Virulence Factors and Pathogenicity of Staphylococcus aureus

Abstract

This chapter will explore the virulence factors and pathogenicity mechanisms of Staphylococcus aureus, a major human pathogen responsible for a wide range of infections. It will provide a detailed analysis of the key virulence factors, including surface proteins like adhesins and Protein A, various exotoxins such as alpha-toxin and Panton-Valentine leukocidin (PVL), and important enzymes like coagulase and hyaluronidase. The chapter will also examine how these factors contribute to immune evasion, tissue damage, and the formation of biofilms, leading to chronic and healthcare-associated infections. By understanding these mechanisms, we can better combat S. aureus infections and reduce their significant global health impact.

1. Introduction

Staphylococcus aureus is an important bacterial pathogen that affects humans and causes a variety of clinical manifestations [1]. It is the world’s most significant opportunistic human pathogen, known for its ability to bypass the immune system and cause various infections [2]. Commonly found in the human microbiota, S. aureus colonizes various sites within the human body, particularly in the nasal area, but also including the skin, throat, and gastrointestinal tract [3].

While it typically does not cause infections, S. aureus can lead to severe infections if it penetrates the skin and enters the bloodstream or internal tissues [4]. S. aureus infections range from mild skin and tissue infections to life-threatening conditions such as endocarditis, chronic osteomyelitis, pneumonia, and bacteremia, all of which are associated with serious morbidity and high mortality [5]. Many of these infections are iatrogenic, often linked to the colonization of indwelling medical devices [6]. The body’s inflammatory response, triggered by macrophages and cytokines, summons neutrophils to the site of infection following bacterial invasion [7]. The primary method of managing S. aureus infections is through the defense mechanisms of the human body, primarily phagocytosis by specialized phagocytes like macrophages and neutrophils [8]. However, S. aureus has developed several strategies to evade the immune response [8]. To survive and adapt to various environmental niches, S. aureus has evolved a complex regulatory network for controlling virulence factor production in a temporal and host-specific manner [9]. These virulent factors enable the organism to evade host defenses, bind to cells and tissue matrices, disseminate within hosts, and degrade tissues and cells for survival and nourishment [10]. The molecular pathogenesis of staphylococcal infections involves a myriad of mechanisms and factors that underscore the bacterium’s adaptability and virulence [11].

2. Staphylococcus aureus virulent factors and pathogenicity

2.1 The ability to adhere to host cells and resist physical removal

2.1.1 Collagen adhesin protein (Cna) is encoded by the cna gene

Collagen adhesin protein is a crucial virulence factor in S. aureus [12]. A critical step in initiating and persisting in multiple bacterial infections is the bacterial adhesion to collagen, the most abundant protein in humans [12]. This adhesion is vital for S. aureus to establish infections, particularly in collagen-rich tissues such as joints, bones, and heart valves, leading to conditions like osteomyelitis, septic arthritis, and endocarditis [13]. The cna gene, which encodes collagen adhesin, belongs to the microbial surface components recognizing adhesive matrix molecules (MSCRAMM) family and is not present in every strain of S. aureus [14]. The encoded protein comprises an N-terminal signaling peptide, a non-repetitive (A region), multiple repeated units (B region), a cell wall anchor region, a transmembrane section, and a small, positively charged cytoplasmic tail [12]. The A region of Cna is entirely responsible for its collagen-binding activity, making it a key factor in the pathogen’s ability to adhere to and invade host tissues [13]. This binding facilitates the colonization and subsequent infection of the host, contributing to the bacterium’s ability to evade the immune system and persist within the host [8]. The presence of Cna enhances the pathogenicity of S. aureus by enabling it to anchor to host tissues, resist phagocytosis, and form biofilms [15]. Biofilms provide a protective environment for the bacteria, increasing their resistance to antibiotics and the host immune response [15]. By integrating these mechanisms, S. aureus can cause chronic and recurrent infections, highlighting the importance of Cna as a virulence factor [12]. Understanding the role of collagen adhesin protein in S. aureus pathogenicity is essential for developing targeted therapies to prevent and treat infections caused by this formidable pathogen.

