Epic Immune Battles of History: Neutrophils vs. Staphylococcus aureus

REVIEW published: 30 June 2017 doi: 10.3389/fcimb.2017.00286 Epic Immune Battles of History: Neutrophils vs. Staphylococcus aureus Fermin E. Guerra, Timothy R. Borgogna, Delisha M. Patel, Eli W. Sward and Jovanka M. Voyich * Department of Microbiology and Immunology, Montana State University, Bozeman, MT, United States Edited by: Lee-Ann H. Allen, University of Iowa, United States Reviewed by: Francis Alonzo, Loyola University Chicago, United States Alison Criss, University of Virginia, United States *Correspondence: Jovanka M. Voyich Received: 30 March 2017 Accepted: 12 June 2017 Published: 30 June 2017 Citation: Guerra FE, Borgogna TR, Patel DM, Sward EW and Voyich JM (2017) Epic Immune Battles of History: Neutrophils vs. Staphylococcus aureus. Front. Cell. Infect. Microbiol. 7:286. doi: 10.3389/fcimb.2017.00286 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: host-pathogen interactions, innate immunity, immune evasion, host defense, phagocytosis, chemotaxis, Staphylococcus aureus INTRODUCTION Polymorphonuclear leukocytes (PMNs or neutrophils) are the first line of defense against bacterial pathogens that have breached epithelial barriers. Within minutes of bacterial invasion, neutrophils respond to soluble factors including chemokines and cytokines and are recruited to the site of infection where they ingest microbes. Subsequently, neutrophils expose microorganisms to antimicrobial proteins, peptides, and reactive oxygen species to kill the invading pathogen. This is a delicate process that must eliminate the pathogen while controlling excessive inflammation. Concurrently, neutrophils secrete cytokines and chemokines to continue to recruit neutrophils Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 1 June 2017 | Volume 7 | Article 286 Guerra et al. Neutrophils vs. Staphylococcus aureus where ingestion of bacteria can take place. For detailed reviews of neutrophil chemotaxis, adhesion to the epithelium, and transmigration, please refer to (Kolaczkowska and Kubes, 2013; de Oliveira et al., 2016). Herein, we will focus on virulence factors produced by S. aureus to inhibit specific neutrophil receptors from binding host and bacterial derived ligands, which results in impaired neutrophil priming, activation, chemotaxis, and adhesion to the endothelium. and enhance other host responses to infection. Finally, neutrophil death is essential for proper resolution of infection and must be regulated to minimize bystander damage while continuing to signal if more immune response is needed or if tissue repair should begin. These potent mechanisms are effective at eliminating most fungal and bacterial microorganisms. However, successful pathogens have developed strategies to disrupt various neutrophil functions to cause infection. S. aureus is a highly-adaptable Gram-positive pathogen estimated to colonize 50–60% of the population (Wertheim et al., 2005; Gorwitz et al., 2008). It is also a leading cause of infections ranging from superficial skin abscesses to life-threatening diseases, including septicemia and necrotizing pneumonia (Klevens et al., 2007; Kobayashi et al., 2015). The ability of S. aureus to cause human disease is based in part on its ability to evade the innate immune response, thereby circumventing rapid elimination. Many factors contribute to S. aureus pathogenesis. These include production of numerous toxins, such as the barrel forming two-component toxins capable of directly lysing host immune cells (Menestrina et al., 2003), and tissue destroying enzymes including protease, lipase, and hyaluronidase, as well as many surface proteins and adhesins linked to virulence (Lowy, 1998). In this review, we will focus on evasion strategies used by S. aureus to disrupt neutrophil functions essential for bacterial clearance. First, we will highlight virulence factors produced by S. aureus to alter neutrophil priming, activation, chemotaxis, and adhesion. Then, we will discuss strategies used by S. aureus to subvert neutrophil killing by antimicrobial peptides and proteins and reactive oxygen species. Additionally, we will examine recent literature investigating mechanisms used by S. aureus to modulate neutrophil cell death programs. Finally, we will highlight the reciprocal communication between S. aureus and the neutrophil emphasizing sensing and adaptive responses used by S. aureus to recognize and respond to neutrophil challenge. The review will conclude with an overview of potential therapeutic approaches aimed at disrupting bacterial sensing and signaling to decrease production of virulence factors during neutrophil interaction and discuss putative immunotherapies to boost immune responses to S. aureus while limiting inflammatory damage caused by neutrophils. NEUTROPHIL PRIMING: A POTENTIAL TARGET OF S. AUREUS? Priming refers to the ability of a primary agonist to enhance a neutrophil’s response to a secondary stimulus (Swain et al., 2002). There are many known neutrophil priming agents including: complement components C3a and C5a (Skjeflo et al., 2014), interferon-γ (IFN-γ) (Edwards et al., 1988), interleukin8 (IL-8) (Mitchell et al., 2003), and tumor-necrosis factorα (TNF-α; Rainard et al., 2000). Bacterial derived products such as N-formyl methionyl peptide, formyl-methionyl-leucyl phenylalanine (fMLF), peptidoglycan, and S. aureus cytolytic toxins also demonstrate an ability to prime neutrophil (...truncated)