Staphylococcal Protein A Is a Key Factor in Neutrophil Extracellular Traps Formation

Hoppenbrouwers, Tamara; Sultan, Andi R.; Abraham, Tsion E; Toom, Nicole A. Lemmens-den; Maňásková, Silvie Hansenová; Cappellen, Wiggert A. van; Houtsmuller, Adriaan B.; Wamel, Willem J. B. van; Maat, Moniek P.M. de; Neck, Johan W. van

doi:10.3389/fimmu.2018.00165

Cited by 32 publications

(34 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although the majority of SpA is cell-anchored, 6.5% to 15% is secreted before sorting (O'Halloran et al, 2015) or released from the cell wall after enzymatic cleavage by LytM (Becker et al, 2014). We observed that the concentration of recombinant multi-domain SpA needed to decrease C1q deposition on an antigenic surface is lower than the amount reported to be secreted by Newman or USA300 strains in vitro (Hoppenbrouwers et al, 2018).…”

Section: Discussionmentioning

confidence: 63%

Staphylococcal protein A inhibits complement activation by interfering with IgG hexamer formation

Cruz

Boer

Strasser

et al. 2020

Preprint

View full text Add to dashboard Cite

IgG molecules are essential players in the human immune response against bacterial infections. An important effector of IgG-dependent immunity is the induction of complement activation, a reaction that triggers a variety of responses that help to kill bacteria. Antibody-dependent complement activation is promoted by the organization of target-bound IgGs into hexamers that are held together via noncovalent Fc-Fc interactions. Here we show that Staphylococcal protein A (SpA), an important virulence factor and vaccine candidate of Staphylococcus aureus, effectively blocks IgG hexamerization and subsequent complement activation. Using native mass spectrometry and high-speed atomic force microscopy, we demonstrate that SpA blocks IgG hexamerization through competitive binding to the Fc-Fc interaction interface on IgG monomers. In concordance, we show that SpA interferes with the formation of (IgG)6:C1q complexes and prevents downstream complement activation on the surface of S. aureus. Lastly, we demonstrate that IgG3 antibodies against S. aureus can potently induce complement activation even in the presence of SpA. Altogether, this study identifies SpA as an immune evasion protein that specifically blocks IgG hexamerization.

show abstract

Section: Discussionmentioning

confidence: 63%

Staphylococcal protein A inhibits complement activation by interfering with IgG hexamer formation

Cruz

Boer

Strasser

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…To confirm the role of SpA in promoting bacterial adhesion to vWF, we studied the attachment of the S. aureus Newman strain, known to largely express SpA (15–17), onto vWF immobilized on microtiter wells. Wild-type (WT) bacteria adhered to vWF in large amounts, whereas bacteria from the Newman Δ spa strain lacking the adhesin did to a much lower extent (Fig.…”

Section: Resultsmentioning

confidence: 99%

Binding of Staphylococcus aureus Protein A to von Willebrand Factor Is Regulated by Mechanical Force

Viela

Prystopiuk

Leprince

et al. 2019

mBio

View full text Add to dashboard Cite

Binding ofStaphylococcus aureusto the large plasma glycoprotein von Willebrand factor (vWF) is controlled by hydrodynamic flow conditions. Currently, we know little about the molecular details of this shear-stress-dependent interaction. Using single-molecule atomic force microscopy, we demonstrate that vWF binds to theS. aureussurface protein A (SpA) via a previously undescribed force-sensitive mechanism. We identify an extremely strong SpA-vWF interaction, capable of withstanding forces of ∼2 nN, both in laboratory and in clinically relevant methicillin-resistantS. aureus(MRSA) strains. Strong bonds are activated by mechanical stress, consistent with flow experiments revealing that bacteria adhere in larger amounts to vWF surfaces when the shear rate is increased. We suggest that force-enhanced adhesion may involve conformational changes in vWF. Under force, elongation of vWF may lead to the exposure of a high-affinity cryptic SpA-binding site to which bacteria firmly attach. In addition, force-induced structural changes in the SpA domains may also promote strong, high-affinity binding. This force-regulated interaction might be of medical importance as it may play a role in bacterial adherence to platelets and to damaged blood vessels.IMPORTANCEStaphylococcus aureusprotein A (SpA) binds to von Willebrand factor (vWF) under flow. While vWF binding to SpA plays a role inS. aureusadherence to platelets and endothelial cells under shear stress, the molecular basis of this stress-dependent interaction has not yet been elucidated. Here we show that the SpA-vWF interaction is regulated by a new force-dependent mechanism. The results suggest that mechanical extension of vWF may lead to the exposure of a high-affinity cryptic SpA-binding site, consistent with the shear force-controlled functions of vWF. Moreover, strong binding may be promoted by force-induced structural changes in the SpA domains. This study highlights the role of mechanoregulation in controlling the adhesion ofS. aureusand shows promise for the design of small inhibitors capable of blocking colonization under high shear stress.