2.1.2 Clumping factors encoded by the clfA and clfB genes

These genes are part of the microbial surface components recognizing the adhesive matrix molecules (MSCRAMM) family [16]. Clumping factor proteins A (ClfA) and B (ClfB) facilitate the pathogen’s adhesion to host tissues by binding to the blood plasma protein fibrinogen (Fg), with ClfA targeting the γ-chain and ClfB the α-chain [16]. This differential binding enhances S. aureus’ ability to form clumps, resist immune clearance, and establish infections [17]. ClfA, in particular, plays a crucial role in S. aureus-induced platelet aggregation, contributing to the pathogen’s ability to cause severe bloodstream infections [2]. The clfA and clfB genes are distinct, non-allelic, and not closely linked, unlike other MSCRAMM-encoding genes such as fnbA and fnbB [18]. These clumping factors promote bacterial aggregation, biofilm formation, and resistance to both immune defenses and antibiotics, significantly enhancing S. aureus pathogenicity [19].

2.1.3 Fibronectin-binding proteins (FnBPs) encoded by the fnbA and fnbB genes

These proteins, FnBPA and FnBPB, facilitate the formation of biofilms on indwelling medical devices such as central venous catheters and prosthetic joints [20]. Biofilm-associated infections are particularly challenging to treat with antibiotics due to the dormant state of many cells within the biofilm matrix [21]. Most strains of S. aureus produce two similar fibronectin-binding proteins, FnBPA and FnBPB, encoded by closely linked genes [18]. The aforementioned proteins are a member of the MSCRAMM family, which are proteins on the cell surface that binds to both fibrinogen and fibronectin [22]. In methicillin-resistant S. aureus (MRSA) strains, FnBPs play a key role in biofilm formation, enhancing the bacterium’s ability to persist in the host and resist antibiotic treatment [23]. FnBPs bind to fibronectin in the extracellular matrix (ECM), which in turn interacts with the α5β1 integrin on host cells through the Arg-Gly-Asp (RGD) motif in fibronectin [24]. This interaction forms a bridge between S. aureus and host cell integrins, facilitating bacterial adherence and colonization [24]. By promoting biofilm formation and mediating adhesion to host tissues, FnBPs significantly enhance the pathogenicity of S. aureus, making infections difficult to eradicate [24].

2.1.4 Elastin-binding protein of Staphylococcus aureus (EbpS) encoded by ebp gene

Elastin, a crucial component of the elastic fiber extracellular matrix (ECM) along with microfibrillar elements, is abundant in tissues requiring elasticity, such as the heart, skin, and major blood vessels [25]. It consists of tropoelastin monomers, which are cross-linked by modified lysine side chains and deposited in tissues [25]. S. aureus expresses elastin-binding protein (EbpS) as an integral membrane protein on the cell surface, rather than as a cell-wall-associated protein [15].EbpS specifically attaches to the N-terminal region of elastin, promoting the attachment of soluble elastin peptides and tropoelastin to S. aureus cells [26]. However, EbpS does not facilitate bacterial adherence to immobilized elastin and, therefore, is not considered a microbial surface component recognizing adhesive matrix molecule (MSCRAMM) [26]. This selective binding capability aids S. aureus in colonizing and infecting elastic tissue-rich environments, contributing to its pathogenicity in host tissues that require elasticity [17].

2.1.5 Serine-aspartate repeat-containing protein (Sdr) encoded by sdrC, sdrD, and sdrE genes

Sdr proteins (from SD Repeat) are characterized by an R region with multiple serine-aspartate repeats [27]. The sdr locus in S. aureus encodes three proteins: SdrC, SdrD, and SdrE [28]. While SdrC is consistently present, SdrD and SdrE are variably found, with SdrE linked to more invasive strains [28]. These proteins, part of the MSCRAMM family, primarily bind to bone sialoprotein and fibrinogen, enhancing S. aureus’ adhesion to host tissues [13]. This adhesion facilitates biofilm formation, protects the bacteria from immune responses and antibiotics, and is crucial in infections involving bones and blood vessels [19]. By promoting biofilm formation and aiding in tissue colonization, Sdr proteins significantly contribute to S. aureus pathogenicity, making the bacterium more adept at establishing and maintaining infections [19].

