Protein Disulfide Isomerase and Extracellular Adherence Protein Cooperatively Potentiate Staphylococcal Invasion into...

Area of Science:

• Microbiology and Immunology
• Cell Biology
• Biochemistry

Background:

• Staphylococcus aureus invades host cells, often residing in non-professional phagocytes, which aids in evading immune responses and antibiotic treatments.
• Bacterial internalization typically involves bacterial surface proteins binding to host cell receptors, bridged by extracellular matrix proteins like fibronectin.
• The secreted extracellular adherence protein (Eap) from S. aureus is known to promote bacterial uptake but its precise mechanism remains unclear.

Purpose of the Study:

• To elucidate the mechanism by which Eap facilitates the invasion of host cells by Staphylococcus aureus and other bacteria.
• To investigate the role of protein disulfide isomerase (PDI) in Eap-mediated bacterial uptake.
• To explore the potential of targeting PDI as a therapeutic strategy against S. aureus infections.

Main Methods:

• Investigated Eap's effect on PDI activity on endothelial cell surfaces.
• Assessed the impact of PDI activity on integrin activation and fibronectin binding.
• Examined the role of Eap and PDI in the uptake of S. aureus and Staphylococcus carnosus into endothelial cells.

Main Results:

• Eap significantly enhances protein disulfide isomerase (PDI) activity on the surface of endothelial cells.
• PDI activation by Eap leads to β1-integrin activation and increased fibronectin binding, facilitating S. aureus internalization.
• Eap promotes the uptake of S. carnosus by enabling its binding to the fibronectin-α5β1 integrin complex via PDI.

Conclusions:

• Protein disulfide isomerase (PDI) is essential for the uptake of bacteria, including S. aureus and S. carnosus, into host cells.
• Eap's ability to promote bacterial invasion is critically dependent on its enhancement of cell-surface PDI enzymatic activity.
• Targeting PDI activity presents a novel therapeutic avenue for combating Staphylococcus aureus infections by inhibiting bacterial entry into host cells.