show abstract

“…The pneumonia-causing pathogen, Staphylococcus aureus ( S. aureus ), has also been detected in the airways of COPD patients (70, 71), notably in much older populations (72). This is particularly important because S. aureus can directly trigger NET formation (73), and might thus influence the cycle of pathogen–NETopathic inflammation in COPD. Despite there being high levels of NETs in the COPD airways, there is a deficiency in effective pathogen clearance.…”

Section: Pulmonary Pathogen-initiated Netopathic Inflammationmentioning

confidence: 99%

NETopathic Inflammation in Chronic Obstructive Pulmonary Disease and Severe Asthma

et al. 2019

View full text Add to dashboard Cite

Neutrophils play a central role in innate immunity, inflammation, and resolution. Unresolving neutrophilia features as a disrupted inflammatory process in the airways of patients with chronic obstructive pulmonary disease (COPD) and severe asthma. The extent to which this may be linked to disease pathobiology remains obscure and could be further confounded by indication of glucocorticoids or concomitant respiratory infections. The formation of neutrophil extracellular traps (NETs) represents a specialized host defense mechanism that entrap and eliminate invading microbes. NETs are web-like scaffolds of extracellular DNA in complex with histones and neutrophil granular proteins, such as myeloperoxidase and neutrophil elastase. Distinct from apoptosis, NET formation is an active form of cell death that could be triggered by various microbial, inflammatory, and endogenous or exogenous stimuli. NETs are reportedly enriched in neutrophil-dominant refractory lung diseases, such as COPD and severe asthma. Evidence for a pathogenic role for respiratory viruses (e.g., Rhinovirus), bacteria (e.g., Staphylococcus aureus) and fungi (e.g., Aspergillus fumigatus) in NET induction is emerging. Dysregulation of this process may exert localized NET burden and contribute to NETopathic lung inflammation. Disentangling the role of NETs in human health and disease offer unique opportunities for therapeutic modulation. The chemokine CXCR2 receptor regulates neutrophil activation and migration, and small molecule CXCR2 antagonists (e.g., AZD5069, danirixin) have been developed to selectively block neutrophilic inflammatory pathways. NET-stabilizing agents using CXCR2 antagonists are being investigated in proof-of-concept studies in patients with COPD to provide mechanistic insights. Clinical validation of this type could lead to novel therapeutics for multiple CXCR2-related NETopathologies. In this Review, we discuss the emerging role of NETs in the clinicopathobiology of COPD and severe asthma and provide an outlook on how novel NET-stabilizing therapies via CXCR2 blockade could be leveraged to disrupt NETopathic inflammation in disease-specific phenotypes.

show abstract

Staphylococcal Protein A Is a Key Factor in Neutrophil Extracellular Traps Formation

Cited by 32 publications

References 39 publications

Staphylococcal protein A inhibits complement activation by interfering with IgG hexamer formation

Staphylococcal protein A inhibits complement activation by interfering with IgG hexamer formation

Binding of Staphylococcus aureus Protein A to von Willebrand Factor Is Regulated by Mechanical Force

NETopathic Inflammation in Chronic Obstructive Pulmonary Disease and Severe Asthma

Contact Info

Product

Resources

About