2.1.6 The extracellular adherence protein (Eap), AKA major histocompatibility class II analogous protein (Map), encoded by map gene

The extracellular adherence protein (Eap), also known as major histocompatibility class II analogous protein (Map), is encoded by the map gene. Unlike MSCRAMM proteins that are cell surface-bound, Eap is a secreted protein classified as a Secreted Expanded Repertoire Adhesive Molecule (SERAM) [13]. Eap plays a crucial role in S. aureus pathogenesis by aiding bacterial adherence and evading host defenses [29]. Eap binds strongly to extracellular matrix proteins such as fibrinogen, fibronectin, bone sialoprotein, vitronectin, and thrombospondin, enhancing bacterial adhesion and promoting chronic infections [13]. It also has a high tendency to form oligomers, leading to S. aureus aggregation [30]. Additionally, Eap can interact with intercellular adhesion molecule-1 (ICAM-1), modulating the inflammatory response and contributing to the pathogen’s ability to persist in the host [30]. Overall, Eap significantly contributes to the virulence of S. aureus by facilitating bacterial adhesion, promoting aggregation, and interfering with host immune responses [30].

2.1.7 Intercellular adhesion proteins encoded by the icaA, icaB, icaC, icaD, and icaR genes

The most important virulence factor of S. aureus bacteria is their capability to attach and form biofilms [13]. The icaADBC gene locus is essential for synthesizing polysaccharide intracellular adhesion (PIA), also known as poly-N-acetyl-β-(1–6)-glucosamine (PIA/PNAG), which contributes to biofilm formation and adherence [31]. The icaR gene negatively regulates this locus. IcaA and IcaD function as glucosyltransferases that produce short PIA/PNAG oligomers [31]. IcaC helps bind these oligomers into longer polymer chains and is involved in their transport to the cell surface [31]. On the surface, IcaB facilitates the partial deacetylation of PIA/PNAG, which is crucial for maintaining biofilm integrity and surface adhesion [31]. These proteins collectively enhance S. aureus’ ability to adhere to surfaces and form biofilms, significantly contributing to its pathogenicity by protecting the bacteria from host immune responses and antibiotic treatment [13].

2.1.8 Staphylokinase (plasminogen activator) is encoded by the sak gene

Staphylokinase interacts with host plasminogen to form active plasmin, a proteolytic enzyme that degrades the extracellular matrix, facilitating bacterial penetration and tissue invasion [30]. This enhances the spread and proliferation of S. aureus [30]. Staphylokinase also binds to alpha-defensins, human neutrophil-derived bactericidal peptides, neutralizing their antimicrobial properties [32]. This interaction helps S. aureus resist innate immune defenses, making staphylokinase crucial for bacterial survival and virulence [32].

2.2 The ability to resist innate immune defenses (antiphagocytosis)

2.2.1 Capsule encoded by cap5 and cap8 genes

Capsular polysaccharides (CP) in S. aureus are key virulence factors [33]. While older literature suggested up to 11 serotypes, only serotypes 1, 2, 5, and 8 have been chemically characterized [34]. Notably, 75–80% of human isolates belong to CP types 5 (CP5) or 8 (CP8) [35]. The capsule helps S. aureus evade the immune system by masking surface proteins and opsonins, preventing recognition by phagocytic cells [36]. Additionally, the secretion of extracellular fibrinogen-binding protein (Efb) further inhibits phagocytic uptake, enhancing the bacterium’s ability to persist and cause infections [36].

