Subterfuge and sabotage: evasion of host innate defenses by invasive gram-positive bacterial pathogens

Abstract

The development of a severe invasive bacterial infection in an otherwise healthy individual is one of the most striking and fascinating aspects of human medicine. A small cadre of gram-positive pathogens of the genera Streptococcus and Staphylococcus stand out for their unique invasive disease potential and sophisticated ability to counteract the multifaceted components of human innate defense. This review illustrates how these leading human disease agents evade host complement deposition and activation, impede phagocyte recruitment and activation, resist the microbicidal activities of host antimicrobial peptides and reactive oxygen species, escape neutrophil extracellular traps, and promote and accelerate phagocyte cell death through the action of pore-forming cytolysins. Understanding the molecular basis of bacterial innate immune resistance can open new avenues for therapeutic intervention geared to disabling specific virulence factors and resensitizing the pathogen to host innate immune clearance.

Keywords: Staphylococcus aureus; Streptococcus agalactiae; Streptococcus pneumoniae; Streptococcus pyogenes; immune evasion; innate immunity.

Figure 1

Inhibition of complement activation and interference with complement effectors by gram-positive pathogens. Gram-positive pathogens have multiple strategies to defend against complement activation and function, including (1) preventing the formation and activity of the C3 convertase, (2) proteasomal degradation of C3b, (3) blocking C3b deposition on bacterial surfaces, (4) preventing formation and activity of the C5 convertase, (5) proteasomal degradation of C5a, and (6) resistance to lysis by the membrane attack complex (MAC).

Figure 2

Gram-positive pathogens interfere with ROS production and function. Engulfment of bacteria triggers NADPH oxidase (NOX)-dependent generation of superoxide. Bacterial superoxide dismutase (SOD) accelerates the generation of hydrogen peroxide from superoxide. Bacteria subsequently neutralize hydrogen peroxide by using enzymes that (1) convert peroxide to alcohol, (2) convert peroxide to molecular oxygen or (3) possess iron-containing molecules or generate nitric oxide to prevent Fenton chemistry. Depleting hydrogen peroxide prevents formation of highly bactericidal hypochlorite. Gram-positive bacteria additionally have molecules such as pigment, which acts as a molecular shield against superoxide anions. The most bactericidal ROS species are indicated in green.

Figure 3

Gram-positive pathogens physically alter their surface to thwart antimicrobial granule contents. Gram-positive bacteria produce (1) Antimicrobial peptide (AMP) binding molecules or (2) AMP degrading enzymes, which prevent AMP access. The density and altered charge of molecules such as lipoteichoic acid (LTA), wall teichoic acid (WTA) and exopolysaccharide capsule further prevent AMPs from accessing the bacterial membrane (3). Modification of peptidoglycan (PPG) prevents cleavage and degradation by lysozyme (4).

Figure 4

Dual specificity therapeutic agents that target bacterial virulence factors to increase susceptibility to host cell clearance mechanisms and increase the host cell response could provide a multi-faceted approach to treatment. One such example is a squalene synthesis inhibitor, which blocks staphyloxanthin production (1) while simultaneously enhancing the capacity of neutrophils to produce NETs (2).