Force Nanoscopy\nDemonstrates Stress-Activated Adhesion\nbetween Staphylococcus aureus Iron-Regulated\nSurface Determinant Protein B and Host Toll-like Receptor 4

The Staphylococcus aureus iron-regulated\nsurface determinant protein B (IsdB) has recently been shown to bind\nto toll-like receptor 4 (TLR4), thereby inducing a strong inflammatory\nresponse in innate immune cells. Currently, two unsolved questions\nare (i) What is the molecular mechanism of the IsdB-TLR4 interaction?\nand (ii) Does it also play a role in nonimmune systems? Here, we use\nsingle-molecule experiments to demonstrate that IsdB binds TLR4 with\nboth weak and extremely strong forces and that the mechanostability\nof the molecular complex is dramatically increased by physical stress,\nsustaining forces up to 2000 pN, at a loading rate of 10<sup>5</sup> pN/s. We also show that TLR4 binding by IsdB mediates time-dependent\nbacterial adhesion to endothelial cells, pointing to the role of this\nbond in cell invasion. Our findings point to a function for IsdB in\npathogen–host interactions, that is, mediating strong bacterial\nadhesion to host endothelial cells under fluid shear stress, unknown\nuntil now. In nanomedicine, this stress-dependent adhesion represents\na potential target for innovative therapeutics against S. aureus-resistant strains.