Defining the human lung pathodegradome of the V8 protease from Staphylococcus aureus

Area of Science:

• Microbiology
• Immunology
• Proteomics

Background:

• Staphylococcus aureus is a major human pathogen.
• Extracellular proteases, like V8 protease (SspA), are crucial for S. aureus virulence.
• Host targets of SspA remain largely undefined.

Purpose of the Study:

• To comprehensively identify host protein targets of S. aureus V8 protease (SspA).
• To elucidate the mechanisms by which SspA manipulates host immunity and contributes to disease.

Main Methods:

• Utilized a high-efficiency N-Terminomic approach (TAGS-CR).
• Captured approximately 320 biologically relevant V8 protease targets in the human lung proteome.

Main Results:

• Identified V8 protease targets involved in complement system modulation (e.g., Complement C3).
• Demonstrated disruption of neutrophil functions (ROS production, migration, phagocytosis, degranulation).
• Showed targeting of epithelial barrier proteins (zona occludens, alpha actinin) and actin.
• Revealed exploitation of nutritional immunity by targeting iron-complexed proteins (transferrins, hemopexin, hemoglobin).
• Identified disruption of immune regulators like gelsolin.

Conclusions:

• S. aureus V8 protease (SspA) extensively manipulates host defenses, including complement, neutrophils, and epithelial barriers.
• SspA plays a significant role in nutritional immunity and inflammation.
• This study provides a comprehensive map of SspA targets, revealing conserved virulence mechanisms.