scholarly journals Bacterial pathogens under high-tension: Staphylococcus aureus adhesion to von Willebrand factor is activated by force

2019 ◽  
Vol 6 (7) ◽  
pp. 321-323
Author(s):  
Felipe Viela ◽  
Pietro Speziale ◽  
Giampiero Pietrocola ◽  
Yves F. Dufrêne
Keyword(s):  
Staphylococcus Aureus ◽  
Von Willebrand Factor ◽  
Bacterial Pathogens ◽  
High Tension ◽  
Von Willebrand ◽  
Willebrand Factor

Single-molecule imaging of von Willebrand factor reveals tension-dependent self-association

Blood ◽  
2021 ◽  
Vol 138 (23) ◽  
pp. 2425-2434
Author(s):  
Hongxia Fu ◽  
Yan Jiang ◽  
Wesley P. Wong ◽  
Timothy A. Springer
Keyword(s):  
Von Willebrand Factor ◽  
Single Molecule ◽  
Molecular Mechanisms ◽  
Tensile Force ◽  
Sharp Decrease ◽  
Hydrodynamic Drag ◽  
High Tension ◽  
Self Association ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract von Willebrand factor (VWF) is an ultralong concatemeric protein important in hemostasis and thrombosis. VWF molecules can associate with other VWF molecules, but little is known about the mechanism. Hydrodynamic drag exerts tensile force on surface-tethered VWF that extends it and is maximal at the tether point and declines linearly to 0 at the downstream free end. Using single-molecule fluorescence microscopy, we directly visualized the kinetics of binding of free VWF in flow to surface-tethered single VWF molecules. We showed that self-association requires elongation of tethered VWF and that association increases with tension in tethered VWF, reaches half maximum at a characteristic tension of ∼10 pN, and plateaus above ∼25 pN. Association is reversible and hence noncovalent; a sharp decrease in shear flow results in rapid dissociation of bound VWF. Tethered primary VWF molecules can recruit more than their own mass of secondary VWF molecules from the flow stream. Kinetics show that instead of accelerating, the rate of accumulation decreases with time, revealing an inherently self-limiting self-association mechanism. We propose that this may occur because multiple tether points between secondary and primary VWF result in lower tension on the secondary VWF, which shields more highly tensioned primary VWF from further association. Glycoprotein Ibα (GPIbα) binding and VWF self-association occur in the same region of high tension in tethered VWF concatemers; however, the half-maximal tension required for activation of GPIbα is higher, suggesting differences in molecular mechanisms. These results have important implications for the mechanism of platelet plug formation in hemostasis and thrombosis.

scholarly journals Staphylococcus Aureus Iron-Regulated Surface Determinant B (IsdB) Protein Interacts with von Willebrand Factor and Promotes Adherence to Endothelial Cells.

2021 ◽  
Author(s):  
Mariangela J Alfeo ◽  
Anna Pagotto ◽  
Giulia Barbieri ◽  
Timothy J Foster ◽  
Karen Vanhoorelbeke ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Endothelial Cells ◽  
Von Willebrand Factor ◽  
Iron Transport ◽  
Matrix Proteins ◽  
Potential Therapeutic Target ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Micromolar Range

Abstract Staphylococcus aureus is the cause of a spectrum of diseases in humans and animals. The molecular basis of this pathogenicity lies in the expression of a variety of virulence factors, including proteins that mediate adherence to the host plasma and extracellular matrix proteins. In this study, we discovered that the iron-regulated surface determinant B (IsdB) protein, besides being involved in iron transport and vitronectin binding, interacts with von Willebrand Factor (vWF). IsdB-expressing bacteria bound to both soluble and immobilized vWF. The binding of recombinant IsdB to vWF was blocked by heparin and reduced at high ionic strength. Furthermore, treatment with ristocetin, an allosteric agent that promotes the exposure of the A1 domain of vWF, potentiates the binding of IsdB to vWF. Both near-iron transporter motifs NEAT1 and NEAT2 of IsdB individually bound recombinant A1 domain with KD values in the micromolar range. The binding of IsdB and adhesion of S. aureus expressing IsdB to monolayers of activated endothelial cells was significantly inhibited by a monoclonal antibody against the A1 domain and by IsdB reactive IgG from patients with staphylococcal endocarditis. This suggests the importance of IsdB in adherence of S. aureus to the endothelium colonization and as potential therapeutic target.

