Force Nanoscopy Demonstrates Stress-Activated Adhesion between <i>Staphylococcus aureus</i> Iron-Regulated Surface Determinant Protein B and Host Toll-like Receptor 4

The <i>Staphylococcus aureus</i> iron-regulated surface determinant protein B (IsdB) has recently been shown to bind to toll-like receptor 4 (TLR4), thereby inducing a strong inflammatory response in innate immune cells. Currently, two unsolved questions are (i) What is the molecular mechanism of the IsdB-TLR4 interaction? and (ii) Does it also play a role in nonimmune systems? Here, we use single-molecule experiments to demonstrate that IsdB binds TLR4 with both weak and extremely strong forces and that the mechanostability of the molecular complex is dramatically increased by physical stress, sustaining forces up to 2000 pN, at a loading rate of 10⁵ pN/s. We also show that TLR4 binding by IsdB mediates time-dependent bacterial adhesion to endothelial cells, pointing to the role of this bond in cell invasion. Our findings point to a function for IsdB in pathogen-host interactions, that is, mediating strong bacterial adhesion to host endothelial cells under fluid shear stress, unknown until now. In nanomedicine, this stress-dependent adhesion represents a potential target for innovative therapeutics against <i>S. aureus</i>-resistant strains.