Immune responses to the gonococcus after natural infection ordinarily result in little immunity to reinfection, due to antigenic variation of the gonococcus, and redirection or suppression of immune responses. Brinton and colleagues demonstrated that parenteral immunization of male human volunteers with a purified pilus vaccine gave partial protection against infection by the homologous strain. However, the vaccine failed in a clinical trial. Recent vaccine development efforts have focused on the female mouse model of genital gonococcal infection. Here we discuss the state of the field, including our unpublished data regarding efficacy in the mouse model of either viral replicon particle (VRP) vaccines, or outer membrane vesicle (OMV) vaccines. The OMV vaccines failed, despite excellent serum and mucosal antibody responses. Protection after a regimen consisting of a PorB-VRP prime plus recombinant PorB boost was correlated with apparent Th1, but not with antibody, responses. Protection probably was due to powerful adjuvant effects of the VRP vector. New tools including novel transgenic mice expressing human genes required for gonococcal infection should enable future research. Surrogates for immunity are needed. Increasing antimicrobial resistance trends among gonococci makes development of a vaccine more urgent.
Eighty percent of Neisseria gonorrhoeae strains and some Neisseria meningitidis strains encode a 57-kb gonococcal genetic island (GGI). The GGI was horizontally acquired and is inserted in the chromosome at the replication terminus. The GGI is flanked by direct repeats, and site-specific recombination at these sites results in excision of the GGI and may be responsible for its original acquisition. Although the role of the GGI in N. meningitidis is unclear, the GGI in N. gonorrhoeae encodes a type IV secretion system (T4SS). T4SS are versatile multi-protein complexes and include both conjugation systems as well as effector systems that translocate either proteins or DNA–protein complexes. In N. gonorrhoeae, the T4SS secretes single-stranded chromosomal DNA into the extracellular milieu in a contact-independent manner. Importantly, the DNA secreted through the T4SS is effective in natural transformation and therefore contributes to the spread of genetic information through Neisseria populations. Mutagenesis experiments have identified genes for DNA secretion including those encoding putative structural components of the apparatus, peptidoglycanases which may act in assembly, and relaxosome components for processing the DNA and delivering it to the apparatus. The T4SS may also play a role in infection by N. gonorrhoeae. During intracellular infection, N. gonorrhoeae requires the Ton complex for iron acquisition and survival. However, N. gonorrhoeae strains that do not express the Ton complex can survive intracellularly if they express structural components of the T4SS. These data provide evidence that the T4SS is expressed during intracellular infection and suggest that the T4SS may provide an advantage for intracellular survival. Here we review our current understanding of how the GGI and type IV secretion affect natural transformation and pathogenesis in N. gonorrhoeae and N. meningitidis.
It is well-known that gonorrhea can be acquired repeatedly with no apparent development of protective immunity arising from previous episodes of infection. Symptomatic infection is characterized by a purulent exudate, but the host response mechanisms are poorly understood. While the remarkable antigenic variability displayed by Neisseria gonorrhoeae and its capacity to inhibit complement activation allow it to evade destruction by the host’s immune defenses, we propose that it also has the capacity to avoid inducing specific immune responses. In a mouse model of vaginal gonococcal infection, N. gonorrhoeae elicits Th17-driven inflammatory–immune responses, which recruit innate defense mechanisms including an influx of neutrophils. Concomitantly, N. gonorrhoeae suppresses Th1- and Th2-dependent adaptive immunity, including specific antibody responses, through a mechanism involving TGF-β and regulatory T cells. Blockade of TGF-β alleviates the suppression of specific anti-gonococcal responses and allows Th1 and Th2 responses to emerge with the generation of immune memory and protective immunity. Genital tract tissues are naturally rich in TGF-β, which fosters an immunosuppressive environment that is important in reproduction. In exploiting this niche, N. gonorrhoeae exemplifies a well-adapted pathogen that proactively elicits from its host innate responses that it can survive and concomitantly suppresses adaptive immunity. Comprehension of these mechanisms of gonococcal pathogenesis should allow the development of novel approaches to therapy and facilitate the development of an effective vaccine.