Staphylococcus aureus in Inflammatory Diseases: History
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Contributor:
Huanquan Chen
,
Junyan Zhang
,
Ying He
,
Zhuoyi Lv
,
Zhengtong Liang
,
Jianze Chen
,
Peishan Li
,
Jiawei Liu
,
Hongchen Yang
,
Ailin Tao
,
Xueting Liu

Staphylococcus aureus is a very common Gram-positive bacterium, and S. aureus infections play an extremely important role in a variety of diseases. Staphylococcus aureus (S. aureus), a Gram-positive bacterium, is one of the most notorious human pathogens, causing illnesses ranging from mild skin and wound infections to fatal sepsis or multi-organ failure. Inflammatory cells play an important role in S. aureus infection. S. aureus infection and toxins can activate a variety of inflammatory cells, such as keratinocytes, helper T cells, innate lymphoid cells (ILCs), macrophages, dendritic cells (DCs), mast cells, neutrophils, eosinophils, and basophils, which release inflammatory factors that accumulate at the site of infection and cause an inflammatory response.

  • Staphylococcus aureus
  • toxin
  • inflammatory cells
  • pyroptosis

1. Virulence Factors of S. aureus

The virulence factors of S. aureus can be divided into the following categories: (1) secreted virulence factors, including toxins and superantigens, the main function of which is to disrupt host cell membranes and induce target cell lysis and inflammation [1]; (2) extracellular enzymes, the main function of which is to break down host molecules for nutrition, promote bacterial survival and dissemination, etc. [1]; (3) surface proteins of S. aureus, whose main functions are adhesion, invasion, and immune escape [2], and (4) pathogen-associated molecular patterns (PAMPs), which promote inflammatory responses [3].

1.1. Secreted Virulence Factors

S. aureus can secrete a variety of enzymes and virulence factors that affect the immune system, leading to immune system dysregulation and the proliferation of auto-reactive T cells, as well as the development or progression of chronic autoimmune diseases. Virulence factors of S. aureus include pore-forming toxins (PFTs) [4], phenol-soluble modulins (PSMs) [5], exfoliative toxins (ETs) [6], and superantigens (SAgs) [7] that activate different types of immune cells and cause several different inflammatory and infectious diseases.

1.1.1. PFTs

PFTs are important virulence factors secreted by bacteria that lead to cell lysis by forming pore structures in eukaryotic cell membranes. PFTs exert their toxic effects mainly by altering the permeability of cell membranes, leading to cell death [4]. However, the disruption of cell permeability is often preceded by the release of cytokines and the activation of intracellular protein kinases. PFTs include α-hemolysin (Hla) [8], β-hemolysin (Hlb), γ-hemolysin (Hlg) [9][10], α-toxin [11], and Panton–Valentine leukocidin (PVL) [12].
  • Hla, Hlb, and Hlg
Haemolysin is a pore-forming toxin, also known as a membrane-disrupting toxin. Haemolysin is a substance that lyses red blood cells and releases hemoglobin, a sensitive, complementary fixed antibody that binds specifically to the antigen type of the red blood cell. This antibody can be produced by stimulation of the surface antigen and can cause red blood cells to lyse and release hemoglobin [13]. Haemolysin includes Hla, Hlb, and Hlg.
Hla can induce the formation of small pores in the cell membrane, leading to the rapid release of K+ ions as well as inducing the production of interleukin-1β (IL-1β), IL-6, and IL-8 [8][14][15][16]. Activated endothelial and epithelial cells induce the activation of caspase-1 and the production of NLRP3-inflammasome through the release of nitric oxide (NO), leading to extracellular Ca2+ influx, the production of pro-inflammatory cytokines, and the pyroptosis of monocytes. Ca2+ influx also activates caspase-12, activates caspase-3, and induces apoptosis. Hla also acts on Toll-like receptor (TLR) 3/4 and mediates necroptosis [16][17][18][19][20][21].
Hlb and Hlg can promote inflammasome formation containing procaspase-1, ASC, and NLRP3. Inflammasome activation promotes the release of IL-1β and IL-18. Activated caspase-1 can also cleave GSDMD to form the N-terminal cleavage product of GSDMD, and these together induce pyroptosis [9][10].
2.
α-Toxin
α-Toxin is a lecithin enzyme that breaks down lecithin, which is an important component of cell membranes. Therefore, α-toxin can damage the cell membrane of many cells, causing hemolysis, tissue necrosis, and vascular endothelial cell damage, increasing vascular permeability, and causing edema. α-Toxin activates macrophages and induces the activation of Th1 via CXCL-10. Th1 cells express interferon-γ (IFN-γ) in AD. α-Toxin induces early phagosomes (Rab5, Rab22b) to form autophagosomes (ILC3, Rab7), which induces cellular autophagy [11]. α-Toxin also activates RIPK3, caspase-8, and caspase-12, mediating necroptosis and apoptosis. α-Toxin acts in AD, granulomatous polyangiitis (GPA), pneumonia, chronic sinusitis, sepsis, and other diseases [22][23][24][25][26][27][28].
3.
PVL
PVL is a pore-forming toxin produced by S. aureus that causes leukocyte destruction [12]. PVL can induce the lysis of macrophages and neutrophils, leading to cell death [29][30]. PVL activates receptor-interacting serine threonine kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase-like protein (MLKL) through tumor necrosis factor receptor 1 (TNFR1) and TLR3/4, forming a complex that leads to necroptosis. PVL can also lead to apoptosis. PVL also stimulates K+ efflux, NLRP3 inflammasome production, and caspase-1 activation, leading to pyroptosis [10][31][32][33][34][35][36]. PVL causes pneumonia through the above cell death mechanisms [33][37][38][39][40][41].

1.1.2. PSMs

PSMs are a family of amphipathic alpha-helical peptides found in Staphylococci [5]. PSMs contribute to biofilm structure and the propagation of biofilm-associated infections. PSMs include PSMα, PSMβ, and PSMγ.
  • PSMα
PSMα can induce necroptosis in atopic dermatitis and pneumonia [42][43][44][45][46]. PSMα induces the release of IL-1α and IL-36α from keratinocytes and induces the release of the pro-inflammatory cytokine IL-17, which mediates the skin inflammatory response to cause S. aureus infection [42]. PSMα induces the activation of keratinocytes and neutrophils, resulting in a series of pro-inflammatory responses (including cytokine production, leukocyte activation, and neutrophil chemotaxis) [47][48].
PSMα also activates and phosphorylates MLKL, as well as increases the expression and secretion of lactate dehydrogenase. Through MLKL and lactate dehydrogenase, PSMα can induce neutrophil necroptosis. The necroptosis of cells is the main pathological manifestation of S. aureus pneumonia [44].
2.
PSMβ
PSMβ has an important role in the formation of biofilms. PSMβ activates and induces neutrophil aggregation through formyl-peptide receptor 2 (FPR2), which induces an inflammatory response [49]. In addition to the role of surfactant, PSMβ can also lyse erythrocytes and destroy them. However, in addition to the common properties of PSM, the unique role of PSMβ in S. aureus itself has not yet been investigated [5].
3.
PSMγ (δ Toxin)
The S. aureus δ toxin is a member of the PSM family. The δ toxin is cytolytic to neutrophils and erythrocytes.
The δ toxin is cytolytic to neutrophils and erythrocytes. The staphylococcal δ-toxin promotes allergic skin disease in mice by inducing mast cell degranulation [50]. The δ toxin is an enterotoxin that is cytotoxic and increases cellular cAMP expression to inhibit water absorption in the ileum by altering the concentration of Na+ and Cl− in the mucosa, causing diarrhea [51].

1.1.3. Proteases

  • ETs
ETs are extremely specific serine proteases secreted by S. aureus. ETs can play a role in AD [6]. ETs are the primary toxins that play a role in staphylococcal scalded skin syndrome (SSSS), an abscessing skin disease [52].
ETs specifically recognize and hydrolyze the cell adhesion molecule desmoglein 1 (Dsg1), causing the dissociation of keratinocytes in human and animal skin and promoting skin infection by S. aureus. Three distinct ET subtypes (ETA, ETB, and ETD) were identified in S. aureus [53].
2.
Serine Protease-Like Proteins (Spls)
Spls play a role in T cells and result in asthma [54]. Spls recognize and hydrolyze desmoplastic proteins in the superficial skin layer, inducing skin peeling and blister formation [55][56][57][58][59]. Spls trigger IgE antibody responses in most asthmatics. Peripheral blood T cells produce Th 2 cytokines after Spls stimulation. Therefore, Spls are considered to be triggering allergens in the allergic airway response to S. aureus [54]. T cells of CF patients produced more TH2 cytokines after stimulation by Spls [60]. Increased IgE concentrations of Spls were detected in the serum of CF patients relative to healthy controls [60].
3.
Staphopain B (SspB)
SspB is a human strain of S. aureus that secretes papain-like proteases, and SspB has bacterial virulence. SspB can activate macrophages and lead to apoptosis [61]. SspB may contribute to the recruitment of host cells, including immunomodulatory pDCs and/or macrophages, which contribute to the initiation and maintenance of a chronic inflammatory state by S. aureus [62].

1.1.4. SAgs

SAgs are a class of antigenic substances composed of bacterial exotoxins and retroviral proteins. They bind to most T cells and provide signals for T cell activation. SAgs are highly efficient T-cell mitogens and manipulate the host immune system. They can directly activate T lymphocytes, triggering the release of a large number of pro-inflammatory cytokines, such as IFN-γ, IL-2, and tumor necrosis factor (TNF) [7][63][64]. SAgs include Staphyloccucal enterotoxins (SEs) and toxic shock syndrome toxin 1 (TSST-1).
  • SEs
SEs include SEA, SEB, SEC, SEG, SHE, SEI, SEM, SEO, and SEQ (Table 1). SEA and SEB can play a role in Th1, Th2, and Th22 cells and induce apoptosis. In nasal polyposis, SEB can induce IL-21 expression, and IL-21 also induces differentiation of Th17 [65][66]. SEA can lead to AD and asthma. SEB can cause AD, asthma, and chronic sinusitis. SEC can also lead to AD and cancer [67][68][69]. SEA serves as a potent stimulant of PBMCs and induces the release of large amounts of cytokines and chemokines through the Src, ERK, and STAT pathways [70]. SEB, SEG, SHE, SEI, SEM, SEO, and SEQ can also lead to food poisoning [71][72][73][74][75][76].
Table 1. The mechanisms and characteristics of different types of SEs.
SEs Functions
SEA Anti-protein hydrolase, supercarcinogenic and emetic toxin, causes food poisoning, but no diarrheal activity
SEB Increase in the number of T lymphocytes, as well as the concentration of pro-inflammatory cytokines and inflammatory mediators in the intestinal mucosa; increase mucosal permeability and intestinal secretion
SEC Supercarcinogenic and emetic toxin, but no diarrheal activity
SEG Reversible destruction of intestinal cell ultrastructure
SEH Causes food poisoning
SEI Reversibly disrupts enterocyte ultrastructure and exhibits weak emetic activity
SEM Strong emetic potential
SEO Has emetic activity
SEQ Significantly stable for heat treatment and digestive enzyme degradation, and exhibits significant supercarcinogenic and emetic activity
2.
TSST-1
TSST-1 is a bacterial SAg produced and secreted by S. aureus. TSST-1 can activate CD4+ T cells to produce large amounts of cytokines and lead to a systemic toxic response. In AD, TSST-1 can lead to B lymphocytes and keratinocytes [25][77].

1.1.5. Secreted Enzymes (Exoenzymes) and Effectors

In addition to toxins, S. aureus secretes many virulence factors with proenzymatic effects. These proenzymatic virulence factors can be broadly classified into two types: cofactors, which are used to activate host enzymes, and enzymes that lyse and destroy host cells and tissues. Secreted enzymes (exoenzymes) and cofactors act on different substances with different specific mechanisms of action, but their main function is to break down host cells and tissues to obtain nutrients for their growth, reproduction, and propagation [1]. Secreted enzymes and effectors include EsxA, EsxB, coagulase (Coa), nuclease (Nuc), and adenosine synthase (AdsA), and staphopain (SspB).
  • EsxA and EsxB
EsxA and EsxB are small acidic proteins secreted by the early-secretion antigen-6 secretion system (ESS) as potential T-cell antigens of S. aureus. ESS is the basic virulence factor of S. aureus. EsxA and EsxB mediate the release of S. aureus from host cells, which can cause apoptosis [78][79].
2.
Coa
Coa is an enzyme produced by S. aureus. Coa has thrombospondin-like activity and coagulates plasma treated with citric or oxalic acid. Coa can induce coagulation with vascular hemophilia factor binding protein [80]. Coa can lead to apoptosis [81].
3.
Nuc and AdsA
Nuc can disrupt biofilms by breaking down extracellular DNA (eDNA) as well as mediating the escape of S. aureus from the NET. The NET is an innate immune defense mechanism by means of which invading pathogens are removed [82][83]. Moreover, Nuc can degrade DNA in abscesses or NETs.
The degradation product, nucleotide monophosphate, can be a substrate for the synthesis of another adenylate, synthase A (AsdA). AdsA degrades DNA into deoxyadenosine, which induces the apoptosis of macrophages around NETs by caspase-3 activation. Thus, AsdA can promote the survival of S. aureus [84]. Nuc and AdsA can induce bacteraemia and nephrapostasis [85].
4.
Extracellular Adhesion Protein (Eap)
Eap is the substance that mediates the adhesion of bacteria to host cells. In the early stages of infection, S. aureus adheres and colonizes through the expression of Eap, secondary to infection. Eap can act on T cells and lung epithelial cells. It can also work in psoriasis and CF [86].