2.2.2 Cardiolipin synthase is encoded by cls1 and cls2 genes

Cardiolipin synthase converts phosphatidylglycerol (PG) to cardiolipin (CL), a crucial phospholipid in staphylococcal membrane [37]. The alteration of the bacterial membrane composition, particularly the increase in CL, helps S. aureus evade last-line antibiotics like daptomycin by impairing their membrane penetration [37]. Additionally, these membrane changes reduce neutrophil chemotaxis, aiding the bacteria in evading phagocytosis and enhancing its pathogenicity [37].

2.3 The ability to evade adaptive immune defenses (immune evasion)

2.3.1 Adenosine synthase (AdsA) is encoded by the adsA gene

S. aureus is a human pathogen that produces extracellular adenosine to evade the host immune system, primarily through the adenosine synthase (AdsA) 5′-nucleotidase function [38]. In mammals, adenosine triphosphate (ATP) is converted to adenosine via a two-step process: ecto-nucleoside triphosphate diphosphohydrolases (Ecto-NTDPases) hydrolyze ATP and ADP into AMP, and 5′ nucleotidases hydrolyze AMP into adenosine, with the activity dependent on Apyrase conserved regions (ACRs) [39]. When S. aureus infects host tissues, it releases two enzymes, nuclease and AdsA. Nuclease degrades neutrophil extracellular traps (NETs) DNA into deoxyadenylate (dAMP), which is subsequently converted by AdsA into 2′-deoxyadenosine (dAdo) [8]. dAdo activates the Caspase-3 pathway, inducing macrophage apoptosis [8]. Consequently, S. aureus restricts macrophage infiltration into abscess communities, preventing phagocytosis and leading to recurrent and persistent infections [38].

2.3.2 Chemotaxis inhibitory protein of Staphylococcus (CHIPS) encoded by chp gene

Chemotaxis inhibitory protein (CHIPS) plays a crucial role in evading the host’s first line of defense [40]. It inhibits the response of human neutrophils and monocytes to complement anaphylatoxin C5a and formylated peptides, such as N-formyl-methionyl-leucyl-phenylalanine (fMLP) [41]. CHIPS achieves this by binding directly to the C5a receptor (C5aR) and the formylated peptide receptor (FPR), thereby blocking the calcium responses induced by C5a and fMLP. This action prevents bacterial phagocytosis by leukocytes [41].

2.3.3 Staphylococcal complement inhibitor (SCIN) encoded by scn gene

S. aureus mitigates the host immune response by excreting staphylococcal complement inhibitor (SCIN) residues [42]. SCIN reduces the activity of central complement convertases, thereby decreasing phagocytosis after opsonization and eliminating downstream effector activities [41]. SCIN molecules (SCIN, SCIN-B, and SCIN-C) specifically block C3 convertases (C4b2a and C3bBb) to prevent the generation of C3b/iC3b, phagocytosis, and C5a formation [43]. SCIN does not directly bind to C3b but instead binds to the activated C3 convertase, leading to the stabilization and inactivation of this complex [43].

2.3.4 Staphylococcal protein A (SpA) is encoded by the spa gene

Evasion of the host immune system is integral to S. aureus’ pathogenicity and is facilitated by the cell wall-associated protein A (SpA) [44]. SpA binds to the Fc fragments of immunoglobulin G (IgG), preventing phagocytosis and classical pathway complement fixation [45]. Both the innate and adaptive immune systems are impaired by SpA, which belongs to the MSCRAMM family [8]. SpA interacts with both the Fc and Fab parts of immunoglobulins to counteract antibody-mediated opsonophagocytic processes and induce the expansion and apoptotic destruction of B-cell populations [46]. Additionally, SpA mediates the attachment of S. aureus to von Willebrand factor (VWF), a protein present at sites of endothelial damage, potentially playing a role in the initiation of intravascular infections [47].

