Neutrophil-generated oxidative stress and protein damage in Staphylococcus aureus

Abstract

Staphylococcus aureus is a ubiquitous, versatile and dangerous pathogen. It colonizes over 30% of the human population, and is one of the leading causes of death by an infectious agent. During S. aureus colonization and invasion, leukocytes are recruited to the site of infection. To combat S. aureus, leukocytes generate an arsenal of reactive species including superoxide, hydrogen peroxide, nitric oxide and hypohalous acids that modify and inactivate cellular macromolecules, resulting in growth defects or death. When S. aureus colonization cannot be cleared by the immune system, antibiotic treatment is necessary and can be effective. Yet, this organism quickly gains resistance to each new antibiotic it encounters. Therefore, it is in the interest of human health to acquire a deeper understanding of how S. aureus evades killing by the immune system. Advances in this field will have implications for the design of future S. aureus treatments that complement and assist the host immune response. In that regard, this review focuses on how S. aureus avoids host-generated oxidative stress, and discusses the mechanisms used by S. aureus to survive oxidative damage including antioxidants, direct repair of damaged proteins, sensing oxidant stress and transcriptional changes. This review will elucidate areas for studies to identify and validate future antimicrobial targets.

Keywords: Staphylococcus aureus; antioxidant defenses; host–pathogen interface; neutrophils; oxidative stress; protein oxidation.

Figure 1.

Neutrophils inflict cellular damage on S. aureus by (A) phagocytosis and exposure to oxidants generated by NADPH oxidase, MPO and nitric oxide synthase or by (B) releasing NETs that contain high amounts of chromatin, calprotectin and MPO. (C) The oxidative burst of neutrophils generates oxidants enzymatically and non-enzymatically that react with and damage cellular macromolecules including lipids, proteins and DNA.

Figure 2.

The oxidants HOCl and H₂O₂ readily react with amino acids to generate a plethora of oxidation products. (A) Cysteine reacts with both HOCl and H₂O₂ to generate sulfenic acid, which can either form a disulfide with an adjacent thiol or be further oxidized to sulfinic and sulfonic acids. (B) Both HOCl and H₂O₂ oxidize the sulfur of methionine to methionine sulfoxide. Amino acids that contain nitrogen in their side chain, (C) histidine and (D) lysine, react with HOCl to generate chloramines. Lysine chloramine can be hydrolyzed to allysine, which can form a Schiff base with an adjacent lysine to give both inter and intramolecular crosslinks. (E) HOCl reacts with tyrosine to form chlorotyrosine. This process is also facilitated by the transfer of a chlorine atom from lysine chloramine to an adjacent tyrosine. (F) Finally, chloramines can be formed on the alpha amine of free amino acids by the reaction with HOCl. These chloramines degrade to various electrophiles including glyoxal, acrolein and p-hydroxyphenylacetaldehyde that can react with and damage cellular macromolecules.

Figure 3.

Staphylococcus aureus synthesizes small molecule antioxidants including (A) bacillithiol, (B) coenzyme A and (C) staphyloxanthin to protect itself from host-generated oxidants.

Figure 4.

Staphylococcus aureus uses multiple mechanisms to survive the host oxidative burst including antioxidant proteins and small molecules to neutralize oxidants, enzymes that repair protein damage and oxidant sensing transcriptional regulators.