1.2. Surface Proteins of S. aureus (Cell Wall-Anchored (CWA) Proteins)

Invasion of organs and tissues by S. aureus from the blood stream requires not only immune evasion but also adhesion. Biofilm formation is an important way for S. aureus to maintain infection. Adhesion, proliferation, and detachment are the main processes of biofilm formation.
Surface proteins of S. aureus constitute a range of virulence factors, known as CWA proteins. CWA proteins play a key role in the adhesion phase. The sorting signal of CWA proteins is responsible for covalently coupling proteins to peptidoglycan (PGN) [87]. There are 24 different CWA proteins on the surface of S. aureus, including microbial surface components recognizing adhesive matrix molecules (MSCRAMMs), the near iron transporter (NEAT) motif protein family, three-helical bundle motif protein A, G5-E repeat family, legume-lectin, and cadherin-like domain protein [88]. CWA proteins play an important role in extracellular matrix (ECM) adhesion, host cell invasion, and immune response evasion. Therefore, targeting CWA proteins with vaccines can counteract S. aureus infections [89].

1.2.1. MSCRAMM

MSCRAMMs are a series of proteins with similar amino acid sequences and very similar structures and functions. MSCRAMMs consist of two folded subdomains similar to IgG, and the two folded subdomains are adjacent to each other. MSCRAMM plays an important role in tissue invasion during S. aureus infection, including enabling S. aureus to adhere to and invade host cells and tissues, evade host immune attack, and induce biofilm formation [87]. Therefore, targeting the MSCRAMM protein is an alternative immunotherapeutic direction for the therapy of S. aureus infections [90].

1.2.2. Staphylococcal Protein A (SpA)

SPA is a protein that forms the cell wall of S. aureus. It was found that SpA can form a complex with human immunoglobulin, and the complex formed by the two can induce the necrosis of various immune cells in the body [91]. SpA can induce apoptosis and cause osteomyelitis [92][93][94][95].
The second immunoglobulin-binding protein (Sbi) belongs to SpA and consists of four triple-helix bundles arranged in tandem. Two of the triple-helix bundles bind similarly to those of SpA and IgG. Sbi non-covalently binds lipoteichoic acid (LTA), which then binds to the cell envelope and helps S. aureus to evade attack by the host immune system.
S. aureus Sbi can induce IL-33 production from keratinocytes in AD [96]. IL-33 can induce itch. IL-33 is a type 2 cytokine and a major regulator of chronic itch [97]. Sbi-inducible expression of IL-33 causes pruritus in AD [98]. It is therefore a virulence factor that promotes type 2 immune response.

1.3. PAMPs

PAMPs are bacterial-specific structures that typically activate TLRs, which act as neutrophil activators [3]. PAMPs of S. aureus include triacyl lipopetides, diacyl lipoproteins, and LTA.

1.3.1. Triacyl Lipopetides and Diacyl Lipoproteins

Triacyl lipopetides and diacyl lipoproteins are components of the Staphylococcal cell wall that provide structural integrity and protection against virulence organisms from the host immune system. Triacyl lipopetides and diacyl lipoproteins can be distinguished by subtle differences in TLR 1 and TLR 6 interactions with TLR2 [99]. Triacyl lipopetides and diacyl lipoproteins can induce activation of the TLR 2 and NLRP3 inflammasome. NLRP3 activation induces pyroptosis. Lipopetides and diacyl lipoproteins can induce the activation of TLR 2 and the NLRP3 inflammasome [10][45][100]. Triacyl lipopetides and diacyl lipoproteins can make use of sepsis [45][101].

1.3.2. LTA

LTA is an adhesion affinity agent associated with surface adhesion and a modulator of the bacteria’s own cell wall lysis enzymes (Muramidases). LTA is released from the bacteria after rupture and death. LTA can induce the phenomenon of passive immune killing. LTA promotes macrophage activation and the expression of IL-1β and IL-18 [102]. LTA activates neutrophils and macrophages and leads to pyroptosis. LTA can also work in food poisoning [102][103][104][105].

1.3.3. PGN

PGN is the main structural component of the cell wall [106], a glycopolymer that maintains the shape of the bacteria. PGN is also a key factor in bacterial recognition by the host immune system [107].
PGN induces the activation of keratinocytes, Langerhans cells (LCs), mast cells, macrophages, CD4+T cells, Th1 cells, and microglia, and induces the release of several cytokines, including TNF-α, IL-1, and IL-4 [108][109][110][111][112][113][114][115][116][117][118]. PGN causes autophagy, which drives AD, sepsis, pneumonia, and psoriasis [108][109][110][111][112][119][120]
S. aureus contains large amounts of SpA, which evades phagocytosis and uptake by phagocytes by binding to immunoglobulin (Ig) molecules and then covering the bacterial surface. Peptidoglycan can promote the B-cell superantigen activity of SpA [121].

2. Different Inflammatory Cell Types Involved in S. aureus Pathogenesis

The cells involved in S. aureus infection and inflammation include keratinocytes, T cells (helper T cells, ILCs), macrophages, DCs, mast cells, neutrophils, eosinophils, and basophils.

2.1. Keratinocytes/Epithelial Cells

Keratinocytes are the main cellular components that make up the epidermis. S. aureus expresses PSMα, which is a group of secreted virulence peptides.
In AD, S. aureus accumulates in the lysosomes of keratinocytes and induces IL-1α secretion via TLR9 [122]. S. aureus expresses PSMα acting on keratinocytes, induces IL-1α and IL-36α release from keratinocytes via myd88 signaling, induces γδt cell and ILC3 production of IL-17, and promotes neutrophil infiltration [42]. In addition, S. aureus promotes IL-36α secretion from keratinocytes and promotes IgE production and allergic inflammatory response [46]. S. aureus promotes IL-1β expression by keratinocytes and induces skin regeneration through keratinocyte-dependent IL-1R-MyD88 signaling [123].
S. aureus Sbi promotes IL33 secretion by keratinocytes, and IL-33 promotes type 2 immune responses [96][124]. IL-33 also has an important role in pruritus [125]. S. aureus diacylated lipoprotein is a TLR2 and TLR6 ligand, which activates keratinocytes via TLR2-TLR6 heterodimers to produce TSLP, which promotes T(H)2-type inflammation and thus AD [126]. The keratinocyte-expressed TSLP acts directly on TRPA1-positive sensory neurons, triggering intense pruritus-induced scratching [127].
In nasal polyp tissue, S. aureus can directly induce the release of the epithelial cell-derived cytokines TSLP and IL-33 by binding to TLR 2, thereby potentially propagating the expression of type 2 cytokines IL-5 and IL-13 in nasal polyp tissue [128][129][130][131].

2.2. Helper T Cells (Th Cells)

2.2.1. T Helper 1 (Th1) Cells

Th1 cells are CD4+ cells that mainly secrete IL-2, IFN-γ, and TNF-β (tumor necrosis factor β), which are involved in regulating cellular immunity, assisting in the differentiation of cytotoxic T cells, mediating cellular immune responses, and participating in delayed hypersensitivity reactions. IFN-γ, IL-2, and TNF-β can drive inflammatory responses [132].
S. aureus infection can induce Th1-type inflammatory responses in different diseases. Enterotoxin B (SEB) induces Th1 activation in chronic sinusitis; α-toxin promotes Th1 activation via CXCL10 in AD [23][24][69][133]. Activated Th1 cells release the cytokine IFN-γ. IFN-γ is a driver of chronic inflammation in the chronic phase of AD, and the overexpression of IFN-γ can lead to recurrent inflammation and pruritus, causing lichenoid degeneration of the skin [77][134]. In contrast, psoriasis is also a chronic disease mediated by Th1 cytokines, and IL-12 mediates the differentiation of Th1 cells [135].

2.2.2. Th2 Cells

Th2 cells (which are CD4+ T cells) are important cells in the type 2 inflammatory pathway. th2 secretes IL-4, IL-5, and IL-13 and stimulates type 2 immunity, as evidenced by the production of high levels of IgE and eosinophils. Type 2 immunity is a specific immune response that includes both innate and adaptive immunity and contributes to the formation of an immune barrier on the mucosal surface to a clear response to pathogens [136]. Th2 cells are formed by the induced differentiation of Th0 cells by IL-4 produced by basophils, eosinophils, mast cells, natural killer cells (NK), or already differentiated Th2 cells.
In AD infection with S. aureus, keratinocytes can express TSLP, IL33 [96][124], and IL-19 [137], which can induce the Th2 expression of IL-4, IL-10, IL-13, and IL-31, causing an inflammatory response. IL-4 and IL-31 play important roles in itchiness [128][129][137]. S. aureus was found to induce the expression of IL-8, IL-19, and IL-22, which induced increased expression of Th2 cytokines [110][137][138]. S. aureus PGN action on LCs induces Th2 cells in the skin via CCL17, and it induces IL-18 stimulation of CD4+ T cells to produce IL-4 to induce Th2 cytokine expression [109][110]. Staphylococcal α-toxin mediates the expression of Th2 cytokines IL-4 and IL-13 through STAT6, leading to increased keratin-forming cell death [139].
It was found that antigen-specific regulatory T (Treg) cells can also induce Th2 cell proliferation [140]. S. aureus PGN action on LCs induces Th2 cells in the skin via CCL17, and it induces the IL-18 stimulation of CD4+ T cells to produce IL-4, which induces Th2 cytokine expression [109][110]. In addition, staphylococcal α-toxin mediates the expression of Th2 cytokines IL-4 and IL-13 through STAT6, leading to increased keratin-forming cell death [139]. SEB can also act on eosinophils, monocytes, and Treg cells to induce Th2 cytokine expression and induce the Th2 proliferation and secretion of IL-10 to aggravate skin inflammation [140][141]. In asthma, eosinophils induce the activation of Th2 and express IL-5 in conjunction with basophils [142]. In chronic sinusitis, Th2 cytokines can activate B cells, release IgE, and indirectly mediate eosinophil inflammation [143]. Th2 cytokines can reduce filamentous protein expression in keratinocytes, further exacerbating the disruption of skin barrier function [144]. Th2 expresses IL-4, IL-10, IL-13, and IL-31, inducing epidermal thickening, sensitization, inflammation, and pruritus [145][146]. Th2 also reduces the expression of AMP, HBD-2, HBD-3, filamentous polymerase, and epidermal proteins, further promoting the proliferation of S. aureus and exacerbating flora imbalance. The activation of keratinocytes increased the expression of endogenous serine proteases, induced inflammatory responses and tissue damage, and released various cytokines. Serine protease V8 and the serine protease strip toxin cleave corneal adhesion proteins, including DSG-1, leading to increased desquamation [128][129].