2.3.5 Staphylococcal binder of immunoglobulin (Sbi) encoded by the sbi gene

S. aureus’ second immunoglobulin-binding protein (Sbi) has two N-terminal domains that bind the IgG Fc region similarly to protein A, and two domains that bind to the C3 complement, facilitating its futile consumption in the fluid phase [44]. Sbi, a 436-amino acid protein associated with the bacterial envelope, contains one functional immunoglobulin-binding domain and a second immunoglobulin-binding motif, both similar to the five immunoglobulin-binding repeats (E, A, B, C, and D) of SpA [48]. Sbi forms a tripartite complex with complement factor C3d and factor H, leading to the consumption of C3 and inhibiting the pathogen’s opsonophagocytic clearance [49].

2.4 The ability to compete for iron and other nutrients (iron uptake)

2.4.1 Iron-regulated surface determinant (Isd) series of proteins encoded by isdA, isdB, isdC, isdD, isdE, isdF, isdG, isdH, isdI, and srtB genes

The iron-regulated surface determinant (isd) cluster of genes was first identified in 2002, with Hazmanian et al. proposing in 2003 that the Isd protein series forms a heme transport pathway across the cell wall and membrane [50]. In S. aureus, the Isd system comprises nine iron-regulated proteins: IsdA, IsdB, IsdC, and IsdH/HarA, which are cell wall-anchored surface proteins; IsdDEF, a membrane-localized transporter; and IsdG and IsdI, heme-degrading cytoplasmic enzymes [50]. This sequence of Isd proteins interacts with heme proteins, extracts the heme molecule, and transfers it through the cell wall to the membrane, where it is translocated to the cytoplasm [51].

2.5 The ability to disseminate and spread the infection (exoenzymes, secretion system)

2.5.1 Aureolysin is encoded by aur gene

S. aureus secretes a metalloproteinase known as aureolysin, encoded by the aur gene, which exists in two allelic forms: type I and type II [52]. In vitro, aureolysin degrades plasma proteinase inhibitors, α1-antichymotrypsin and α1-proteinase, and activates prothrombin in human plasma. It also influences T and B lymphocyte stimulation by polyclonal activators and inhibits lymphocyte immunoglobulin production [30]. Additionally, aureolysin activates the glutamyl endopeptidase precursor (V8 protease), also synthesized by S. aureus By specifically inactivating ClfB via cleavage of its N-terminal domain, aureolysin modulates bacterial cell surface proteins, facilitating bacterial cell detachment from colonized sites and promoting the infectious spread of the organism [53].

2.5.2 Hyaluronate lyase is encoded by the hysA gene

The enzyme hyaluronate lyase (HL), a long-neglected potential virulence determinant of S. aureus, is an extracellular enzyme that degrades the mucopolysaccharide hyaluronic acid (HA), the major intercellular component in human and animal connective tissue [54]. HL removes the 1,4-glycosidic bond between D-glucuronic acid residues and N-acetyl-β-D-glucosamine in hyaluronan, leading to the secretion of unsaturated polysaccharides [54]. The key end product of this process is 2-acetamido-2-deoxy-3-O-(β-D-gluco-4-enepyranosyluronic acid)-D-glucose [54].

2.5.3 Lipase is encoded by the geh gene

The lipase enzyme (glycerol ester hydrolase, EC 3.1.1.3) interacts with host granulocytes, enhancing bacterial survival by inhibiting bactericidal lipids [55]. It releases significant amounts of fatty acids, particularly octadecenoic acid, in human plasma [56]. Lipases support the survival of S. aureus in the fatty secretions of mammalian skin, indirectly contributing to its pathogenicity. The expression of lipase-encoding genes is also directly induced during infection, underscoring their role in bacterial virulence [55].

2.5.4 Glutamyl endopeptidase precursor (V8 protease) is encoded by the sspA gene

The enzyme glutamyl endopeptidase, also known as V8 protease preferably cleaves peptide bonds on the carboxyl-terminal side of aspartate and glutamate [57]. This enzyme plays a crucial role in the invasion and infection of human tissues [57]. Together with other extracellular proteases, it is needed for the proteolytic development of SspB thiol protease and the inactivation of SspC, an inhibitor of SspB. V8 protease is the most essential degrading protease of fibronectin-binding protein (FnBP) and surface protein A, both of which are involved in the attachment of S. aureus to host cells [58]. Additionally, it may defend bacteria against host protection by cleaving the immunoglobulins IgG, IgA, and IgM, and may also contribute to the stabilization of lipase secretion [59].

