PL15 Development of immunotherapeutic approaches against gonorrhea

Multidrug-resistant (MDR) Neisseria gonorrhoeae (Ng) is a global health problem. Targeting virulence factors can circumvent the ability of gonococci to resist conventional antimicrobials. Resistance to such agents, if it were to occur, would result loss of bacterial fitness; attenuated ‘escape mutants’ would be susceptible to host immune defenses. A unique gonococcal immune evasion strategy involves capping of lipooligosaccharide (LOS) with sialic acid by gonococcal sialyltransferase (Lst), utilizing host-derived CMP-sialic acid (CMP-Neu5Ac in humans). LOS Neu5Ac renders gonococci resistant to complement (by binding the complement inhibitor, factor H (FH)) and cationic antimicrobial peptides (CAMPs). LOS sialylation is important for gonococcal virulence in humans and in experimental mouse models. A chimeric protein that fuses the gonococcal binding domains of human FH (lacks complement-inhibiting activity) with human IgG1 Fc (FH/Fc) enhances complement activation on the bacterium and mediates complement-dependent killing of a wide array of gonococcal isolates in vitro. Intravaginal administration of FH/Fc attenuates bacterial burden in the mouse vaginal colonization model. Gonococcal Lst has broad substrate specificity and can utilize CMP salts of sialic acid analogs, such as legionaminic (CMP-Leg) or ketodeoxynonulosonic (CMP-Kdn). Incorporation of Leg or Kdn into LOS substitutes for the Neu5Ac sialic acid cap and restores bacterial susceptibility to complement and CAMPs. Intravaginal CMP-Leg or CMP-Kdn administration mediates CAMP-dependent clearance of MDR Ng in mice. An LOS epitope that is recognized by monoclonal antibody (mAb) 2C7 is expressed by ~95% of Ng isolates in vivo, can also be sialylated and is critical for virulence. The 2C7 epitope has also been fashioned as a vaccine candidate and is pending a human trial. mAb 2C7 delivered either intravaginally or systemically, or as a DNA-encoded mAb (passive vaccination) clears gonococci from mouse vaginas in a complement-dependent manner. In conclusion, targeting LOS-related virulence mechanisms is an innovate approach to combat MDR Ng.