17 and IL-23 [38], and human monocyte-derived DCs secrete IL-23 and IL-10 upon stimulation with Gc in vitro [27] and [37]. Other mechanisms of immunosuppression include induction of apoptosis in antigen presenting cells (APC) through the NLRP3 inflammasome

pathway [33] and inhibition of DC-induced proliferation of T cells [32]. Gc Opa proteins that bind CEACAM1 3-MA datasheet were reported to down-regulate proliferation of activated CD4+ T cells and also B cells [39] and [40], although these findings have been questioned by others [41]. Gc also induces a polyconal IgM+ B cell response with poor specificity to the bacteria [42]. Mechanisms to evade specific antibodies include the expression of blocking antigens, production of IgA1 protease, molecular mimicry, retreat into epithelial cells, blebbing

of membranes to create a decoy, and changes in the antigenicity of surface molecules due to an extensive capacity for uptake and incorporation of DNA from other neisseriae, or in the case of Gc pili, recombination between the expressed pilin gene and silent loci. Phase variable expression of LOS biosynthesis genes and genes that encode surface molecules, buy PF-02341066 such as opa genes, also contributes to evasion of specific antibodies [43]. Progress on gonorrhea vaccines lags behind that of several other STIs for many reasons. First, repeat infections are common and correlates of protection

in humans have not been identified. Second, early vaccine efforts were frustrated by the highly antigenically variable surface of Gc and the lack of a small laboratory animal model for identifying protective responses and for systematic testing of antigens and immunization routes. Finally, there has been a lack of a concerted effort in this area. Only two antigens, killed whole cells and purified pilin, have been tested in clinical trials, which occurred however over 30 years ago and were unsuccessful [35]. These failures discouraged research, funding and commercial interest in gonorrhea vaccines. Advances in microbial pathogenesis, immunology, molecular epidemiology, combined with new infection models and the powerful new tools of genomics, proteomics and glycomics justify a renewed and intensified research focus on gonorrhea vaccine development. Knowledge of the specific immune mechanisms that protect against Gc infection is severely lacking. An estimated 20–35% of men become infected following a single exposure to an infected woman; the risk for women exposed to an infected man is estimated at 60–90% [44]. Comprehensive studies are needed to identify factors that might explain differential susceptibility to infection (Fig. 2). The lack of evidence that natural infection induces immunity to reinfection also seriously limits our ability to prospectively define the types of immune responses that an effective vaccine must induce.