2.2.3. Th17 Cells

Th17 is a newly discovered subpopulation of T cells that secrete IL-17, which is important in autoimmune diseases and the body’s defense response. Transforming growth factor β (TGF-β), IL-6, IL-23, and IL-21 play active roles in the differentiation and formation of Th17 cells, while IFN-γ, IL-4, cytokine signaling (IFN-γ), IL-4, suppressor of cytokine signaling 3 (Socs3), and IL-2 inhibit its differentiation [147].
Th17 cells have a crucial role in host defense. Dysregulated Th17 responses mediate various autoimmune and inflammatory diseases. IL-6, TGF-β, and IL-23, secreted by macrophages and DCs, induce the activation and differentiation of Th17. Th17 cells are recruited into the skin and interact with keratinocytes and fibroblasts to promote epidermal tissue repair [134]. Th17 cells also express IL-17, IL-22, and IL-26. IL-17 can coordinate local tissue by upregulating pro-inflammatory cytokines and chemokines (including IL-1β, IL-6, TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), KC/CXCL1, MCP-1/CCL2, MIP-2/CXCL2, MCP-3/CCL7, and MIP-3α/CCL20, and matrix metal proteinases (MMPs)), enabling the migration of activated T cells through the ECM [148][149][150].
S. aureus triggers a strong Th17-type response in skin effector T cells, inducing Th17 to produce IL-17A, IL-17F, and IL-22 [151]. S. aureus promotes keratinocyte expression of IL1β, promotes differentiation of Th17, and promotes skin inflammation [152]. SEB induces IL-21 secretion by Follicular helper T (Tfh), induces differentiation of Th17, and acts in nasal polyp disease [65][66].
In septic arthritis caused by S. aureus infection, S. aureus activates immune cell-specific macrophages and DCs to release pro-inflammatory mediators, such as TNF-α, IL-1β, IL-6, and IL-21, which induce RORγt, RORγt, and CD4 T cells to differentiate into Th17 cells [153][154][155]. Th17 cells produce the pro-inflammatory cytokine IL-17, which directly stimulates arthritic inflammation by binding to receptors on immune cells, stimulating the production of more pro-inflammatory cytokines, chemokines, and other inflammatory mediators, including NO and MMPs, while TNF-α, IL-1β, and IL-6 upregulate MMPs, which can promote cartilage degradation and enhance joint destruction [156][157].
IL-17 activates macrophages to express TNF-α and IL-1β as well as fibroblasts to produce IL-6, IL-8, and MMPs; it also stimulates blood endothelial cells to produce chelators and the p38 MAPK-dependent expression of VCAM-1 and ICAM-1, which contribute to immune cell evasion from blood to tissue [151]. In mouse studies, ICAM-1 was upregulated on endothelial cells in the diseased skin of CD18 (β2-integrin) (CD18hypo) mice, whereas in vivo S. aureus extracellular adhesion protein prevented T cell vascular migration to the inflamed skin of CD18 (β2-integrin) (CD18hypo) mice but did not inhibit their proliferation and activation [86]. IL-17 also promoted epithelial cell stimulation by IL-8 and granulocyte colony-stimulating factor (G-CSF), induced neutrophil migration and activation, and synergistically enhanced the induction of TNF-α. IL-22 not only triggers a pro-inflammatory response, but also inhibits terminal differentiation of keratinocytes and induces Th2-type inflammation [138].
In psoriasis, IL-17 can activate macrophages to express TNF-α and IL-1β, thereby inducing fibroblast activation [151]. In inflammatory areas of the skin, Th17 can increase the inflammatory response of the skin, and IL-17A can strongly induce IL-19 expression in keratinocytes. IL-19 also induces the expression of Th2 cytokines [137][158].

2.2.4. Tregs

Tregs, characterized by an expression of the forkhead transcription factor FOXP3 and IL-2R α chain CD25, play a central role in maintaining tolerance to self and preventing an overexcited inflammatory response to infection [159]. S. aureus induces the proliferation of effector memory T (Tem) cells and the activation of Treg cells and Th17 responses through cutaneous LCs [160][161]. Th17 and Treg cells antagonize each other, and Th17/Treg cell imbalance can trigger or exacerbate the disease process in AD [162]. After superantigenic stimulation of SEs, Treg cells lose their immunosuppressive activity, and a Treg induces Th2 proliferation and the secretion of IL-10 to aggravate the skin inflammatory response [140].

2.2.5. Tfh Cells

Tfh cells are a specialized subset of CD4+ T cells located in B cell follicles that induce B and T cell interactions and release cytokines to promote germinal center (GC) formation, promote the differentiation of GC B cells into memory B cells or plasma cells, and drive the maturation of high-affinity antibodies [163]. The Tfh cells express CXC chemokine receptor 5 (CXCR5) [164], ICOS [165], programmed death-1 (PD-1) [166], cytotoxic T lymphocyte antigen 4 (CTLA-4) [167], B-cell lymphoma-6 (BCL-6) [168], and IL-21 [66].
In S. aureus-infected chronic rhinosinusitis with nasal polyposis (CRSwNP), Tfh can migrate into lymphoid aggregates (lymphoid aggregates resemble germinal centers) and interact with B cells to induce the proliferation and differentiation of naive B cells to plasma cells [65]. Tfh is also involved in the B cell-mediated immune response induced by the S. aureus vaccine [169]. In nasal polyposis, IL-21 expression was increased after SEB stimulation. IL-21 can also induce the differentiation of Th17 [65][66].
However, there has been minimal research on this aspect of the mechanism of Tfh in S. aureus infection, and future research in this direction may allow the mechanism of S. aureus infection to be further deciphered and allow for more comprehensive counseling for clinical treatment.

2.2.6. Th9 Cells

Recently, researchers have identified another novel and unique population of immunomodulatory cells. Th9 cells were initially thought to be a subpopulation of Th2 cells that could produce IL-9 [170]. Th9 cells have been shown to act on many cell types associated with asthma, including T cells, B cells, mast cells, eosinophils, neutrophils, and epithelial cells, and therefore may be important in the pathophysiology of allergic asthma [171]. Moreover, Th9 has been found to be a major factor in regulating immunity to autoimmune diseases [172] and tumor immunity [173].
There are few studies on this aspect of the mechanism of S. aureus infection promoting Th9-type inflammatory response, which may be a direction for further research.

2.3. ILCs

ILCs are lymphocytes that do not express the diverse antigen receptor types expressed on T and B cells [174]. ILCs comprise a heterogeneous population of immune cells that maintain barrier function and can initiate a protective or pathological immune response in response to infection [175].
ILCs can be divided into ILC1, ILC2, and ILC3 types. In cell-mediated effector immunity, ILC1, ILC2, and ILC3 are involved in type 1, type 2, and type 17 immune responses, respectively [176]. S. aureus and S. aureus muramyl dipeptide (MDP) can activate ILC2 and promote type 2 immune response [131]. In AD, PSMα induces the production of ILC3, which is involved in the mediation of skin inflammation [42]. In patients with AD infection with S. aureus, the expansion of ILC3 is involved in mediating skin inflammation [77].
However, little is known about the relationship between S. aureus infection and ILCs. This could be another direction in the study of the mechanism of S. aureus infection in the future.

2.4. Macrophages

Macrophages are cellular components of the innate immune system and are present in almost all tissues, contributing to immunity, repair, and homeostasis [177]. When S. aureus infects humans, epithelial cells recognize the invading S. aureus through pathogen recognition receptors (PRRs), which induce the production of pro-inflammatory cytokines and chemokines, leading to the recruitment and activation of phagocytes, including GM-CSF, G-CSF, IL-1β, IL-6, and IL-8 [178].
Phagocytosis of S. aureus triggers the TLR2-dependent signaling and activation of the NLRP3 inflammasome, leading to the recruitment of ASC and the activation of cystathione-1, causing cells to release cytokines IL-1β and IL-18 and inducing apoptosis [179][180]. S. aureus was found to survive and replicate in macrophages, which deliver nutrients to lysosomal-engulfing S. aureus to promote bacterial growth, and promote bacterial persistence during infection by limiting reactive oxygen species (ROS) and RNS production by macrophages through lipoic acid synthesis [181][182].

2.5. DCs

DCs are the most powerful specialized antigen-presenting cells in the body and are highly efficient in the uptake, processing, and presentation of antigens. Immature DCs have a strong migratory capacity and mature DCs can effectively activate initial T cells and are central to the initiation, regulation, and maintenance of the immune response. They are usually found in small numbers in contact with external skin and their immature forms can be found in the blood. When activated, they move to the lymphoid tissue to interact with T and B cells to stimulate and control the appropriate immune response.
S. aureus activates macrophages and DCs to release pro-inflammatory mediators, such as TNF-α, IL-1β, IL-6, and IL-21, which induce RORγt to produce IL-17A, IL-17F, and IL-21 and induce CD4 T cells to differentiate into Th17 cells [153][154][155].
TSLP released by keratinocytes in AD is a potent activator of DCs, triggering the production of Th2-attracting chemokines, such as CCL17/TARC and CCL22/MDC, and inducing Th2 differentiation through upregulation of these cells by OX40L, which activates Th2 cells [183]. In experiments with psoriatic mice, S. aureus Eap was found to disrupt cell–cell contacts between T cells and DCs in vitro, blocking T cell extravasation into inflamed skin to inhibit psoriasis [86].
LCs are the major DCs in the normal epidermis, and DCs are the major antigen-presenting cells [184]. Epidermal exposure to S. aureus induces the proliferation of effector memory T (Tem) cells and limited Treg cell activation and Th17 responses, and LCs directly interact with S. aureus via the pattern recognition receptor langerin (CD207), which interacts directly with S. aureus [160][161]. LCs express TLRs that recognize bacterial and viral products, and the TLR2-mediated transduction of S. aureus-derived signals is severely impaired in LCs with AD skin [185]. The DC-mediated blockade of human T cell activation and proliferation, PVL, targets DCs to blunt CD4+ T lymphocyte activation and kills DCs, leading to impaired T cell responses and increased infection [186].

2.6. Mast Cells

Mast cells are granulocytes that disintegrate to release granules and the substances in the granules. Such granules in the blood contain heparin, histamine, and 5-hydroxytryptamine, which can drive tachyphylactic allergic reactions (inflammation) in tissues, especially in asthma. Mast cells are the main effector cells of inflammation, and mast cells act as antigen-presenting cells and induce Th1 and Th2 cell development.
In patients with AD, S. aureus infection leads to an increase in the number of mast cells, which proliferate within mast cells and mediate Th1 cell development as well as the development of chronic inflammation, leading to the release of Th1 cytokines and the upregulation of IFN, manifested as edema within the lamina propria [187][188]. In mast cells, PGN from S. aureus stimulates mast cells in a TLR2-dependent manner, producing TNF-α, IL-4, IL-5, IL-6, and IL-13, and S. aureus also triggers TNFα and IL-8 release by binding to CD48 [111][112].
The δ toxin induces mast cell degranulation, which is dependent on intracellular PI3K activation and free calcium ion influx. δ toxin-induced mast cell degranulation differs from conventional IgE cross-linking in that this action does not require the presence of an antigen. IgE enhances δ toxin-induced mast cell degranulation, promotes IgE and IL-4 production, and leads to skin inflammation. However, AD is a chronic inflammatory skin disease caused by mast cells, leading to immunoglobulin-E (lgE)-mediated hypersensitivity [50][189].
S. aureus-expressed SAgs can also trigger mast cell degranulation via IgE and FcεR, and SEs may also trigger direct histamine release from mast cell degranulation via unknown receptors [190]. In asthma, the airways are hyperreactive, and mast cells release histamine and various cytokines that attract the accumulation of eosinophils, causing epithelial cell damage and respiratory distress [191][192].
Although mast cells may help clear the infection, S. aureus may use mast cells to evade detection and immune clearance.

2.7. Neutrophils

Neutrophils are a type of myeloid leukocyte and some of the major responders in acute inflammation. Activated neutrophils mediate inflammation by synthesizing and secreting cytokines, chemokines, leukotrienes, and prostaglandins. Neutrophils synthesize and secrete the chemokine CXCL8 to recruit more neutrophils and express IL-1, IL-6, IL-12, TGF-β, and TNF-α, reactivating neutrophils and other cells of the immune system [193].
S. aureus can recruit and activate neutrophils at the site of infection [194]. In AD and pneumonia, PSMα can induce the expression of IL-1α and IL-36 and induce neutrophil death, leading to disease exacerbation [43][44]. γδ T cells mediate IL-17 responses and induce neutrophil recruitment, pro-inflammatory cytokines IL-1α, IL-1β, and TNF, and host defense peptides, while rapid neutrophil recruitment enhances S. aureus colonization in the skin [195]. IL-17 also promotes IL-8 and G-CSF stimulation of epithelial cells, induces neutrophil migration and activation, synergistically enhances TNF-α induction, and increases antimicrobial peptide (AMP) production [151].
Neutrophils induce IL-20 expression, which contributes to psoriasis, wound healing, and anti-inflammatory effects [135]. S. aureus LTA promotes the expression of neutrophil factors TNF-α and IL-8. IL-8 also attracts neutrophils to accumulate in the intestine, leading to the activation and attraction of polymorphonuclear leukocytes (PMN), causing an inflammatory response in the intestine during food poisoning [103]. The α toxin produces IL-1β via TLR2, NOD2, FPR1, and ASC/NLRP3 inflammasome induced by neutrophils, and IL-1β can induce thymic stromal lymphopoietin and contribute to abscess formation [149][196]. S. aureus α toxin produces IL-1β via TLR2, NOD2, FPR1, and ASC/NLRP3 inflammasomes induced by neutrophils expressing IL-1β [196]. In GPA, the activation of neutrophils, by expressing neutrophil extracellular trap products (NET-derived products), plays a role in the disease [197].

