Neutrophils in innate host defense against Staphylococcus aureus infections

Abstract

Staphylococcus aureus has been an important human pathogen throughout history and is currently a leading cause of bacterial infections worldwide. S. aureus has the unique ability to cause a continuum of diseases, ranging from minor skin infections to fatal necrotizing pneumonia. Moreover, the emergence of highly virulent, drug-resistant strains such as methicillin-resistant S. aureus in both healthcare and community settings is a major therapeutic concern. Neutrophils are the most prominent cellular component of the innate immune system and provide an essential primary defense against bacterial pathogens such as S. aureus. Neutrophils are rapidly recruited to sites of infection where they bind and ingest invading S. aureus, and this process triggers potent oxidative and non-oxidative antimicrobial killing mechanisms that serve to limit pathogen survival and dissemination. S. aureus has evolved numerous mechanisms to evade host defense strategies employed by neutrophils, including the ability to modulate normal neutrophil turnover, a process critical to the resolution of acute inflammation. Here we provide an overview of the role of neutrophils in host defense against bacterial pathogens and discuss strategies employed by S. aureus to circumvent neutrophil function.

Fig. 1

Neutrophil emigration from vascular space to site of infection followed by phagocytosis and microbial killing. Marginating neutrophils survey post-capillary venules for signs of inflammation or invading microorganisms, undergoing transient tethering interactions with endothelial cells that facilitate neutrophil rolling along the endothelial wall and allow neutrophils to search for host- and/or microbe-derived chemotactic signals. Chemotactic molecules diffusing from the site of infection and into the bloodstream bind specific receptors on the neutrophil surface, arresting the rolling process and inducing firm adherence to the endothelial wall. Firm adherence subsequently leads to neutrophil transmigration through the endothelial wall into the tissue, a process known as extravasation. Once in the tissue, primed neutrophils chemotactically migrate to the site of infection where they recognize and phagocytose invading microorganisms. Within the phagosome of the activated neutrophil, microbes are destroyed by NADPH oxidase-derived reactive oxygen species and antimicrobial proteins released upon granule fusion with the phagosome (degranulation). See text for details. CR complement receptor, FcR Fc receptor, MPO myeloperoxidase

Fig. 2

S. aureus immune evasion mechanisms and possible outcomes of bacteria–neutrophil interaction. A Immune evasion by S. aureus includes strategies that serve to prevent recognition, inhibit chemotaxis, moderate ROS, protect against AMPs, and directly damage immune cells. B Phagocytic uptake of bacteria triggers production of ROS and degranulation, working collectively to kill ingested bacteria, after which neutrophils undergo apoptosis to be removed by macrophages and promote healthy resolution of infection. Alternatively, bacterial pathogens can alter normal neutrophil turnover, promoting either a delay in neutrophil apoptosis or an accelerated neutrophil lysis. Alteration of normal neutrophil turnover facilitates pathogen survival and promotion of disease. APS antimicrobial peptide-sensing system, Aur aureolysin, CHIPS chemotaxis inhibitory protein of S. aureus, CP capsular polysaccharide, Hla α-toxin, HlgABC γ-hemolysin, LukGH LukF-G and LukS-H, MprF multiple peptide resistance factor, PIA polysaccharide intercellular adhesion, PSMs phenol-soluble modulins, PVL Panton–Valentine leukocidin, Sbi second binding protein of immunoglobulin, SCIN staphylococcal inhibitor of complement, SOD superoxide dismutase, TSST toxic shock syndrome toxin, VraFG vancomycin-resistant-associated gene, ABC transporter