2.5.5 Cysteine protease (staphopain) A encoded by scpA and B encoded by sccpB genes, cysteine proteinase inhibitor (staphostatins) encoded by scpC and sspC genes

Cysteine protease is a critical virulence factor in S. aureus, playing a significant role in evading the host’s innate immune response [30]. It cleaves elastin in connective tissues, pulmonary surfactant protein A in the lungs, and the chemokine receptor CXCR2 in leukocytes [60]. By degrading surfactant protein A, cysteine protease inhibits neutrophil bacterial phagocytosis, and by targeting CXCR2, it prevents neutrophil activation and chemotaxis [60]. This dual action significantly hampers the host’s ability to mount an effective immune response against the bacterium [61]. Additionally, staphostatins, which suppress staphopain cysteine protease by blocking its active site, are essential for protecting cytoplasmic proteins from premature degradation [60]. These proteases are associated with bacterial growth, viability, and morphology, further contributing to the pathogen’s ability to cause persistent and recurrent infections [30].

2.5.6 Staphylocoagulase is encoded by the coa gene and the von Willebrand factor binding protein is encoded by the vWbp gene

Coagulation is a key innate defense mechanism that captures and immobilizes bacterial pathogens in a clot [7]. S. aureus exploits this process through two primary virulence factors: coagulase and von Willebrand factor binding protein (vWbp) [7]. Coagulase, a polypeptide produced by S. aureus, binds to and activates prothrombin, which converts fibrinogen into fibrin [62]. This activation promotes blood clotting and facilitates the formation of abscesses, aiding in the pathogen’s survival and contributing to severe infections such as lethal bacteremia [62]. Similarly, vWbp functions as an additional coagulase, enabling the bacteria to form thromboembolic lesions [63]. This not only assists in bacterial dissemination but also helps S. aureus evade opsonophagocytic clearance by host immune cells, thereby enhancing its ability to persist in the host and cause chronic infections [63].

2.5.7 ESAT-6 secretion system (ESS) (AKA type VII secretion system (T7SS)) encoded by esaA, esaB, esaD, esaE, esaG1-9, essA, essB, essC, esxA, esxB, esxC, and esxD genes

The ESAT-6 secretion system (ESS) in S. aureus is essential for its virulence and persistence in infections, such as murine abscesses, pneumonia, and chronic infections in cystic fibrosis patients [64]. The ESS consists of six components: EsxA (a secreted WXG100 protein), EsaB (a regulatory protein), EssC (a membrane protein crucial for secretion), and other transmembrane proteins (EssA and EssB) [65]. EsxA and EsxB contribute significantly to virulence by promoting bacterial dissemination and colonization, and their absence leads to significantly reduced virulence [65]. The T7SS also secretes a nuclease toxin, EsaD, whose activity is regulated by binding to the antitoxin EsaG [66]. Other components such as EsaB, which has a ubiquitin-like fold, regulate the ESS machinery, and membrane proteins EssA, EssB, and EssC facilitate the secretion process [66]. This system is vital for S. aureus’s ability to evade the host immune system and establish persistent infections [66].

2.6 Toxins

2.6.1 Hemolysins: α-hemolysin encoded by the hly/hla gene, β-hemolysin encoded by the hlb gene, δ-hemolysin encoded by the hld gene, γ-hemolysin encoded by hlgA, hlgB, and hlgC genes