2.8. Eosinophils (Eos)

Eosinophils are considered to be the effector cells associated with infection and the cause of tissue damage. Eosinophils can express a range of ligand receptors that play a role in cell growth, adhesion, chemotaxis, degranulation, and intercellular interactions. Eosinophils synthesize, store, and secrete cytokines, chemokines, and growth factors. Eosinophils can function as antigen-presenting cells and can regulate the immune system [198].
In AD, S. aureus produces exotoxins that can amplify the allergic response by directly activating other immune cells, such as eosinophils. Eosinophil inflammation can be induced by SEB. Eosinophils lead to epidermal damage, tissue swelling, and inflammatory cell recruitment through the release of toxic mediators, including eosinophil cationic protein (ECP), major basic proteins, eosinophil-derived neurotoxins, and eosinophil peroxidase (EPO) [199][200]. In addition, activated eosinophils can promote antimicrobial defense by releasing mitochondrial DNA associated with granule proteins [201].
In asthma, eosinophils are not only involved in the release of granulins, lipid mediators, ROS, cytokines, and growth factors that trigger the Th2 response [142]. The IL-5 cytokines of Th2, GM-CSF, and IL-3 induce the eosinophil response and eosinophil maturation. IL-3 and GM-CSF also induce eosinophil recruitment [202][203].
In CRSwNP, S. aureus can also cause eosinophil inflammation by inducing IgE [143].

2.9. Basophils

Basophils are a type of leukocyte that originate from bone marrow hematopoietic pluripotent stem cells that differentiate and mature in the bone marrow and enter the bloodstream. Basophils are important cells for S. aureus respecting the virulence of AD and asthma [191][204].
S. aureus SAgs, including SEA, SEB, SEC, and TSST-1, also directly activate B lymphocytes and induce specific IgE-dependent mast cells and basophil degranulation to release histamine, further exacerbating AD and promoting adaptive cellular and humoral type 2 immunity [77].
NOD2 and TLR2 ligands trigger basophil activation by interacting with dermal fibroblasts in AD-like skin inflammation [205]. S. aureus was found to induce skin basophil aggregation and increase IL-4 expression. Basophil-derived IL-4 inhibited skin IL-17A production by TCRγδ+ cells and promoted S. aureus infection of the skin. Basophils secrete IL-6 to promote Th17 responses and inhibit the IL-17A production of IL-4 via STAT6 inhibition of the IL-17A promoter to promote S. aureus infection [206], while Toll-like expressing receptor-expressing epidermal keratinocytes recognize invasion and respond to LTA by inducing the expression of cytokines such as TSLP, which leads to basophil recruitment and IL-4 production [104].

2.10. B Cells

In inflammatory and neoplastic diseases, B cells play a regulatory role by secreting regulatory cytokines, such as IL-10, or by relying on the secretion of antibodies. B cells can act in concert with other immunomodulatory cells, such as Treg cells. TSST-1 can induce B cell apoptosis [207]. LTA inhibits LPS-induced B cell proliferation by reducing ERK phosphorylation through the TLR2 signaling pathway [208]. The S. aureus-induced activation of Th2 triggers B cells to produce IgE in response to allergens and autoantigens, indirectly mediating eosinophil inflammation [143]. Tfh and ILCs can also induce B cell differentiation [65][191].
In the disease response to S. aureus infection, there are many other cells involved besides those mentioned above. As a major human pathogen, S. aureus induces cell activation in various cell types, releases various cytokines, and causes apoptosis, which is important in S. aureus infections. However, the cellular mechanisms are not yet clear, including the role of Th9, Tfh, and ILCs in the pathogenesis of S. aureus. This may be another direction for studies on S. aureus infection in the future.
A summary of the inflammatory cells activated by S. aureus in several diseases is shown in Figure 1.
Figure 1. Inflammatory cell types in the pathogenesis of Staphylococcus aureus. Different virulence factors of S. aureus can induce activation of Tfh, Th1, Th2, Th9, and Th17 cells, which play a role in chronic sinusitis, AD, asthma, itch, psoriasis, septic arthritis, and CGD. Eos: eosinophils, Bas: basophils, MC: mast cells, Mø: macrophage.

