For free-living bacteria, survival depends upon sequestering nutrients from the environment and thwarting hostile conditions, including temperature shifts, pH differences, oxygen availability, and nutrient scarcity. By contrast, the pathogenic Neisseria species are exquisitely adapted to the obligate human host and as such experience fewer environmental insults but must compete with human defenses to acquire nutrients and to survive. While temperature is fixed in the human host, pH can range, depending on the niche in the body. Oxygen availability also varies by niche, forcing the pathogenic Neisseria species to adapt their energy generation metabolism to the availability of this electron acceptor.
With respect to evasion of host defenses, the pathogenic Neisseria species are facile foes. They recruit neutrophils to the infected site, whose onslaught they can effectively survive. They are paradigm examples of use of high-frequency phase and antigenic variation to thwart host immunity and detection. They have developed sophisticated efflux systems that not only enable avoidance of toxic antimicrobial peptides but also cross-resistance to antibacterial drugs, contributing to the AMR crisis, at least in N. gonorrhoeae. The pathogenic Neisseria species are also masters at molecular mimicry and hijacking nutrients from the human host. They decorate their lipooligosaccharide with sialic acid, sequestered from the host. They also decorate their surface with human factor H to circumvent complement-mediated killing.
The pathogenic Neisseria species are also perfectly equipped to pirate metals from human proteins whose function is to sequester metals away from invading pathogens, a process known as nutritional immunity. Outer membrane transporters have evolved the capacity to specifically recognize human metal-binding proteins and subsequently extract the metal and transport it into the cell for the metabolic needs of the pathogen. Most of the TonB-dependent transporters produced by the Neisseriae are known or suspected to transport iron after hijacking it from host metal depots. The transferrin-iron acquisition system is comprised of two outer membrane proteins: TbpA, a TonB-dependent transporter, and TbpB, a cognate surface lipoprotein. Two transporters are zinc repressed and have been shown to interact with human S100 proteins whose normal function is to sequester zinc and/or manganese away from bacterial invaders. TdfH binds to and extracts zinc from human calprotectin (S100A8/A9); TdfJ binds to and extracts zinc from human psoriasin (S100A7). Because these transporters are well conserved among the pathogenic Neisseriae, expressed in vivo and presented on the cell surface, we have pursued them as potential drug and/or vaccine targets.