α-Hemolysin is a hydrophilic protein of approximately 33 kDa that assembles into a heptameric pre-pore complex upon integration with the target cell membrane [67]. This complex forms a β-barrel channel consisting of 14 anti-parallel β-strands, with each protomer contributing two strands [67]. By binding to the ADAM10 receptor on alveolar epithelial cells, α-hemolysin enhances ADAM10 metalloprotease activity, leading to E-cadherin cleavage and subsequent pore formation [68]. This disruption impairs neutrophil function and triggers cytokine release [68]. In contrast, β-Hemolysin, a neutral sphingomyelinase, hydrolyzes sphingomyelin in the plasma membrane to generate phosphocholine and ceramide, essential for its hemolytic activity [69]. δ-Hemolysin destabilizes cell membranes through pore formation, membrane curvature alteration, or solubilization at high concentrations [70]. The phenol-soluble modulins (PSMs) family, including δ-hemolysin and PSMα peptides, contribute to S. aureus virulence by disrupting host cell membranes [71]. γ-Hemolysin, consisting of HlgA, HlgB, and HlgC, mimics leukocidins by forming pores in host cell membranes, aiding in bacterial survival and immune evasion [71].

2.6.2 Panton-Valentine leucocidin (PVL) is encoded by lukS-PV and lukF-PV genes

The toxin, known as Panton-Valentine leukocidin (PVL), is composed of two components: LukS-PV and LukF-PV [67]. These components are synthesized separately and then combined to form a heptameric pore on neutrophil membranes, leading to neutrophil lysis [67]. PVL is part of the synergohymenotropical toxin family, which includes γ-hemolysin and other leukocidins such as LukE-LukD [72]. PVL induces cell activation through Ca²⁺ influx and pore formation, which occurs in two successive and independently inhibitable steps [72].

2.6.3 Exfoliative toxin encoded by eta and etb genes

Exfoliative toxins (ETs) are high-substrate-specific serine proteases that selectively target and hydrolyze desmosomal proteins in the skin [73]. Specifically, ETD and ETA are responsible for the skin manifestations seen in staphylococcal scalded skin syndrome and bullous impetigo [73]. These toxins act as serine proteases, with Dsg-1 (desmoglein-1) being their primary target [53]. Dsg-1 is crucial for maintaining cell-to-cell adhesion among keratinocytes [53]. When ETs cleave Dsg-1, it disrupts this adhesion, leading to the separation of keratinocytes and the resultant epidermal tissue layer separation characteristic of these skin conditions [74]. Additionally, ETs may also act as potential superantigens [74].

2.6.4 Toxic shock syndrome toxin-1 (TSST)-1 is encoded by the tsst-1 gene

The tsst-1 gene encodes a 21.9 kDa extracellular toxin that induces cytokine secretion from epithelial cells, antigen-presenting cells (APCs), and T lymphocytes, leading to toxic shock syndrome (TSS) [75]. Acting as a superantigen, it triggers T-cells by binding the variable portion of the β-chain of the T-cell receptor to major histocompatibility complex class I molecules on target T-cells outside the peptide-binding groove [76]. This results in the massive, non-specific activation of T-cells, significantly contributing to the pathogenicity of S. aureus [76].

2.6.5 Staphylococcal enterotoxin (SE) is encoded by sea, seb, sec1, sec3, sed, see, seh, selk, and selq genes

Staphylococcal enterotoxins (SEs) are superantigens primarily responsible for the symptoms of food poisoning [77]. They can activate large populations of T-cells (~20–30%), resulting in a massive production of cytokines [78]. These protein toxins bind directly to major histocompatibility complex class II on antigen-presenting cells and specific Vβ regions of the T-cell receptor, leading to potentially life-threatening immune system stimulation [79]. This mechanism significantly contributes to the pathogenicity of S. aureus [79].

3. Conclusion

In conclusion, S. aureus demonstrates a wide range of virulence factors that significantly enhance its ability to cause disease. These factors enable the bacterium to efficiently colonize host tissues, evade immune responses, and cause substantial damage. By disrupting host cell membranes, manipulating coagulation pathways, and triggering excessive immune responses, S. aureus can persist and thrive within the host environment. Understanding these mechanisms highlights potential therapeutic targets and strategies for effectively managing and preventing S. aureus infections, emphasizing the importance of continued research in this field.

Acknowledgments

I would like to extend my sincere gratitude to the University of Jeddah for their support and resources that made this work possible.

Conflict of interest

The author declares no conflict of interest.