This entry is adapted from the peer-reviewed paper 10.3390/toxins14070464

References

  1. Tam, K.; Torres, V.J. Staphylococcus aureus Secreted Toxins and Extracellular Enzymes. Microbiol. Spectr. 2019, 7, 2.
  2. Foster, T.J.; Geoghegan, J.A.; Ganesh, V.K.; Höök, M. Adhesion, invasion and evasion: The many functions of the surface proteins of Staphylococcus aureus. Nat. Rev. Microbiol. 2014, 12, 49–62.
  3. Askarian, F.; Wagner, T.; Johannessen, M.; Nizet, V. Staphylococcus aureus modulation of innate immune responses through Toll-like (TLR), (NOD)-like (NLR) and C-type lectin (CLR) receptors. FEMS Microbiol. Rev. 2018, 42, 656–671.
  4. Verma, P.; Gandhi, S.; Lata, K.; Chattopadhyay, K. Pore-forming toxins in infection and immunity. Biochem. Soc. Trans. 2021, 49, 455–465.
  5. Otto, M. Phenol-soluble modulins. Int. J. Med. Microbiol. 2014, 304, 164–169.
  6. Yagi, S.; Wakaki, N.; Ikeda, N.; Takagi, Y.; Uchida, H.; Kato, Y.; Minamino, M. Presence of staphylococcal exfoliative toxin A in sera of patients with atopic dermatitis. Clin. Exp. Allergy 2004, 34, 984–993.
  7. Spaulding, A.R.; Salgado-Pabón, W.; Kohler, P.L.; Horswill, A.R.; Leung, D.Y.; Schlievert, P.M. Staphylococcal and streptococcal superantigen exotoxins. Clin. Microbiol. Rev. 2013, 26, 422–447.
  8. Cassidy, P.; Harshman, S. Studies on the binding of staphylococcal 125I-labeled alpha-toxin to rabbit erythrocytes. Biochemistry 1976, 15, 2348–2355.
  9. Becker, K.A.; Fahsel, B.; Kemper, H.; Mayeres, J.; Li, C.; Wilker, B.; Keitsch, S.; Soddemann, M.; Sehl, C.; Kohnen, M.; et al. Staphylococcus aureus Alpha-Toxin Disrupts Endothelial-Cell Tight Junctions via Acid Sphingomyelinase and Ceramide. Infect. Immun. 2018, 86, e00606-17.
  10. Muñoz-Planillo, R.; Franchi, L.; Miller, L.S.; Núñez, G. A critical role for hemolysins and bacterial lipoproteins in Staphylococcus aureus-induced activation of the Nlrp3 inflammasome. J. Immunol. 2009, 183, 3942–3948.
  11. Mulcahy, M.E.; O’Brien, E.C.; O’Keeffe, K.M.; Vozza, E.G.; Leddy, N.; McLoughlin, R.M. Manipulation of Autophagy and Apoptosis Facilitates Intracellular Survival of Staphylococcus aureus in Human Neutrophils. Front. Immunol. 2020, 11, 565545.
  12. Adler, A.; Temper, V.; Block, C.S.; Abramson, N.; Moses, A.E. Panton-Valentine leukocidin-producing Staphylococcus aureus. Emerg. Infect. Dis. 2006, 12, 1789–1790.
  13. Wiseman, G.M. The hemolysins of Staphylococcus aureus. Bacteriol. Rev. 1975, 39, 317–344.
  14. Bubeck Wardenburg, J.; Patel, R.J.; Schneewind, O. Surface proteins and exotoxins are required for the pathogenesis of Staphylococcus aureus pneumonia. Infect. Immun. 2007, 75, 1040–1044.
  15. Lizak, M.; Yarovinsky, T.O. Phospholipid scramblase 1 mediates type i interferon-induced protection against staphylococcal α-toxin. Cell Host Microbe 2012, 11, 70–80.
  16. Bhakdi, S.; Muhly, M.; Korom, S.; Hugo, F. Release of interleukin-1 beta associated with potent cytocidal action of staphylococcal alpha-toxin on human monocytes. Infect. Immun. 1989, 57, 3512–3519.
  17. Suttorp, N.; Fuhrmann, M.; Tannert-Otto, S.; Grimminger, F.; Bhadki, S. Pore-forming bacterial toxins potently induce release of nitric oxide in porcine endothelial cells. J. Exp. Med. 1993, 178, 337–341.
  18. Craven, R.R.; Gao, X.; Allen, I.C.; Gris, D.; Bubeck Wardenburg, J.; McElvania-Tekippe, E.; Ting, J.P.; Duncan, J.A. Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. PLoS ONE 2009, 4, e7446.
  19. Suttorp, N.; Seeger, W.; Dewein, E.; Bhakdi, S.; Roka, L. Staphylococcal alpha-toxin-induced PGI2 production in endothelial cells: Role of calcium. Am. J. Physiol. 1985, 248, C127–C134.
  20. Berube, B.J.; Bubeck Wardenburg, J. Staphylococcus aureus α-toxin: Nearly a century of intrigue. Toxins 2013, 5, 1140–1166.
  21. Grimminger, F.; Rose, F.; Sibelius, U.; Meinhardt, M.; Pötzsch, B.; Spriestersbach, R.; Bhakdi, S.; Suttorp, N.; Seeger, W. Human endothelial cell activation and mediator release in response to the bacterial exotoxins Escherichia coli hemolysin and staphylococcal alpha-toxin. J. Immunol. 1997, 159, 1909–1916.
  22. Iacovache, I.; Bischofberger, M.; van der Goot, F.G. Structure and assembly of pore-forming proteins. Curr. Opin. Struct. Biol. 2010, 20, 241–246.
  23. Breuer, K.; Wittmann, M.; Kempe, K.; Kapp, A.; Mai, U.; Dittrich-Breiholz, O.; Kracht, M.; Mrabet-Dahbi, S.; Werfel, T. Alpha-toxin is produced by skin colonizing Staphylococcus aureus and induces a T helper type 1 response in atopic dermatitis. Clin. Exp. Allergy 2005, 35, 1088–1095.
  24. Kasraie, S.; Niebuhr, M.; Kopfnagel, V.; Dittrich-Breiholz, O.; Kracht, M.; Werfel, T. Macrophages from patients with atopic dermatitis show a reduced CXCL10 expression in response to staphylococcal α-toxin. Allergy 2012, 67, 41–49.
  25. Schlievert, P.M.; Roller, R.J.; Kilgore, S.H.; Villarreal, M.; Klingelhutz, A.J.; Leung, D.Y.M. Staphylococcal TSST-1 Association with Eczema Herpeticum in Humans. mSphere 2021, 6, e00608-21.
  26. Okano, M.; Fujiwara, T.; Kariya, S.; Higaki, T.; Haruna, T.; Matsushita, O.; Noda, Y.; Makihara, S.; Kanai, K.; Noyama, Y.; et al. Cellular responses to Staphylococcus aureus alpha-toxin in chronic rhinosinusitis with nasal polyps. Allergol. Int. 2014, 63, 563–573.
  27. Kang, S.S.; Noh, S.Y.; Park, O.J.; Yun, C.H.; Han, S.H. Staphylococcus aureus induces IL-8 expression through its lipoproteins in the human intestinal epithelial cell, Caco-2. Cytokine 2015, 75, 174–180.
  28. Kwak, Y.K.; Vikström, E.; Magnusson, K.E.; Vécsey-Semjén, B.; Colque-Navarro, P.; Möllby, R. The Staphylococcus aureus alpha-toxin perturbs the barrier function in Caco-2 epithelial cell monolayers by altering junctional integrity. Infect. Immun. 2012, 80, 1670–1680.
  29. Gillet, Y.; Issartel, B.; Vanhems, P.; Fournet, J.C.; Lina, G.; Bes, M.; Vandenesch, F.; Piémont, Y.; Brousse, N.; Floret, D.; et al. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 2002, 359, 753–759.
  30. Finck-Barbançon, V.; Duportail, G.; Meunier, O.; Colin, D.A. Pore formation by a two-component leukocidin from Staphylococcus aureus within the membrane of human polymorphonuclear leukocytes. Biochim. Biophys. Acta 1993, 1182, 275–282.
  31. Yanai, M.; Rocha, M.A.; Matolek, A.Z.; Chintalacharuvu, A.; Taira, Y.; Chintalacharuvu, K.; Beenhouwer, D.O. Separately or combined, LukG/LukH is functionally unique compared to other staphylococcal bicomponent leukotoxins. PLoS ONE 2014, 9, e89308.
  32. Melehani, J.H.; James, D.B.; DuMont, A.L.; Torres, V.J.; Duncan, J.A. Staphylococcus aureus Leukocidin A/B (LukAB) Kills Human Monocytes via Host NLRP3 and ASC when Extracellular, but Not Intracellular. PLoS Pathog. 2015, 11, e1004970.
  33. Holzinger, D.; Gieldon, L.; Mysore, V.; Nippe, N.; Taxman, D.J.; Duncan, J.A.; Broglie, P.M.; Marketon, K.; Austermann, J.; Vogl, T.; et al. Staphylococcus aureus Panton-Valentine leukocidin induces an inflammatory response in human phagocytes via the NLRP3 inflammasome. J. Leukoc. Biol. 2012, 92, 1069–1081.
  34. Spaan, A.N.; Vrieling, M.; Wallet, P.; Badiou, C.; Reyes-Robles, T.; Ohneck, E.A.; Benito, Y.; de Haas, C.J.; Day, C.J.; Jennings, M.P.; et al. The staphylococcal toxins γ-haemolysin AB and CB differentially target phagocytes by employing specific chemokine receptors. Nat. Commun. 2014, 5, 5438.
  35. Staali, L.; Monteil, H.; Colin, D.A. The staphylococcal pore-forming leukotoxins open Ca2+ channels in the membrane of human polymorphonuclear neutrophils. J. Membr. Biol. 1998, 162, 209–216.
  36. Noda, M.; Kato, I.; Hirayama, T.; Matsuda, F. Mode of action of staphylococcal leukocidin: Effects of the S and F components on the activities of membrane-associated enzymes of rabbit polymorphonuclear leukocytes. Infect. Immun. 1982, 35, 38–45.
  37. Chow, S.H.; Deo, P.; Yeung, A.T.Y.; Kostoulias, X.P.; Jeon, Y.; Gao, M.L.; Seidi, A.; Olivier, F.A.B.; Sridhar, S.; Nethercott, C.; et al. Targeting NLRP3 and Staphylococcal pore-forming toxin receptors in human-induced pluripotent stem cell-derived macrophages. J. Leukoc. Biol. 2020, 108, 967–981.
  38. Kitur, K.; Parker, D.; Nieto, P.; Ahn, D.S.; Cohen, T.S.; Chung, S.; Wachtel, S.; Bueno, S.; Prince, A. Toxin-induced necroptosis is a major mechanism of Staphylococcus aureus lung damage. PLoS Pathog. 2015, 11, e1004820.
  39. Shallcross, L.J.; Fragaszy, E.; Johnson, A.M.; Hayward, A.C. The role of the Panton-Valentine leucocidin toxin in staphylococcal disease: A systematic review and meta-analysis. Lancet Infect. Dis. 2013, 13, 43–54.
  40. Genestier, A.L.; Michallet, M.C.; Prévost, G.; Bellot, G.; Chalabreysse, L.; Peyrol, S.; Thivolet, F.; Etienne, J.; Lina, G.; Vallette, F.M.; et al. Staphylococcus aureus Panton-Valentine leukocidin directly targets mitochondria and induces Bax-independent apoptosis of human neutrophils. J. Clin. Investig. 2005, 115, 3117–3127.
  41. Huang, J.; Zhang, T.; Zou, X.; Wu, S.; Zhu, J. Panton-valentine leucocidin carrying Staphylococcus aureus causing necrotizing pneumonia inactivates the JAK/STAT signaling pathway and increases the expression of inflammatory cytokines. Infect. Genet. Evol. 2020, 86, 104582.
  42. Nakagawa, S.; Matsumoto, M.; Katayama, Y.; Oguma, R.; Wakabayashi, S.; Nygaard, T.; Saijo, S.; Inohara, N.; Otto, M.; Matsue, H.; et al. Staphylococcus aureus Virulent PSMα Peptides Induce Keratinocyte Alarmin Release to Orchestrate IL-17-Dependent Skin Inflammation. Cell Host Microbe 2017, 22, 667–677.e5.
  43. Gray, B.; Hall, P.; Gresham, H. Targeting agr- and agr-Like quorum sensing systems for development of common therapeutics to treat multiple gram-positive bacterial infections. Sensors 2013, 13, 5130–5166.
  44. Zhou, Y.; Niu, C.; Ma, B.; Xue, X.; Li, Z.; Chen, Z.; Li, F.; Zhou, S.; Luo, X.; Hou, Z. Inhibiting PSMα-induced neutrophil necroptosis protects mice with MRSA pneumonia by blocking the agr system. Cell Death Dis. 2018, 9, 362.
  45. Hanzelmann, D.; Joo, H.S.; Franz-Wachtel, M.; Hertlein, T.; Stevanovic, S.; Macek, B.; Wolz, C.; Götz, F.; Otto, M.; Kretschmer, D.; et al. Toll-like receptor 2 activation depends on lipopeptide shedding by bacterial surfactants. Nat. Commun. 2016, 7, 12304.
  46. Patrick, G.J.; Liu, H.; Alphonse, M.P.; Dikeman, D.A.; Youn, C.; Otterson, J.C.; Wang, Y.; Ravipati, A.; Mazhar, M.; Denny, G.; et al. Epicutaneous Staphylococcus aureus induces IL-36 to enhance IgE production and ensuing allergic disease. J. Clin. Investig. 2021, 131, e143334.
  47. McKevitt, A.I.; Bjornson, G.L.; Mauracher, C.A.; Scheifele, D.W. Amino acid sequence of a deltalike toxin from Staphylococcus epidermidis. Infect. Immun. 1990, 58, 1473–1475.
  48. Kretschmer, D.; Gleske, A.K.; Rautenberg, M.; Wang, R.; Köberle, M.; Bohn, E.; Schöneberg, T.; Rabiet, M.J.; Boulay, F.; Klebanoff, S.J.; et al. Human formyl peptide receptor 2 senses highly pathogenic Staphylococcus aureus. Cell Host Microbe 2010, 7, 463–473.
  49. Rautenberg, M.; Joo, H.S.; Otto, M.; Peschel, A. Neutrophil responses to staphylococcal pathogens and commensals via the formyl peptide receptor 2 relates to phenol-soluble modulin release and virulence. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2011, 25, 1254–1263.
