Immunity against Staphylococcus aureus cutaneous infections

Abstract

Complications arising from cutaneous and soft tissue infections with Staphylococcus aureus are a major clinical problem owing to the high incidence of these infections and the widespread emergence of antibiotic-resistant bacterial strains. If prophylactic vaccines or immunotherapy for certain patient populations are to be developed as an alternative to antibiotics, it will be essential to better understand the immune mechanisms that provide protection against S. aureus skin infections. Recent discoveries have identified a key role for interleukin-1 (IL-1)- and IL-17-mediated immune responses in promoting neutrophil recruitment to the site of infection in the skin, a process that is required for host defence and bacterial clearance. This Review describes these new insights and discusses their potential impact on immune-based therapies and vaccination strategies.

Figure 1. Anatomy of cutaneous immune responses

a | Normal skin has constitutive innate immune mechanisms, including the epidermal barrier, normal skin microflora, antimicrobial peptides and a low temperature and pH. These mechanisms help to prevent infection by pathogenic microorganisms from the environment. b | During a Staphylococcus aureus cutaneous infection, the epidermal barrier is breached and keratinocytes and resident skin immune cells (such as Langerhans cells and γδ T cells in the epidermis, and dendritic cells, macrophages, fibroblasts, mast cells, B and T cells, plasma cells and natural killer (NK) cells in the dermis) produce pro-inflammatory cytokines, chemokines and adhesion molecules. These molecules promote the recruitment from the bloodstream of neutrophils, which help to control the infection by forming an abscess. Neutrophil abscess formation is a hallmark of S. aureus infections (which are typically characterized as pyogenic infections) and is required for bacterial clearance. Pro-inflammatory cytokines also induce the production of antimicrobial peptides (such as β-defensins and cathelicidins) that have bacteriostatic or bactericidal activity against S. aureus. c | Neutrophils phagocytose opsonized bacteria using Fc and complement receptors. Following this uptake into phagosomes, there are multiple mechanisms that promote bacterial killing. The first is the oxidative burst, which generates reactive oxygen species (such as O₂⁻, H₂O₂ and HOCl) through NADPH oxidase and myeloperoxidase. These species can directly kill bacteria but also produce a charge in the phagocytic membrane to promote enzymatic killing. Second, the phagosome contains antimicrobial peptides (such as cathelicidins, lysozyme, azurocidin and α-defensins), which have direct microbicidal activity. Third, proteinases (such as cathepsin G, neutrophil elastase, gelatinase, neutrophil collagenase and proteinase 3) and acid hydrolases degrade bacterial components. Last, proteins that sequester essential nutrients limit bacterial growth; such proteins include lactoferrin (which sequesters iron and copper), transcobalamin II (which binds vitamin B12) and neutrophil gelatinase-associated lipocalin (NGAL; which binds bacterial siderophores, preventing the extraction of iron). If S. aureus enters the cytoplasm of neutrophils, there is an abundance of calprotectin, which sequesters Mn²⁺ and Zn²⁺ to inhibit bacterial growth. C3b, complement component C3b; CR1, complement receptor type 1.

Figure 2. Major host cell signalling pathways involved in the immune response against S. aureus cutaneous infections

Toll-like receptor 2 (TLR2), which is activated by Staphylococcus aureus lipopeptides and lipoteichoic acid, and interleukin-1 receptor 1 (IL-1R1), which is activated by IL-1α and IL-1β, both signal through the adaptor molecule MYD88 (myeloid differentiation primary response protein 88). MYD88 triggers the activation of IRAK4 (IL-1R-associated kinase 4) and TRAF6 (TNFR-associated factor 6), leading to the activation of NF-κB (nuclear factor-κB), C/EBPβ/δ (CCAAT/enhancer-binding protein-β/δ) and MAPKs (mitogen-activated protein kinases, such as JNK (JUN N-terminal kinase), p38 and ERK1 (extracellular signal-regulated kinase 1) or ERK2). TLR2 also uses TIRAP (TIR domain-containing adaptor protein) to initiate signalling. The IL-17RA–IL-17RC complex, which is expressed mainly on epithelial cells, is activated by IL-17A and IL-17F homodimers or heterodimers and uses ACT1 (NF-κB activator 1) to activate similar pathways to MYD88. STAT3 (signal transducer and activator of transcription 3) is a transcription factor that is activated downstream of various cytokine (IL-6, IL-10, IL-11, IL-19, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27 and IL-35) receptors and growth factor receptors (EGFR, FGFR, IGFR, HER2, HGFR, PDGFR, VEGFR and GCSFR). Each of these signalling pathways leads to the activation of transcription factors that alone or in combination promote the transcription of pro-inflammatory mediators involved in the immune response against S. aureus. ATF1, activating transcription factor 1; CREB, cAMP-responsive element-binding protein; ELK1, ETS-like protein 1; IκB, inhibitor of NF-κB; JAK, Janus kinase; TYK2, tyrosine kinase 2.