scholarly journals Von Willebrand factor and ADAMTS13 impact on the outcome of Staphylococcus aureus sepsis

2019 ◽  
Vol 18 (3) ◽  
pp. 722-731 ◽  
Author(s):  
Marijke Peetermans ◽  
Severien Meyers ◽  
Laurens Liesenborghs ◽  
Karen Vanhoorelbeke ◽  
Simon F. De Meyer ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Von Willebrand Factor ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Coagulases as Determinants of Protective Immune Responses against Staphylococcus aureus

2012 ◽  
Vol 80 (10) ◽  
pp. 3389-3398 ◽  
Author(s):  
Molly McAdow ◽  
Andrea C. DeDent ◽  
Carla Emolo ◽  
Alice G. Cheng ◽  
Barry N. Kreiswirth ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Responses ◽  
Von Willebrand Factor ◽  
Subunit Vaccine ◽  
Gene Sequences ◽  
Content Type ◽  
A Subunit ◽  
Von Willebrand ◽  
Willebrand Factor

ABSTRACTDuring infection,Staphylococcus aureussecretes two coagulases (Coa and von Willebrand factor binding protein [vWbp]), which, following an association with host prothrombin and fibrinogen, form fibrin clots and enable the establishment of staphylococcal disease. Within the genomes of differentS. aureusisolates, coagulase gene sequences are variable, and this has been exploited for a classification of types. We show here that antibodies directed against the variable prothrombin binding portion of coagulases confer type-specific immunity through the neutralization ofS. aureusclotting activity and protection from staphylococcal disease in mice. By combining variable portions of coagulases from North American isolates into hybrid Coa and vWbp proteins, a subunit vaccine that provided protection against challenge with different coagulase-typeS. aureusstrains in mice was derived.

scholarly journals Adaptation of Staphylococcus aureus to ruminant and equine hosts involves SaPI-carried variants of von Willebrand factor-binding protein

2010 ◽  
Vol 77 (6) ◽  
pp. 1583-1594 ◽  
Author(s):  
David Viana ◽  
José Blanco ◽  
María Ángeles Tormo-Más ◽  
Laura Selva ◽  
Caitriona M. Guinane ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Von Willebrand Factor ◽  
Binding Protein ◽  
Factor Binding ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Multimodal imaging of bacterial-host interface in mice and piglets with Staphylococcus aureus endocarditis

2020 ◽  
Vol 12 (568) ◽  
pp. eaay2104
Author(s):  
Peter Panizzi ◽  
Marvin Krohn-Grimberghe ◽  
Edmund Keliher ◽  
Yu-Xiang Ye ◽  
Jana Grune ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Von Willebrand Factor ◽  
Immune Cell ◽  
Binding Protein ◽  
Thrombin Inhibitor ◽  
Bacterial Colony ◽  
Factor Binding ◽  
Von Willebrand ◽  
Willebrand Factor

Acute bacterial endocarditis is a rapid, difficult to manage, and frequently lethal disease. Potent antibiotics often cannot efficiently kill Staphylococcus aureus that colonizes the heart’s valves. S. aureus relies on virulence factors to evade therapeutics and the host’s immune response, usurping the host’s clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor–binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we codeveloped therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, are bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor–binding protein in mice with S. aureus endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal, and improved survival. Aortic or tricuspid S. aureus endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging. Our data map a route toward adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.

scholarly journals Adhesion of Staphylococcus aureus to the vessel wall under flow is mediated by von Willebrand factor–binding protein

Blood ◽  
2014 ◽  
Vol 124 (10) ◽  
pp. 1669-1676 ◽  
Author(s):  
Jorien Claes ◽  
Thomas Vanassche ◽  
Marijke Peetermans ◽  
Laurens Liesenborghs ◽  
Christophe Vandenbriele ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Endothelial Cells ◽  
Von Willebrand Factor ◽  
Vessel Wall ◽  
Binding Protein ◽  
Factor Binding ◽  
Key Points ◽  
Platelet Aggregates ◽  
Von Willebrand ◽  
Willebrand Factor

Key PointsvWbp mediates adhesion of S aureus under flow to activated endothelial cells and the subendothelium via VWF. vWbp activates prothrombin and triggers the formation of bacteria–fibrin–platelet aggregates, which enhance adhesion to vessels under flow.

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