A bacterial siren song: intimate interactions between Neisseria and neutrophils

Abstract

Neisseria gonorrhoeae and Neisseria meningitidis are Gram-negative bacterial pathogens that are exquisitely adapted for growth at human mucosal surfaces and for efficient transmission between hosts. One factor that is essential to neisserial pathogenesis is the interaction between the bacteria and neutrophils, which are recruited in high numbers during infection. Although this vigorous host response could simply reflect effective immune recognition of the bacteria, there is mounting evidence that in fact these obligate human pathogens manipulate the innate immune response to promote infectious processes. This Review summarizes the mechanisms used by pathogenic neisseriae to resist and modulate the antimicrobial activities of neutrophils. It also details some of the major outstanding questions about the Neisseria-neutrophil relationship and proposes potential benefits of this relationship for the pathogen.

Figure 1. Neutrophil recruitment to sites of infection by the pathogenic neisseriae

Although pathogenic neisseriae colonize diverse mucosal surfaces in the human body, we have only a limited understanding of how differences in these diverse environments create challenges and opportunities for the bacteria ^, . Pathogenic neisseriae use type IV pili, opacity-associated (Opa) proteins and other adhesins to colonize and occasionally invade the mucosal epithelium. Bacterial products such as lipo-oligosaccharide (LOS), peptidoglycan and lipoproteins, which are released either as free compounds or in outer-membrane vesicles (small red circles), stimulate NOD-like receptor (NLR) and Toll-like receptor (TLR) family pattern recognition receptors (green) on epithelial cells and immune cells such as dendritic cells (DCs), macrophages (Mϕ) and T cells (T¢). As a result, gradients of pro-inflammatory cytokines, including interleukin-6 (IL-6), IL-8, IL-1β, interferon-γ (IFNγ) and IL-17, are established. The cytokines recruit neutrophils (yellow) and induce their migration across the epithelium, where they bind and phagocytose the bacteria.

Figure 2. Interactions of pathogenic neisseriae with neutrophils

A. Avoidance of phagocytosis. Capsular polysaccharides (bacterium with black hatched or grey surface) prevent deposition of complement on Neisseria meningitidis and subsequent phagocytosis by neutrophils. Continual changes in surface antigens (bacteria with different color surfaces) allow neisseriae to avoid triggering the generation of effective opsonic antibodies that would facilitate phagocytosis. B. Induction of phagocytosis. Neisseriae can be phagocytosed by host cells using six different routes, which can be receptor dependent or receptor independent: immunoglobulin G (IgG)-opsonized bacteria bind the Fcγ receptor (FcR); proteolytically inactive C3b (iC3b)-opsonized bacteria bind complement receptor 3 (CR3); pili and porin proteins cooperatively bind CR3; neisserial opacity-associated (Opa) proteins bind CEACAMs; lipo-oligosaccharide (LOS) binds unknown receptors on neutrophils; and receptor-independent macropinocytosis can also occur. C. Protection against neutrophil-mediated antibacterial activities. Neutrophils produce reactive oxygen species (ROS) through the phagocyte NADPH oxidase and myeloperoxidase (MPO). Neisserial proteins such as catalase (KatA), superoxide dismutase (Sod) proteins, the Mnii transport system (MntABC) and l-glutamate transporter (GltT) detoxify or quench ROS. The bacteria also repair proteins damaged by ROS through methionine sulphoxide reductase (MsrAB), and repair DNA damaged by ROS through recombinational (RecA), nucleotide excision (the Uvr proteins) and base excision (MutY) repair of DNA. The pathogenic neisseriae also suppress neutrophil-mediated production of ROS through porins and other mechanisms that are dependent on live bacteria. D. Bacterial defences against non-oxidative factors from neutrophils. Antimicrobial factors that are independent of ROS include antimicrobial peptides (AMPs), proteases, lysozyme and acid. The multiple transferable resistance system (MtrCDE) and fatty acid resistance system (FarAB) in pathogenic neisseriae remove some of these products from the bacterial cytosol. Furthermore, bacterial lipopolysaccharide transporter periplasmic protein A (LptA) and peptidoglycan O-acyltransferase (PacA) modify LOS and peptidoglycan (PG), respectively, to protect the bacteria from these factors. The bacterial proteins NGO1686, RecN, NMB0741 and NMB1828 also protect the bacteria against non-oxidative factors, but their protective mechanisms are unknown. Specific locations of molecules associated with the bacterial envelope (PG, LptA, LOS, NGO1686, MtrCDE, FarAB and MisS) are not shown. HOCl, hypochlorous acid.

Figure 2. Interactions of pathogenic neisseriae with neutrophils

A. Avoidance of phagocytosis. Capsular polysaccharides (bacterium with black hatched or grey surface) prevent deposition of complement on Neisseria meningitidis and subsequent phagocytosis by neutrophils. Continual changes in surface antigens (bacteria with different color surfaces) allow neisseriae to avoid triggering the generation of effective opsonic antibodies that would facilitate phagocytosis. B. Induction of phagocytosis. Neisseriae can be phagocytosed by host cells using six different routes, which can be receptor dependent or receptor independent: immunoglobulin G (IgG)-opsonized bacteria bind the Fcγ receptor (FcR); proteolytically inactive C3b (iC3b)-opsonized bacteria bind complement receptor 3 (CR3); pili and porin proteins cooperatively bind CR3; neisserial opacity-associated (Opa) proteins bind CEACAMs; lipo-oligosaccharide (LOS) binds unknown receptors on neutrophils; and receptor-independent macropinocytosis can also occur. C. Protection against neutrophil-mediated antibacterial activities. Neutrophils produce reactive oxygen species (ROS) through the phagocyte NADPH oxidase and myeloperoxidase (MPO). Neisserial proteins such as catalase (KatA), superoxide dismutase (Sod) proteins, the Mnii transport system (MntABC) and l-glutamate transporter (GltT) detoxify or quench ROS. The bacteria also repair proteins damaged by ROS through methionine sulphoxide reductase (MsrAB), and repair DNA damaged by ROS through recombinational (RecA), nucleotide excision (the Uvr proteins) and base excision (MutY) repair of DNA. The pathogenic neisseriae also suppress neutrophil-mediated production of ROS through porins and other mechanisms that are dependent on live bacteria. D. Bacterial defences against non-oxidative factors from neutrophils. Antimicrobial factors that are independent of ROS include antimicrobial peptides (AMPs), proteases, lysozyme and acid. The multiple transferable resistance system (MtrCDE) and fatty acid resistance system (FarAB) in pathogenic neisseriae remove some of these products from the bacterial cytosol. Furthermore, bacterial lipopolysaccharide transporter periplasmic protein A (LptA) and peptidoglycan O-acyltransferase (PacA) modify LOS and peptidoglycan (PG), respectively, to protect the bacteria from these factors. The bacterial proteins NGO1686, RecN, NMB0741 and NMB1828 also protect the bacteria against non-oxidative factors, but their protective mechanisms are unknown. Specific locations of molecules associated with the bacterial envelope (PG, LptA, LOS, NGO1686, MtrCDE, FarAB and MisS) are not shown. HOCl, hypochlorous acid.

Figure 3. Model for the role of neutrophils in the dissemination and spread of pathogenic neisseriae

Perturbations in the epithelium during neutrophil infiltration enhance the influx of serum and associated nutrients for extracellular neisseriae. Neisseriae that have been phagocytosed by neutrophils may be able to access nutrients from inside the phagosome. Intracellular neisseriae avoid surveillance by humoral immunity. Attachment or phagocytosis by motile neutrophils promotes bacterial movement to deeper or ascendant tissues and transmission to new hosts.