  50. Nakamura, Y.; Oscherwitz, J.; Cease, K.B.; Chan, S.M.; Muñoz-Planillo, R.; Hasegawa, M.; Villaruz, A.E.; Cheung, G.Y.; McGavin, M.J.; Travers, J.B.; et al. Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature 2013, 503, 397–401.
  51. Kapral, F.A. Staphylococcus aureus delta toxin as an enterotoxin. Ciba. Found. Symp. 1985, 112, 215–229.
  52. Ullah, A.; Khan, A.; Al-Harrasi, A.; Ullah, K.; Shabbir, A. Three-Dimensional Structure Characterization and Inhibition Study of Exfoliative Toxin D from Staphylococcus aureus. Front. Pharmacol. 2022, 13, 800970.
  53. Imanishi, I.; Nicolas, A.; Caetano, A.B.; Castro, T.L.P.; Tartaglia, N.R.; Mariutti, R.; Guédon, E.; Even, S.; Berkova, N.; Arni, R.K.; et al. Exfoliative toxin E, a new Staphylococcus aureus virulence factor with host-specific activity. Sci. Rep. 2019, 9, 16336.
  54. Stentzel, S.; Teufelberger, A.; Nordengrün, M.; Kolata, J.; Schmidt, F.; van Crombruggen, K.; Michalik, S.; Kumpfmüller, J.; Tischer, S.; Schweder, T.; et al. Staphylococcal serine protease-like proteins are pacemakers of allergic airway reactions to Staphylococcus aureus. J. Allergy Clin. Immunol. 2017, 139, 492–500.e8.
  55. Melish, M.E.; Glasgow, L.A. Staphylococcal scalded skin syndrome: The expanded clinical syndrome. J. Pediatr. 1971, 78, 958–967.
  56. Bukowski, M.; Wladyka, B.; Dubin, G. Exfoliative toxins of Staphylococcus aureus. Toxins 2010, 2, 1148–1165.
  57. Nishifuji, K.; Sugai, M.; Amagai, M. Staphylococcal exfoliative toxins: “molecular scissors” of bacteria that attack the cutaneous defense barrier in mammals. J. Dermatol. Sci. 2008, 49, 21–31.
  58. Amagai, M.; Yamaguchi, T.; Hanakawa, Y.; Nishifuji, K.; Sugai, M.; Stanley, J.R. Staphylococcal exfoliative toxin B specifically cleaves desmoglein 1. J. Investig. Dermatol. 2002, 118, 845–850.
  59. Oliveira, D.; Borges, A.; Simões, M. Staphylococcus aureus Toxins and Their Molecular Activity in Infectious Diseases. Toxins 2018, 10, 252.
  60. Nordengrün, M.; Abdurrahman, G.; Treffon, J.; Wächter, H.; Kahl, B.C.; Bröker, B.M. Allergic Reactions to Serine Protease-Like Proteins of Staphylococcus aureus. Front. Immunol. 2021, 12, 651060.
  61. Smagur, J.; Guzik, K.; Magiera, L.; Bzowska, M.; Gruca, M.; Thøgersen, I.B.; Enghild, J.J.; Potempa, J. A new pathway of staphylococcal pathogenesis: Apoptosis-like death induced by Staphopain B in human neutrophils and monocytes. J. Innate Immun. 2009, 1, 98–108.
  62. Kulig, P.; Zabel, B.A.; Dubin, G.; Allen, S.J.; Ohyama, T.; Potempa, J.; Handel, T.M.; Butcher, E.C.; Cichy, J. Staphylococcus aureus-derived staphopain B, a potent cysteine protease activator of plasma chemerin. J. Immunol. 2007, 178, 3713–3720.
  63. Bergdoll, M.S.; Crass, B.A.; Reiser, R.F.; Robbins, R.N.; Davis, J.P. A new staphylococcal enterotoxin, enterotoxin F, associated with toxic-shock-syndrome Staphylococcus aureus isolates. Lancet 1981, 1, 1017–1021.
  64. McCormick, J.K.; Yarwood, J.M.; Schlievert, P.M. Toxic shock syndrome and bacterial superantigens: An update. Annu Rev. Microbiol. 2001, 55, 77–104.
  65. Calus, L.; Derycke, L.; Dullaers, M.; Van Zele, T.; De Ruyck, N.; Pérez-Novo, C.; Holtappels, G.; De Vos, G.; Lambrecht, B.N.; Bachert, C.; et al. IL-21 Is Increased in Nasal Polyposis and after Stimulation with Staphylococcus aureus Enterotoxin B. Int. Arch. Allergy Immunol. 2017, 174, 161–169.
  66. Bauquet, A.T.; Jin, H.; Paterson, A.M.; Mitsdoerffer, M.; Ho, I.C.; Sharpe, A.H.; Kuchroo, V.K. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat. Immunol. 2009, 10, 167–175.
  67. Van Zele, T.; Gevaert, P.; Watelet, J.B.; Claeys, G.; Holtappels, G.; Claeys, C.; van Cauwenberge, P.; Bachert, C. Staphylococcus aureus colonization and IgE antibody formation to enterotoxins is increased in nasal polyposis. J. Allergy Clin. Immunol. 2004, 114, 981–983.
  68. Orfali, R.L.; da Silva Oliveira, L.M.; de Lima, J.F.; de Carvalho, G.C.; Ramos, Y.A.L.; Pereira, N.Z.; Pereira, N.V.; Zaniboni, M.C.; Sotto, M.N.; da Silva Duarte, A.J.; et al. Staphylococcus aureus enterotoxins modulate IL-22-secreting cells in adults with atopic dermatitis. Sci. Rep. 2018, 8, 6665.
  69. Hellings, P.W.; Hens, G.; Meyts, I.; Bullens, D.; Vanoirbeek, J.; Gevaert, P.; Jorissen, M.; Ceuppens, J.L.; Bachert, C. Aggravation of bronchial eosinophilia in mice by nasal and bronchial exposure to Staphylococcus aureus enterotoxin B. Clin. Exp. Allergy 2006, 36, 1063–1071.
  70. Liu, X.; Wen, Y.; Wang, D.; Zhao, Z.; Jeffry, J.; Zeng, L.; Zou, Z.; Chen, H.; Tao, A. Synergistic activation of Src, ERK and STAT pathways in PBMCs for Staphylococcal enterotoxin A induced production of cytokines and chemokines. Asian Pac. J. Allergy Immunol. 2020, 38, 52–63.
  71. Naik, S.; Smith, F.; Ho, J.; Croft, N.M.; Domizio, P.; Price, E.; Sanderson, I.R.; Meadows, N.J. Staphylococcal enterotoxins G and I, a cause of severe but reversible neonatal enteropathy. Clin. Gastroenterol. Hepatol. 2008, 6, 251–254.
  72. Liu, Y.; Chen, W.; Ali, T.; Alkasir, R.; Yin, J.; Liu, G.; Han, B. Staphylococcal enterotoxin H induced apoptosis of bovine mammary epithelial cells in vitro. Toxins 2014, 6, 3552–3567.
  73. Hou, F.; Peng, L.; Jiang, J.; Chen, T.; Xu, D.; Huang, Q.; Ye, C.; Peng, Y.; Hu, D.L.; Fang, R. ATP Facilitates Staphylococcal Enterotoxin O Induced Neutrophil IL-1β Secretion via NLRP3 Inflammasome Dependent Pathways. Front. Immunol. 2021, 12, 649235.
  74. Zhao, Y.; Tang, J.; Yang, D.; Tang, C.; Chen, J. Staphylococcal enterotoxin M induced inflammation and impairment of bovine mammary epithelial cells. J. Dairy Sci. 2020, 103, 8350–8359.
  75. Zhao, Y.; Zhu, A.; Tang, J.; Tang, C.; Chen, J. Identification and measurement of staphylococcal enterotoxin M from Staphylococcus aureus isolate associated with staphylococcal food poisoning. Lett. Appl. Microbiol. 2017, 65, 27–34.
  76. Hu, D.L.; Ono, H.K.; Isayama, S.; Okada, R.; Okamura, M.; Lei, L.C.; Liu, Z.S.; Zhang, X.C.; Liu, M.Y.; Cui, J.C.; et al. Biological characteristics of staphylococcal enterotoxin Q and its potential risk for food poisoning. J. Appl. Microbiol. 2017, 122, 1672–1679.
  77. Tian, X.; Huang, Q.; Liang, J.; Wang, J.; Zhang, J.; Yang, Y.; Ye, Q.; He, S.; Li, J.; Wu, Z.; et al. A review of the mechanisms of keratinocytes damage caused by Staphylococcus aureus infection in patients with atopic dermatitis. J. Leukoc. Biol. 2021, 110, 1163–1169.
  78. Cruciani, M.; Etna, M.P.; Camilli, R.; Giacomini, E.; Percario, Z.A.; Severa, M.; Sandini, S.; Rizzo, F.; Brandi, V.; Balsamo, G.; et al. Staphylococcus aureus Esx Factors Control Human Dendritic Cell Functions Conditioning Th1/Th17 Response. Front. Cell. Infect. Microbiol. 2017, 7, 330.
  79. Korea, C.G.; Balsamo, G.; Pezzicoli, A.; Merakou, C.; Tavarini, S.; Bagnoli, F.; Serruto, D.; Unnikrishnan, M. Staphylococcal Esx proteins modulate apoptosis and release of intracellular Staphylococcus aureus during infection in epithelial cells. Infect. Immun. 2014, 82, 4144–4153.
  80. Becker, K.; Heilmann, C.; Peters, G. Coagulase-negative staphylococci. Clin. Microbiol. Rev. 2014, 27, 870–926.
  81. Jin, T.; Zhu, Y.L.; Li, J.; Shi, J.; He, X.Q.; Ding, J.; Xu, Y.Q. Staphylococcal protein A, Panton-Valentine leukocidin and coagulase aggravate the bone loss and bone destruction in osteomyelitis. Cell Physiol. Biochem. 2013, 32, 322–333.
  82. Brinkmann, V.; Reichard, U.; Goosmann, C.; Fauler, B.; Uhlemann, Y.; Weiss, D.S.; Weinrauch, Y.; Zychlinsky, A. Neutrophil extracellular traps kill bacteria. Science 2004, 303, 1532–1535.
  83. Berends, E.T.; Horswill, A.R.; Haste, N.M.; Monestier, M.; Nizet, V.; von Köckritz-Blickwede, M. Nuclease expression by Staphylococcus aureus facilitates escape from neutrophil extracellular traps. J. Innate Immun. 2010, 2, 576–586.
  84. Thammavongsa, V.; Missiakas, D.M.; Schneewind, O. Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death. Science 2013, 342, 863–866.
  85. Winstel, V.; Schneewind, O.; Missiakas, D. Staphylococcus aureus Exploits the Host Apoptotic Pathway To Persist during Infection. mBio 2019, 10, e02270-19.
  86. Wang, H.; von Rohrscheidt, J.; Roehrbein, J.; Peters, T.; Sindrilaru, A.; Kess, D.; Preissner, K.T.; Scharffetter-Kochanek, K. Extracellular adherence protein of Staphylococcus aureus suppresses disease by inhibiting T-cell recruitment in a mouse model of psoriasis. J. Investig. Dermatol. 2010, 130, 743–754.
  87. Foster, T.J. The MSCRAMM Family of Cell-Wall-Anchored Surface Proteins of Gram-Positive Cocci. Trends Microbiol. 2019, 27, 927–941.
  88. Pazos, M.; Peters, K. Peptidoglycan. Subcell. Biochem. 2019, 92, 127–168.
  89. Foster, T.J. Surface Proteins of Staphylococcus aureus. Microbiol. Spectr. 2019, 7, 4.
  90. Rivas, J.M.; Speziale, P.; Patti, J.M.; Höök, M. MSCRAMM--targeted vaccines and immunotherapy for staphylococcal infection. Curr. Opin. Drug Discov. Dev. 2004, 7, 223–227.
  91. Fox, P.G.; Schiavetti, F.; Rappuoli, R.; McLoughlin, R.M.; Bagnoli, F. Staphylococcal Protein A Induces Leukocyte Necrosis by Complexing with Human Immunoglobulins. mBio 2021, 12, e00899-21.
  92. Das, T.; Sa, G.; Chattopadhyay, S.; Ray, P.K. Protein A-induced apoptosis of cancer cells is effected by soluble immune mediators. Cancer Immunol. Immunother. 2002, 51, 376–380.
  93. Sawada, M.; Nakashima, S.; Banno, Y.; Yamakawa, H.; Takenaka, K.; Shinoda, J.; Nishimura, Y.; Sakai, N.; Nozawa, Y. Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells. Oncogene 2000, 19, 3508–3520.
  94. Claro, T.; Widaa, A.; McDonnell, C.; Foster, T.J.; O’Brien, F.J.; Kerrigan, S.W. Staphylococcus aureus protein A binding to osteoblast tumour necrosis factor receptor 1 results in activation of nuclear factor kappa B and release of interleukin-6 in bone infection. Microbiology 2013, 159, 147–154.
  95. Claro, T.; Widaa, A.; O’Seaghdha, M.; Miajlovic, H.; Foster, T.J.; O’Brien, F.J.; Kerrigan, S.W. Staphylococcus aureus protein A binds to osteoblasts and triggers signals that weaken bone in osteomyelitis. PLoS ONE 2011, 6, e18748.
  96. Al Kindi, A.; Williams, H.; Matsuda, K.; Alkahtani, A.M.; Saville, C.; Bennett, H.; Alshammari, Y.; Tan, S.Y.; O’Neill, C.; Tanaka, A.; et al. Staphylococcus aureus second immunoglobulin-binding protein drives atopic dermatitis via IL-33. J. Allergy Clin. Immunol. 2021, 147, 1354–1368.e3.
  97. Garcovich, S.; Maurelli, M.; Gisondi, P.; Peris, K.; Yosipovitch, G.; Girolomoni, G. Pruritus as a Distinctive Feature of Type 2 Inflammation. Vaccines 2021, 9, 303.
  98. Imai, Y. Interleukin-33 in atopic dermatitis. J. Dermatol. Sci. 2019, 96, 2–7.
  99. Takeda, K.; Takeuchi, O.; Akira, S. Recognition of lipopeptides by Toll-like receptors. J. Endotoxin. Res. 2002, 8, 459–463.
  100. Stoll, H.; Dengjel, J.; Nerz, C.; Götz, F. Staphylococcus aureus deficient in lipidation of prelipoproteins is attenuated in growth and immune activation. Infect. Immun. 2005, 73, 2411–2423.
  101. Takeuchi, O.; Kawai, T.; Mühlradt, P.F.; Morr, M.; Radolf, J.D.; Zychlinsky, A.; Takeda, K.; Akira, S. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 2001, 13, 933–940.
  102. Hara, H.; Seregin, S.S.; Yang, D.; Fukase, K.; Chamaillard, M.; Alnemri, E.S.; Inohara, N.; Chen, G.Y.; Núñez, G. The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection. Cell 2018, 175, 1651–1664.e14.