Figure 3. Mechanisms of IL-1α and IL-1β production during S. aureus cutaneous infections

a | Epidermal keratinocytes constitutively contain stores of pre-made interleukin-1α (IL-1α) during resting conditions, which is rapidly released in response to nonspecific injury, inflammation or infection. b | In keratinocytes, Staphylococcus aureus induces an IL-1α-mediated autocrine signalling loop through IL-1 receptor 1 (IL-1R1), which leads to the rapid and continuous production of neutrophil-attracting chemokines, such as CXC-chemokine ligand 1 (CXCL1), CXCL2 and CXCL8. c | The production of IL-1β during S. aureus cutaneous infections requires two signals. Signal 1 involves the transcription of pro-IL-1β, which is induced by the activation of pattern recognition receptors (PRRs), such as TLR2 (Toll-like receptor 2) and NOD2 (nucleotide-binding oligomerization domain-containing protein 2). Signal 2 involves NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome activation, which results in caspase 1-mediated cleavage of pro-IL-1β into active IL-1β. NLRP3 inflammasome activation during S. aureus infections has been shown to be triggered by lysozyme-mediated digestion of S. aureus (which releases peptidoglycan, induces the production of reactive oxygen intermediates and promotes phagosome rupture), by the activation of the purinergic receptor P2X7 by ATP (which is released by stressed or damaged cells during an infection) and by pore-forming toxins of S. aureus, such as the α-, β- and γ-haemolysins. IκB, inhibitor of NF-κB; MDP, muramyl dipeptide; NF-κB, nuclear factor-κB.

Figure 4. The IL-1-mediated cutaneous immune response against S. aureus

Interleukin-1α (IL-1α), which is produced and released by keratinocytes, and IL-1β, which is produced by resident and recruited cells (such as macrophages and dendritic cells (DCs)), trigger the activation of nuclear factor-κB (NF-κB) (and of other important pro-inflammatory signalling molecules, such as C/EBPβ/δ (CCAAT/enhancer binding protein-β/δ) and MAPKs (mitogen-activated protein kinases)). These signalling pathways lead to the production of antimicrobial peptides (such as β-defensins 2 and 3, cathelicidins and RNase 7) that have bacteriostatic and bactericidal activity against Staphylococcus aureus. IL-1-mediated responses also result in the production of pro-inflammatory cytokines, chemokines and adhesion molecules that promote the recruitment of neutrophils from the circulation to the site of S. aureus infection in the skin. Recruited neutrophils form an abscess to help control and limit the spread of the infection, and this is ultimately required for bacterial clearance. TLR2, Toll-like receptor 2.

Figure 5. The IL-17-mediated cutaneous immune response against S. aureus

Interleukin-17A (IL-17A) and IL-17F are produced by various cells in the skin, including γδ T cells in the epidermis (in mice) and T helper 17 (T_H17) cells, γδ T cells, natural killer (NK) cells and NKT cells in the dermis. The production of IL-17A and IL-17F depends on the activation of Toll-like receptor 2 (TLR2) and the production of IL-1α, IL-1β, IL-6 and IL-23, which can be produced by other resident and recruited cells in the skin, such as macrophages and dendritic cells. IL-17A and IL-17F activate IL-17 receptors (IL-17RA–IL-17RC) on epidermal keratinocytes, resulting in the production of antimicrobial peptides (such as β-defensins 2 and 3, and cathelicidins) that have bacteriostatic and bactericidal activity against Staphylococcus aureus, as well as in the production of pro-inflammatory cytokines, chemokines and adhesion molecules that promote the recruitment of neutrophils from the circulation to the site of S. aureus infection in the skin. IL-17-mediated signalling also leads to the production of GM-CSF (granulocyte–macrophage colony-stimulating factor) and G-CSF, which promote neutrophil granulopoiesis in the bone marrow and perhaps locally in the skin. Neutrophils form an abscess to help control and limit the spread of the infection in the skin, and this is ultimately required for bacterial clearance. IL-17-mediated signalling also leads to the production of CC-chemokine ligand 20 (CCL20), which triggers a positive feedback loop by promoting additional recruitment from the circulation of T_H17 cells that preferentially express CC-chemokine receptor 6 (CCR6).

Figure 6. Potential immunomodulatory and vaccination strategies that might help to promote immunity and provide a therapeutic advantage against cutaneous S. aureus infections

a | There are many different targets for immunomodulation (indicated by syringes) that might help to induce protective interleukin-1 (IL-1)- and/or IL-17-mediated cutaneous immune responses against Staphylococcus aureus skin infections. Strategies to promote IL-1-mediated activity could include: activating Toll-like receptors (TLRs) using TLR agonists; enhancing inflammasome activation (for example, using alum, nanoparticles or ATPγS); administering recombinant IL-1α or IL-1β; and blocking IL-1 receptor antagonist (IL-1RA) or the decoy receptor IL-1R2. Strategies to promote IL-17-mediated activity could involve the administration of various factors, including: recombinant cytokines that are known to induce T helper 17 (T_H17) cell responses (such as IL-1α, IL-1β, IL-6, IL-21, IL-23 and transforming growth factor-β (TGFβ)); recombinant IL-17A or IL-17F; and CCL20, which would promote the additional recruitment of CC-chemokine receptor 6 (CCR6)⁺ T_H17 cells. Neutrophil recruitment could be enhanced by administering neutrophil-attracting chemokines. Finally, antimicrobial peptide production by keratinocytes could be enhanced (for example, by administering vitamin D analogues to induce the production of cathelicidins). b | The figure shows potential vaccination strategies aimed at preferentially producing an effective T_H17 cell response against cutaneous S. aureus infections. These include using an intranasal route of vaccination, using adjuvants that promote T_H17 cell responses (such as cholera toxin, curdlan and complete Freund’s adjuvant), addition of recombinant T_H17 cell-inducing cytokines during vaccination (such as IL-1β, IL-6, IL-21, IL-23 and TGFβ) and vaccination with antigens that preferentially induce T_H17 cell responses against S. aureus. DC, dendritic cell.