Staphylococcus aureus: Virulence Factors

Staphylococcus aureus is a notable human pathogen for a variety of infections; suppurative (pus-forming) infections, systemic illness and toxinoses. S. aureus has an extraordinary repertoire of virulence factors that allows it to survive extreme conditions in human and promote tissue colonization, tissue damage, and ensues life-threatening systemic infections.

Capsule

Most strains of S. aureus have capsules (slime layer- polysaccharide). S. aureus capsular antigens are surface-associated, limited in antigenic specificity, and highly conserved among clinical isolates. Capsule inhibits phagocytosis and promotes adherence of the organism to host cells and in prosthetic devices.

Peptidoglycan

Give rigidity to the cell wall, activates complement. Virulence potential of S. aureus cell wall-anchored (CWA) proteins covalently attached to the peptidoglycan is demonstrated in infection models.

Find more about peptidoglycan

MSCRAMM (acronym for “microbial surface components recognizing adhesive matrix molecules”)

Teichoic acid

Teichoic acids are major constituents of Staphylococcus aureus. There are two types of teichoic acid (TAs):

• Lipo-Teichoic Acid (LTA): anchored in the cytoplasmic membrane,
• Cell wall Teichoic Acid (WTA): covalently linked to peptidoglycan in the bacterial cell wall.

Teichoic acids contribute to staphylococcal adhesion and colonization, cell division, and biofilm formation. Overexpression of teichoic acid increases the virulence of S. aureus. In addition, D-alanine (D-Ala) residues on teichoic acids contribute to resistance to cationic antimicrobial peptides such as defensins or cathelicidins, and to glycopeptide antibiotics such as vancomycin or teicoplanin. 

Find more about Teichoic acids (TA).

Protein A

Staphylococcal protein A (SpA) is a key virulence factor that enables S. aureus to evade innate and adaptive immune responses. SpA demonstrates multifaceted roles as a virulence factor.

• Antiphagocytic function: Protein A has an affinity to Fc receptors of the immunoglobulin. When protein A binds to the Fc end of Immunoglobulin, it makes S.aureus inaccessible to the opsonins thus protecting it from being engulfed and subsequently killed by the immune cells.
• Biofilm formation
• Protein A facilitates the adherence of S. aureus to von Willebrand factor (vWF)-coated surfaces such as endovascular catheters.
• Protein A can also stimulate inflammation in the lung by binding to a receptor for tumor necrosis factor 1 (TNFR-1) that is widely distributed on the airway epithelium. This interaction has been shown to play a central role in the pathogenesis of staphylococcal pneumonia.

Fibronectin-binding proteins (FnBPs) FnBPA and FnBPB

• Promote biofilm formation by clinically relevant methicillin-resistant S. aureus (MRSA) strains.

Collagen-binding protein

• One of the cell surface adhesion proteins expressed by Staphylococcus aureus that plays important roles in bacterium-host adherence and in immune evasion.

Extracellular Toxins

1. Cytolytic toxin
   1. Haemolysins :
      1. Lyse RBCs
      2. 4 types i.e., alpha, beta, gamma & delta
   2. Leukocidin:
      1. Damage polymorphonuclear leucocytes and necrosis
      2. Panton-Valentine leukocidin (PVL) is a cytotoxin—one of the β-pore-forming toxins.
2. Enterotoxins
   1. Heat stable toxin responsible for Staphylococcal food poisoning
   2. Once formed enterotoxin is not destroyed even if food is heated sufficiently to kill all viable Staphylococci
   3. Nine antigenic types (A- J except for F). Enterotoxin F is now known as Toxic shock syndrome toxin (TSST-1)
   4. Some strains may produce more than one type of enterotoxins.
3. Exfoliative (epidermolytic toxin): Two forms of epidermolytic toxins (ETA and ETB) of S. aureus split human skin at a site in the upper epidermis. Clinical effects are most common in infants. It is a serine protease which causes splitting of desmosomes or intercellular bridges in the stratum granulosum. Epidermolytic toxins are responsible for staphylococcal scalded skin syndrome in which the outer layer of epidermis gets separated from the underlying tissue

4. Toxic shock syndrome toxin (TSST-1): It’s a staphylococcal superantigen (SAg). Major roles of TSST-1 are as follows:

1. Induce cytokine release from macrophage and T lymphocytes
2. Capable of enhancing the toxic effects of endogenous endotoxin
3. Produce leakage of endothelial cells
4. Penetrate mucosal barrier
5. Staphylococcal superantigen is responsible for almost all menstrual toxic shock syndrome  cases

Enzymes

1. Coagulase (free coagulase)
   1. Activates a coagulase reacting factor (CRF) normally present in plasma, causing the plasma to clot by conversion of fibrinogen to fibrin
   2. May act to coat the bacterial cells with fibrin making them resistant to opsonisation and phagocytosis
   3. Can be detected by tube coagulase test
2. Staphylokinase (fibrinolysin):
   1. Fibrinolytic activity
   2. Antigenically and enzymatically distinct from that produced by Streptococcus
   3. Breaks fibrin clot and allow the spread of infection to contiguous tissues
3. Hyaluronidase: hydrolyses hyaluronic acid present in the intercellular ground substance of connective tissues thus facilitating the spread of the organism to adjacent areas
4. Deoxyribonuclease – degrades DNA
5. Lipase:
   S. aureus lipase (SAL), a triacylglycerol esterase, is an important virulence factor in S. aureus. SAL also contributes to colonization and invasion by S. aureus. It hydrolyzes lipids, making it possible for the bacteria to survive in sebaceous areas of the body.
6. Phospholipases – degrades phospholipase
7. Proteases – causes proteolysis

References and further reading

• O’Riordan, K., & Lee, J. C. (2004). Staphylococcus aureus capsular polysaccharides. Clinical microbiology reviews, 17(1), 218–234. doi:10.1128/cmr.17.1.218-234.2004
• Mistretta, N., Brossaud, M., Telles, F. et al. Glycosylation of Staphylococcus aureus cell wall teichoic acid is influenced by environmental conditions. Sci Rep 9, 3212 (2019) doi:10.1038/s41598-019-39929-1
• Liu, G. Molecular Pathogenesis of Staphylococcus aureus Infection. Pediatr Res 65, 71–77 (2009) doi:10.1203/PDR.0b013e31819dc44d
• https://www.intechopen.com/books/the-rise-of-virulence-and-antibiotic-resistance-in-staphylococcus-aureus/exfoliative-toxins-of-staphylococcus-aureus