  103. Hattar, K.; Grandel, U.; Moeller, A.; Fink, L.; Iglhaut, J.; Hartung, T.; Morath, S.; Seeger, W.; Grimminger, F.; Sibelius, U. Lipoteichoic acid (LTA) from Staphylococcus aureus stimulates human neutrophil cytokine release by a CD14-dependent, Toll-like-receptor-independent mechanism: Autocrine role of tumor necrosis factor- in mediating LTA-induced interleukin-8 generation. Crit. Care Med. 2006, 34, 835–841.
  104. Brauweiler, A.M.; Goleva, E.; Leung, D.Y.M. Staphylococcus aureus Lipoteichoic Acid Initiates a TSLP-Basophil-IL4 Axis in the Skin. J. Investig. Dermatol. 2020, 140, 915–917.e2.
  105. Misawa, Y.; Kelley, K.A.; Wang, X.; Wang, L.; Park, W.B.; Birtel, J.; Saslowsky, D.; Lee, J.C. Staphylococcus aureus Colonization of the Mouse Gastrointestinal Tract Is Modulated by Wall Teichoic Acid, Capsule, and Surface Proteins. PLoS Pathog. 2015, 11, e1005061.
  106. Pasquina-Lemonche, L.; Burns, J.; Turner, R.D.; Kumar, S.; Tank, R.; Mullin, N.; Wilson, J.S.; Chakrabarti, B.; Bullough, P.A.; Foster, S.J.; et al. The architecture of the Gram-positive bacterial cell wall. Nature 2020, 582, 294–297.
  107. Covas, G.; Vaz, F.; Henriques, G.; Pinho, M.G.; Filipe, S.R. Analysis of Cell Wall Teichoic Acids in Staphylococcus aureus. Methods Mol. Biol. 2016, 1440, 201–213.
  108. Arroyo, D.S.; Soria, J.A.; Gaviglio, E.A.; Garcia-Keller, C.; Cancela, L.M.; Rodriguez-Galan, M.C.; Wang, J.M.; Iribarren, P. Toll-like receptor 2 ligands promote microglial cell death by inducing autophagy. FASEB J. 2013, 27, 299–312.
  109. Matsui, K.; Tofukuji, S.; Ikeda, R. CCL17 production by mouse langerhans cells stimulated with Staphylococcus aureus cell wall components. Biol. Pharm. Bull. 2015, 38, 317–320.
  110. Matsui, K.; Wirotesangthong, M.; Nishikawa, A. Peptidoglycan from Staphylococcus aureus induces IL-4 production from murine spleen cells via an IL-18-dependent mechanism. Int. Arch. Allergy Immunol. 2008, 146, 262–266.
  111. Supajatura, V.; Ushio, H.; Nakao, A.; Akira, S.; Okumura, K.; Ra, C.; Ogawa, H. Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity. J. Clin. Investig. 2002, 109, 1351–1359.
  112. Biggs, T.C.; Abadalkareem, R.S.; Hayes, S.M.; Holding, R.E.; Lau, L.C.; Harries, P.G.; Allan, R.N.; Pender, S.L.F.; Walls, A.F.; Salib, R.J. Staphylococcus aureus internalisation enhances bacterial survival through modulation of host immune responses and mast cell activation. Allergy 2021, 76, 1893–1896.
  113. Lin, H.Y.; Tang, C.H.; Chen, J.H.; Chuang, J.Y.; Huang, S.M.; Tan, T.W.; Lai, C.H.; Lu, D.Y. Peptidoglycan induces interleukin-6 expression through the TLR2 receptor, JNK, c-Jun, and AP-1 pathways in microglia. J. Cell. Physiol. 2011, 226, 1573–1582.
  114. Hsu, M.J.; Chang, C.K.; Chen, M.C.; Chen, B.C.; Ma, H.P.; Hong, C.Y.; Lin, C.H. Apoptosis signal-regulating kinase 1 in peptidoglycan-induced COX-2 expression in macrophages. J. Leukoc. Biol. 2010, 87, 1069–1082.
  115. Wang, D.; Xiao, P.L.; Duan, H.X.; Zhou, M.; Liu, J.; Li, W.; Luo, K.L.; Chen, J.J.; Hu, J.Y. Peptidoglycans promotes human leukemic THP-1 cell apoptosis and differentiation. Asian Pac. J. Cancer Prev. 2012, 13, 6409–6413.
  116. Namazi, M.R. Paradoxical exacerbation of psoriasis in AIDS: Proposed explanations including the potential roles of substance P and gram-negative bacteria. Autoimmunity 2004, 37, 67–71.
  117. Ruíz-González, V.; Cancino-Diaz, J.C.; Rodríguez-Martínez, S.; Cancino-Diaz, M.E. Keratinocytes treated with peptidoglycan from Staphylococcus aureus produce vascular endothelial growth factor, and its expression is amplified by the subsequent production of interleukin-13. Int. J. Dermatol. 2009, 48, 846–854.
  118. Wu, H.M.; Wang, J.; Zhang, B.; Fang, L.; Xu, K.; Liu, R.Y. CpG-ODN promotes phagocytosis and autophagy through JNK/P38 signal pathway in Staphylococcus aureus-stimulated macrophage. Life Sci. 2016, 161, 51–59.
  119. Müller, S.; Wolf, A.J.; Iliev, I.D.; Berg, B.L.; Underhill, D.M.; Liu, G.Y. Poorly Cross-Linked Peptidoglycan in MRSA Due to mecA Induction Activates the Inflammasome and Exacerbates Immunopathology. Cell Host Microbe 2015, 18, 604–612.
  120. Zhu, F.; Zhou, Y.; Jiang, C.; Zhang, X. Role of JAK-STAT signaling in maturation of phagosomes containing Staphylococcus aureus. Sci. Rep. 2015, 5, 14854.
  121. Shi, M.; Willing, S.E.; Kim, H.K.; Schneewind, O.; Missiakas, D. Peptidoglycan Contribution to the B Cell Superantigen Activity of Staphylococcal Protein A. mBio 2021, 12, e00039-21.
  122. Moriwaki, M.; Iwamoto, K.; Niitsu, Y.; Matsushima, A.; Yanase, Y.; Hisatsune, J.; Sugai, M.; Hide, M. Staphylococcus aureus from atopic dermatitis skin accumulates in the lysosomes of keratinocytes with induction of IL-1α secretion via TLR9. Allergy 2019, 74, 560–571.
  123. Wang, G.; Sweren, E.; Liu, H.; Wier, E.; Alphonse, M.P.; Chen, R.; Islam, N.; Li, A.; Xue, Y.; Chen, J.; et al. Bacteria induce skin regeneration via IL-1β signaling. Cell Host Microbe 2021, 29, 777–791.e6.
  124. Cayrol, C.; Girard, J.P. Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family. Immunol. Rev. 2018, 281, 154–168.
  125. Liu, B.; Tai, Y.; Achanta, S.; Kaelberer, M.M.; Caceres, A.I.; Shao, X.; Fang, J.; Jordt, S.E. IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy. Proc. Natl. Acad. Sci. USA 2016, 113, E7572–E7579.
  126. Vu, A.T.; Baba, T.; Chen, X.; Le, T.A.; Kinoshita, H.; Xie, Y.; Kamijo, S.; Hiramatsu, K.; Ikeda, S.; Ogawa, H.; et al. Staphylococcus aureus membrane and diacylated lipopeptide induce thymic stromal lymphopoietin in keratinocytes through the Toll-like receptor 2-Toll-like receptor 6 pathway. J. Allergy Clin. Immunol. 2010, 126, 985–993.e3.
  127. Wilson, S.R.; Thé, L.; Batia, L.M.; Beattie, K.; Katibah, G.E.; McClain, S.P.; Pellegrino, M.; Estandian, D.M.; Bautista, D.M. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 2013, 155, 285–295.
  128. Son, E.D.; Kim, H.J.; Park, T.; Shin, K.; Bae, I.H.; Lim, K.M.; Cho, E.G.; Lee, T.R. Staphylococcus aureus inhibits terminal differentiation of normal human keratinocytes by stimulating interleukin-6 secretion. J. Dermatol. Sci. 2014, 74, 64–71.
  129. Williams, M.R.; Nakatsuji, T.; Sanford, J.A.; Vrbanac, A.F.; Gallo, R.L. Staphylococcus aureus Induces Increased Serine Protease Activity in Keratinocytes. J. Investig. Dermatol. 2017, 137, 377–384.
  130. Lan, F.; Zhang, N.; Holtappels, G.; De Ruyck, N.; Krysko, O.; Van Crombruggen, K.; Braun, H.; Johnston, S.L.; Papadopoulos, N.G.; Zhang, L.; et al. Staphylococcus aureus Induces a Mucosal Type 2 Immune Response via Epithelial Cell-derived Cytokines. Am. J. Respir. Crit Care Med. 2018, 198, 452–463.
  131. Hardman, C.S.; Chen, Y.L.; Salimi, M.; Nahler, J.; Corridoni, D.; Jagielowicz, M.; Fonseka, C.L.; Johnson, D.; Repapi, E.; Cousins, D.J.; et al. IL-6 effector function of group 2 innate lymphoid cells (ILC2) is NOD2 dependent. Sci. Immunol. 2021, 6, eabe5084.
  132. Romagnani, S. T-cell subsets (Th1 versus Th2). Ann. Allergy Asthma Immunol. 2000, 85, 9–18; quiz 18, 21.
  133. Pérez Novo, C.A.; Jedrzejczak-Czechowicz, M.; Lewandowska-Polak, A.; Claeys, C.; Holtappels, G.; Van Cauwenberge, P.; Kowalski, M.L.; Bachert, C. T cell inflammatory response, Foxp3 and TNFRS18-L regulation of peripheral blood mononuclear cells from patients with nasal polyps-asthma after staphylococcal superantigen stimulation. Clin. Exp. Allergy 2010, 40, 1323–1332.
  134. Orciani, M.; Campanati, A.; Caffarini, M.; Ganzetti, G.; Consales, V.; Lucarini, G.; Offidani, A.; Di Primio, R. T helper (Th)1, Th17 and Th2 imbalance in mesenchymal stem cells of adult patients with atopic dermatitis: At the origin of the problem. Br. J. Dermatol. 2017, 176, 1569–1576.
  135. Tada, Y.; Asahina, A.; Takekoshi, T.; Kishimoto, E.; Mitsui, H.; Saeki, H.; Komine, M.; Tamaki, K. Interleukin 12 production by monocytes from patients with psoriasis and its inhibition by ciclosporin A. Br. J. Dermatol. 2006, 154, 1180–1183.
  136. Stetson, D.B.; Voehringer, D.; Grogan, J.L.; Xu, M.; Reinhardt, R.L.; Scheu, S.; Kelly, B.L.; Locksley, R.M. Th2 cells: Orchestrating barrier immunity. Adv. Immunol. 2004, 83, 163–189.
  137. Kamijo, H.; Miyagaki, T.; Hayashi, Y.; Akatsuka, T.; Watanabe-Otobe, S.; Oka, T.; Shishido-Takahashi, N.; Suga, H.; Sugaya, M.; Sato, S. Increased IL-26 Expression Promotes T Helper Type 17- and T Helper Type 2-Associated Cytokine Production by Keratinocytes in Atopic Dermatitis. J. Investig. Dermatol. 2020, 140, 636–644.e2.
  138. Chang, H.W.; Yan, D.; Singh, R.; Liu, J.; Lu, X.; Ucmak, D.; Lee, K.; Afifi, L.; Fadrosh, D.; Leech, J.; et al. Alteration of the cutaneous microbiome in psoriasis and potential role in Th17 polarization. Microbiome 2018, 6, 154.
  139. Brauweiler, A.M.; Goleva, E.; Leung, D.Y.M. Th2 cytokines increase Staphylococcus aureus alpha toxin-induced keratinocyte death through the signal transducer and activator of transcription 6 (STAT6). J. Investig. Dermatol. 2014, 134, 2114–2121.
  140. Ou, L.S.; Goleva, E.; Hall, C.; Leung, D.Y. T regulatory cells in atopic dermatitis and subversion of their activity by superantigens. J. Allergy Clin. Immunol. 2004, 113, 756–763.
  141. Laouini, D.; Kawamoto, S.; Yalcindag, A.; Bryce, P.; Mizoguchi, E.; Oettgen, H.; Geha, R.S. Epicutaneous sensitization with superantigen induces allergic skin inflammation. J. Allergy Clin. Immunol. 2003, 112, 981–987.
  142. Jacobsen, E.A.; Ochkur, S.I.; Lee, N.A.; Lee, J.J. Eosinophils and asthma. Curr. Allergy Asthma Rep. 2007, 7, 18–26.
  143. Fujieda, S.; Imoto, Y.; Kato, Y.; Ninomiya, T.; Tokunaga, T.; Tsutsumiuchi, T.; Yoshida, K.; Kidoguchi, M.; Takabayashi, T. Eosinophilic chronic rhinosinusitis. Allergol. Int. 2019, 68, 403–412.
  144. Warner, J.A.; McGirt, L.Y.; Beck, L.A. Biomarkers of Th2 polarity are predictive of staphylococcal colonization in subjects with atopic dermatitis. Br. J. Dermatol. 2009, 160, 183–185.
  145. Dubin, C.; Del Duca, E.; Guttman-Yassky, E. The IL-4, IL-13 and IL-31 pathways in atopic dermatitis. Expert Rev. Clin. Immunol. 2021, 17, 835–852.
  146. Iwaszko, M.; Biały, S.; Bogunia-Kubik, K. Significance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis. Cells 2021, 10, 3000.
  147. Kimura, A.; Kishimoto, T. Th17 cells in inflammation. Int. Immunopharmacol 2011, 11, 319–322.
  148. Tokura, Y. Th17 cells and skin diseases. Nihon Rinsho Meneki Gakkai Kaishi 2012, 35, 388–392.
  149. Koga, C.; Kabashima, K.; Shiraishi, N.; Kobayashi, M.; Tokura, Y. Possible pathogenic role of Th17 cells for atopic dermatitis. J. Investig. Dermatol. 2008, 128, 2625–2630.
  150. Orfali, R.L.; Yoshikawa, F.S.Y.; Oliveira, L.; Pereira, N.Z.; de Lima, J.F.; Ramos YÁ, L.; Duarte, A.; Sato, M.N.; Aoki, V. Staphylococcal enterotoxins modulate the effector CD4(+) T cell response by reshaping the gene expression profile in adults with atopic dermatitis. Sci. Rep. 2019, 9, 13082.
  151. Sugaya, M. The Role of Th17-Related Cytokines in Atopic Dermatitis. Int. J. Mol. Sci. 2020, 21, 1314.
