Epic Immune Battles of History: Neutrophils vs. Staphylococcus aureus

Abstract

Neutrophils are the most abundant leukocytes in human blood and the first line of defense after bacteria have breached the epithelial barriers. After migration to a site of infection, neutrophils engage and expose invading microorganisms to antimicrobial peptides and proteins, as well as reactive oxygen species, as part of their bactericidal arsenal. Ideally, neutrophils ingest bacteria to prevent damage to surrounding cells and tissues, kill invading microorganisms with antimicrobial mechanisms, undergo programmed cell death to minimize inflammation, and are cleared away by macrophages. Staphylococcus aureus (S. aureus) is a prevalent Gram-positive bacterium that is a common commensal and causes a wide range of diseases from skin infections to endocarditis. Since its discovery, S. aureus has been a formidable neutrophil foe that has challenged the efficacy of this professional assassin. Indeed, proper clearance of S. aureus by neutrophils is essential to positive infection outcome, and S. aureus has developed mechanisms to evade neutrophil killing. Herein, we will review mechanisms used by S. aureus to modulate and evade neutrophil bactericidal mechanisms including priming, activation, chemotaxis, production of reactive oxygen species, and resolution of infection. We will also highlight how S. aureus uses sensory/regulatory systems to tailor production of virulence factors specifically to the triggering signal, e.g., neutrophils and defensins. To conclude, we will provide an overview of therapeutic approaches that may potentially enhance neutrophil antimicrobial functions.

Keywords: Staphylococcus aureus; chemotaxis; host defense; host-pathogen interactions; immune evasion; innate immunity; phagocytosis.

Figure 1

S. aureus has an arsenal of virulence factors to inhibit neutrophil activation, chemotaxis, and phagocytosis. Multiple virulence factors produced by S. aureus target key host effector proteins, for example, Efb, Sbi, and SCIN target the complement protein C3 convertase to prevent formation of C3a and C3b. Further studies are needed to determine if the production of these virulence factors are truly redundant or if they have multiple host targets as is the case with Sbi, which also targets immunoglobulins. Bacterial components indicated in red. PLG, plasminogen; SAK, staphylokinase; SspP, staphopain A.

Figure 2

S. aureus produces virulence factors that target different neutrophil bactericidal mechanisms following phagocytosis. Cationic antimicrobial peptides are ineffective toward S. aureus due to the presence of positive charges on the bacterial surface transferred by MprF and DltB. S. aureus secretes virulence factors that degrade antimicrobial proteins and enzymes released into the neutrophil phagosome. In addition, neutrophil reactive oxygen species production is decreased by S. aureus virulence factors that degrade intermediate reactive oxygen species like superoxide and hydrogen peroxide to reduce the formation of the highly bactericidal chemical agent hypochlorous acid. Bacterial components indicated in red. Aur, aureolysin; PRTN3, proteinase 3; CTSG, cathepsin G; SAK, staphylokinase.

Figure 3

The S. aureus SaeR/S two-component system senses neutrophils and neutrophil components to activate an anti-host immune response. Activation of the SaeS histidine kinase results in autophosphorylation which is subsequently transferred to the SaeR response regulator. A promoter binding region recognized by phosphorylated SaeR (SaeR binding sequence) initiates gene transcription of SaeR/S-regulated virulence factors that target neutrophil antimicrobial mechanisms, cell fate and cellular signaling. The immediate genes transcribed by SaeR/S are dependent on the stimulus, i.e., the SaeR/S transcriptional profile is dynamic and specific to the stimulus. Since bacterial sensory-regulatory systems activate multiple virulence factors, therapeutic approaches to inhibit bacterial sensing, and activation is an active area of research. CP, calprotectin.