Adhesive Virulence Factors of Staphylococcus aureus Resist Digestion by Coagulation Proteases Thrombin and Plasmin

Abstract

Staphylococcus aureus (S. aureus) is an invasive and life-threatening pathogen that has undergone extensive coevolution with its mammalian hosts. Its molecular adaptations include elaborate mechanisms for immune escape and hijacking of the coagulation and fibrinolytic pathways. These capabilities are enacted by virulence factors including microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) and the plasminogen-activating enzyme staphylokinase (SAK). Despite the ability of S. aureus to modulate coagulation, until now the sensitivity of S. aureus virulence factors to digestion by proteases of the coagulation system was unknown. Here, we used protein engineering, biophysical assays, and mass spectrometry to study the susceptibility of S. aureus MSCRAMMs to proteolytic digestion by human thrombin, plasmin, and plasmin/SAK complexes. We found that MSCRAMMs were highly resistant to proteolysis, and that SAK binding to plasmin enhanced this resistance. We mapped thrombin, plasmin, and plasmin/SAK cleavage sites of nine MSCRAMMs and performed biophysical, bioinformatic, and stability analysis to understand structural and sequence features common to protease-susceptible sites. Overall, our study offers comprehensive digestion patterns of S. aureus MSCRAMMs by thrombin, plasmin, and plasmin/SAK complexes and paves the way for new studies into this resistance and virulence mechanism.

Current research update on group B streptococcal infection related to obstetrics and gynecology

“…In a similar context, Staphylococcus aureus has been shown to utilize adhesive virulence factors to resist host defenses. The staphylokinase (SAK) protein interacts with the serine protease domain of plasmin, enhancing resistance to digestion ( Risser et al, 2022 ). This interaction with plasmin is crucial for the pathogen’s ability to evade host immune responses.…”

“…This interaction with plasmin is crucial for the pathogen’s ability to evade host immune responses. Additionally, the molecular interactions of human plasminogen with fibronectin-binding proteins further emphasize the significance of protein-protein interactions in bacterial adherence and virulence ( Risser et al, 2022 ). Overall, the ability of bacterial surface proteins to interact with host proteins such as plasminogen and plasmin is a key determinant of pathogenicity.…”

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“…Notwithstanding, the organism produces an arsenal of virulence factors, including toxins, proteases, adhesins, and immune evasion factors [121]. The different virulence factors include extracellular proteins (cytolytic toxins (Panton-Valentine leucocidin, PVL, and haemolysins); enterotoxins (staphylococcal enterotoxins); SEA, SEB, SECn, SED, SEE, SEG, SEH, and SEI plus toxic shock syndrome toxin (TSST-1); exfoliative toxins (ETA and ETB), extracellular adherence protein (Eap), phenol-soluble modulins, microbial surface components recognising adhesive matrix molecules (MSCRAMMs), proteins (protein A and fibronectin-binding proteins-biofilm formation), teichoic acids, capsule, peptidoglycan, and enzymes (coagulase, staphylokinase, hyaluronidase, lipases, phospholipases, proteases, deoxyribonucleases), causing several infections presenting with different clinical manifestations when found in the bloodstream and internal tissues [122][123][124]. The clinical manifestations include infective endocarditis, bacteraemia, skin and soft infections, meningitis, gastroenteritis, toxic shock syndrome, septic arthritis, osteomyelitis, pulmonary infections, and a host of others, which are determined by the type of infection, strain type, and the site of infection [125].…”