  152. Liu, H.; Archer, N.K.; Dillen, C.A.; Wang, Y.; Ashbaugh, A.G.; Ortines, R.V.; Kao, T.; Lee, S.K.; Cai, S.S.; Miller, R.J.; et al. Staphylococcus aureus Epicutaneous Exposure Drives Skin Inflammation via IL-36-Mediated T Cell Responses. Cell Host Microbe 2017, 22, 653–666.e5.
  153. Dey, I.; Bishayi, B. Role of Th17 and Treg cells in septic arthritis and the impact of the Th17/Treg-derived cytokines in the pathogenesis of S. aureus induced septic arthritis in mice. Microb. Pathog. 2017, 113, 248–264.
  154. Dey, I.; Bishayi, B. Role of different Th17 and Treg downstream signalling pathways in the pathogenesis of Staphylococcus aureus infection induced septic arthritis in mice. Exp. Mol. Pathol. 2020, 116, 104485.
  155. Lee, G.R. The Balance of Th17 versus Treg Cells in Autoimmunity. Int. J. Mol. Sci. 2018, 19, 730.
  156. Sultana, S.; Dey, R.; Bishayi, B. Dual neutralization of TNFR-2 and MMP-2 regulates the severity of induced septic arthritis correlating alteration in the level of interferon gamma and interleukin-10 in terms of TNFR2 blocking. Immunol. Res. 2018, 66, 97–119.
  157. Ghosh, R.; Dey, R.; Sawoo, R.; Bishayi, B. Neutralization of IL-17 and treatment with IL-2 protects septic arthritis by regulating free radical production and antioxidant enzymes in Th17 and Tregs: An immunomodulatory TLR2 versus TNFR response. Cell Immunol. 2021, 370, 104441.
  158. Saito, S.; Quadery, A.F. Staphylococcus aureus Lipoprotein Induces Skin Inflammation, Accompanied with IFN-γ-Producing T Cell Accumulation through Dermal Dendritic Cells. Pathogens 2018, 7, 64.
  159. Taylor, A.L.; Llewelyn, M.J. Superantigen-induced proliferation of human CD4+CD25-T cells is followed by a switch to a functional regulatory phenotype. J. Immunol. 2010, 185, 6591–6598.
  160. Seneschal, J.; Clark, R.A.; Gehad, A.; Baecher-Allan, C.M.; Kupper, T.S. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 2012, 36, 873–884.
  161. van Dalen, R.; De La Cruz Diaz, J.S.; Rumpret, M.; Fuchsberger, F.F.; van Teijlingen, N.H.; Hanske, J.; Rademacher, C.; Geijtenbeek, T.B.H.; van Strijp, J.A.G.; Weidenmaier, C.; et al. Langerhans Cells Sense Staphylococcus aureus Wall Teichoic Acid through Langerin To Induce Inflammatory Responses. mBio 2019, 10, e00330-19.
  162. Ma, L.; Xue, H.B.; Guan, X.H.; Shu, C.M.; Wang, F.; Zhang, J.H.; An, R.Z. The Imbalance of Th17 cells and CD4(+) CD25(high) Foxp3(+) Treg cells in patients with atopic dermatitis. J. Eur. Acad. Dermatol. Venereol. 2014, 28, 1079–1086.
  163. Crotty, S. T follicular helper cell differentiation, function, and roles in disease. Immunity 2014, 41, 529–542.
  164. Moser, B. CXCR5, the Defining Marker for Follicular B Helper T (TFH) Cells. Front. Immunol. 2015, 6, 296.
  165. Bossaller, L.; Burger, J.; Draeger, R.; Grimbacher, B.; Knoth, R.; Plebani, A.; Durandy, A.; Baumann, U.; Schlesier, M.; Welcher, A.A.; et al. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J. Immunol. 2006, 177, 4927–4932.
  166. Bennett, F.; Luxenberg, D.; Ling, V.; Wang, I.M.; Marquette, K.; Lowe, D.; Khan, N.; Veldman, G.; Jacobs, K.A.; Valge-Archer, V.E.; et al. Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: Attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses. J. Immunol. 2003, 170, 711–718.
  167. Sage, P.T.; Paterson, A.M.; Lovitch, S.B.; Sharpe, A.H. The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity 2014, 41, 1026–1039.
  168. Johnston, R.J.; Poholek, A.C.; DiToro, D.; Yusuf, I.; Eto, D.; Barnett, B.; Dent, A.L.; Craft, J.; Crotty, S. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 2009, 325, 1006–1010.
  169. Dupont, C.D.; Scully, I.L.; Zimnisky, R.M.; Monian, B.; Rossitto, C.P.; O’Connell, E.B.; Jansen, K.U.; Anderson, A.S.; Love, J.C. Two Vaccines for Staphylococcus aureus Induce a B-Cell-Mediated Immune Response. mSphere 2018, 3, e00217-18.
  170. Chang, H.C.; Sehra, S.; Goswami, R.; Yao, W.; Yu, Q.; Stritesky, G.L.; Jabeen, R.; McKinley, C.; Ahyi, A.N.; Han, L.; et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat. Immunol. 2010, 11, 527–534.
  171. Soussi-Gounni, A.; Kontolemos, M.; Hamid, Q. Role of IL-9 in the pathophysiology of allergic diseases. J. Allergy Clin. Immunol. 2001, 107, 575–582.
  172. Jäger, A.; Dardalhon, V.; Sobel, R.A.; Bettelli, E.; Kuchroo, V.K. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J. Immunol. 2009, 183, 7169–7177.
  173. Purwar, R.; Schlapbach, C.; Xiao, S.; Kang, H.S.; Elyaman, W.; Jiang, X.; Jetten, A.M.; Khoury, S.J.; Fuhlbrigge, R.C.; Kuchroo, V.K.; et al. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat. Med. 2012, 18, 1248–1253.
  174. Vivier, E.; Artis, D.; Colonna, M.; Diefenbach, A.; Di Santo, J.P.; Eberl, G.; Koyasu, S.; Locksley, R.M.; McKenzie, A.N.J.; Mebius, R.E.; et al. Innate Lymphoid Cells: 10 Years On. Cell 2018, 174, 1054–1066.
  175. Ghaedi, M.; Takei, F. Innate lymphoid cell development. J. Allergy Clin. Immunol. 2021, 147, 1549–1560.
  176. Annunziato, F.; Romagnani, C.; Romagnani, S. The 3 major types of innate and adaptive cell-mediated effector immunity. J. Allergy Clin. Immunol. 2015, 135, 626–635.
  177. Gentek, R.; Molawi, K.; Sieweke, M.H. Tissue macrophage identity and self-renewal. Immunol. Rev. 2014, 262, 56–73.
  178. Pidwill, G.R.; Gibson, J.F.; Cole, J.; Renshaw, S.A.; Foster, S.J. The Role of Macrophages in Staphylococcus aureus Infection. Front. Immunol. 2020, 11, 620339.
  179. Thurlow, L.R.; Hanke, M.L.; Fritz, T.; Angle, A.; Aldrich, A.; Williams, S.H.; Engebretsen, I.L.; Bayles, K.W.; Horswill, A.R.; Kielian, T. Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo. J. Immunol. 2011, 186, 6585–6596.
  180. Wang, X.; Eagen, W.J.; Lee, J.C. Orchestration of human macrophage NLRP3 inflammasome activation by Staphylococcus aureus extracellular vesicles. Proc. Natl. Acad. Sci. USA 2020, 117, 3174–3184.
  181. Flannagan, R.S.; Heinrichs, D.E. Macrophage-driven nutrient delivery to phagosomal Staphylococcus aureus supports bacterial growth. EMBO Rep. 2020, 21, e50348.
  182. Grayczyk, J.P.; Alonzo, F., 3rd. Staphylococcus aureus Lipoic Acid Synthesis Limits Macrophage Reactive Oxygen and Nitrogen Species Production To Promote Survival during Infection. Infect. Immun. 2019, 87, e00344-19.
  183. Tatsuno, K.; Fujiyama, T.; Yamaguchi, H.; Waki, M.; Tokura, Y. TSLP Directly Interacts with Skin-Homing Th2 Cells Highly Expressing its Receptor to Enhance IL-4 Production in Atopic Dermatitis. J. Investig. Dermatol. 2015, 135, 3017–3024.
  184. Iwamoto, K.; Nümm, T.J.; Koch, S.; Herrmann, N.; Leib, N.; Bieber, T. Langerhans and inflammatory dendritic epidermal cells in atopic dermatitis are tolerized toward TLR2 activation. Allergy 2018, 73, 2205–2213.
  185. Asahina, A.; Tamaki, K. Role of Langerhans cells in cutaneous protective immunity: Is the reappraisal necessary? J. Dermatol. Sci. 2006, 44, 1–9.
  186. Berends, E.T.M.; Zheng, X.; Zwack, E.E.; Ménager, M.M.; Cammer, M.; Shopsin, B.; Torres, V.J. Staphylococcus aureus Impairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin. mBio 2019, 10, e01918-18.
  187. Matsui, K.; Kanai, S.; Ikuta, M.; Horikawa, S. Mast Cells Stimulated with Peptidoglycan from Staphylococcus aureus Augment the Development of Th1 Cells. J. Pharm. Pharm. Sci. 2018, 21, 296–304.
  188. Hayes, S.M.; Biggs, T.C.; Goldie, S.P.; Harries, P.G.; Walls, A.F.; Allan, R.N.; Pender, S.L.F.; Salib, R.J. Staphylococcus aureus internalization in mast cells in nasal polyps: Characterization of interactions and potential mechanisms. J. Allergy Clin. Immunol. 2020, 145, 147–159.
  189. McFadden, J.P.; Noble, W.C.; Camp, R.D. Superantigenic exotoxin-secreting potential of staphylococci isolated from atopic eczematous skin. Br. J. Dermatol. 1993, 128, 631–632.
  190. Geoghegan, J.A.; Irvine, A.D.; Foster, T.J. Staphylococcus aureus and Atopic Dermatitis: A Complex and Evolving Relationship. Trends Microbiol. 2018, 26, 484–497.
  191. Bachert, C.; Humbert, M.; Hanania, N.A.; Zhang, N.; Holgate, S.; Buhl, R.; Bröker, B.M. Staphylococcus aureus and its IgE-inducing enterotoxins in asthma: Current knowledge. Eur. Respir. J. 2020, 55, 1901592.
  192. Liu, C.; Yang, L.; Han, Y.; Ouyang, W.; Yin, W.; Xu, F. Mast cells participate in regulation of lung-gut axis during Staphylococcus aureus pneumonia. Cell Prolif. 2019, 52, e12565.
  193. Lehman, H.K.; Segal, B.H. The role of neutrophils in host defense and disease. J. Allergy Clin. Immunol. 2020, 145, 1535–1544.
  194. Gough, P.; Ganesan, S.; Datta, S.K. IL-20 Signaling in Activated Human Neutrophils Inhibits Neutrophil Migration and Function. J. Immunol. 2017, 198, 4373–4382.
  195. Marchitto, M.C.; Dillen, C.A.; Liu, H.; Miller, R.J.; Archer, N.K.; Ortines, R.V.; Alphonse, M.P.; Marusina, A.I.; Merleev, A.A.; Wang, Y.; et al. Clonal Vγ6(+)Vδ4(+) T cells promote IL-17-mediated immunity against Staphylococcus aureus skin infection. Proc. Natl. Acad. Sci. USA 2019, 116, 10917–10926.
  196. Cho, J.S.; Guo, Y.; Ramos, R.I.; Hebroni, F.; Plaisier, S.B.; Xuan, C.; Granick, J.L.; Matsushima, H.; Takashima, A.; Iwakura, Y.; et al. Neutrophil-derived IL-1β is sufficient for abscess formation in immunity against Staphylococcus aureus in mice. PLoS Pathog. 2012, 8, e1003047.
  197. Lutalo, P.M.; D’Cruz, D.P. Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener’s granulomatosis). J. Autoimmun. 2014, 48–49, 94–98.
  198. Ravin, K.A.; Loy, M. The Eosinophil in Infection. Clin. Rev. Allergy Immunol. 2016, 50, 214–227.
  199. Gangwar, R.S.; Levi-Schaffer, F. sCD48 is anti-inflammatory in Staphylococcus aureus Enterotoxin B-induced eosinophilic inflammation. Allergy 2016, 71, 829–839.
  200. Prince, L.R.; Graham, K.J.; Connolly, J.; Anwar, S.; Ridley, R.; Sabroe, I.; Foster, S.J.; Whyte, M.K. Staphylococcus aureus induces eosinophil cell death mediated by α-hemolysin. PLoS ONE 2012, 7, e31506.
  201. Gevaert, E.; Zhang, N.; Krysko, O.; Lan, F.; Holtappels, G.; De Ruyck, N.; Nauwynck, H.; Yousefi, S.; Simon, H.U.; Bachert, C. Extracellular eosinophilic traps in association with Staphylococcus aureus at the site of epithelial barrier defects in patients with severe airway inflammation. J. Allergy Clin. Immunol. 2017, 139, 1849–1860.e6.
  202. Kay, A.B. TH2-type cytokines in asthma. Ann. N. Y. Acad. Sci. 1996, 796, 1–8.
  203. Holgate, S.T. Innate and adaptive immune responses in asthma. Nat. Med. 2012, 18, 673–683.
  204. Le, K.Y.; Otto, M. Quorum-sensing regulation in staphylococci-an overview. Front. Microbiol. 2015, 6, 1174.
  205. Jiao, D.; Wong, C.K.; Qiu, H.N.; Dong, J.; Cai, Z.; Chu, M.; Hon, K.L.; Tsang, M.S.; Lam, C.W. NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation. Cell Mol. Immunol. 2016, 13, 535–550.
  206. Leyva-Castillo, J.M.; Das, M.; Kane, J.; Strakosha, M.; Singh, S.; Wong, D.S.H.; Horswill, A.R.; Karasuyama, H.; Brombacher, F.; Miller, L.S.; et al. Basophil-derived IL-4 promotes cutaneous Staphylococcus aureus infection. JCI Insight 2021, 6, e149953.
  207. Zhang, X.; Hu, X.; Rao, X. Apoptosis induced by Staphylococcus aureus toxins. Microbiol. Res. 2017, 205, 19–24.
  208. Kang, S.S.; Kim, S.K.; Baik, J.E.; Ko, E.B.; Ahn, K.B.; Yun, C.H.; Han, S.H. Staphylococcal LTA antagonizes the B cell-mitogenic potential of LPS. Sci. Rep. 2018, 8, 1496.
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