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

2021 ◽  
Vol 118 (7) ◽  
pp. e2016772118 ◽  
Author(s):  
Ana Rita Cruz ◽  
Maurits A. den Boer ◽  
Jürgen Strasser ◽  
Seline A. Zwarthoff ◽  
Frank J. Beurskens ◽  
...  
Keyword(s):  
Complement Activation ◽  
High Speed ◽  
Bacterial Infections ◽  
Protein A ◽  
Native Mass Spectrometry ◽  
Staphylococcal Protein A ◽  
Staphylococcal Protein ◽  
Interaction Interface ◽  
Human Immune Response ◽  
Opsonophagocytic Killing

Immunoglobulin (Ig) G 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 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. Finally, we demonstrate that IgG3 antibodies against S. aureus can potently induce complement activation and opsonophagocytic killing even in the presence of SpA. Together, our findings identify SpA as an immune evasion protein that specifically blocks IgG hexamerization.

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

2020 ◽  
Author(s):  
Ana Rita Cruz ◽  
Maurits A. den Boer ◽  
Jürgen Strasser ◽  
Frank J. Beurskens ◽  
Carla J. C. de Haas ◽  
...  
Keyword(s):  
Complement Activation ◽  
High Speed ◽  
Bacterial Infections ◽  
Protein A ◽  
Native Mass Spectrometry ◽  
Staphylococcal Protein A ◽  
Force Microscopy ◽  
Staphylococcal Protein ◽  
Interaction Interface ◽  
Human Immune Response

AbstractIgG 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.

scholarly journals Glycosylation-dependent opsonophagocytic activity of staphylococcal protein A antibodies

2020 ◽  
Vol 117 (37) ◽  
pp. 22992-23000
Author(s):  
Xinhai Chen ◽  
Miaomiao Shi ◽  
Xin Tong ◽  
Hwan Keun Kim ◽  
Lai-Xi Wang ◽  
...  
Keyword(s):  
Bacterial Pathogens ◽  
Human Monoclonal Antibody ◽  
Functional Characterization ◽  
Protein A ◽  
Therapeutic Benefit ◽  
Staphylococcal Protein A ◽  
Staphylococcal Protein ◽  
Clinical Endpoints ◽  
Vaccine Trials ◽  
Opsonophagocytic Killing

Antibodies may bind to bacterial pathogens or their toxins to control infections, and their effector activity is mediated through the recruitment of complement component C1q or the engagement with Fcγ receptors (FcγRs). For bacterial pathogens that rely on a single toxin to cause disease, immunity correlates with toxin neutralization. Most other bacterial pathogens, including Staphylococcus aureus, secrete numerous toxins and evolved multiple mechanisms to escape opsonization and complement killing. Several vaccine candidates targeting defined surface antigens of S. aureus have failed to meet clinical endpoints. It is unclear that such failures can be solely attributed to the poor selection of antibody targets. Thus far, studies to delineate antibody-mediated uptake and killing of Gram-positive pathogens remain extremely limited. Here, we exploit 3F6-hIgG1, a human monoclonal antibody that binds and neutralizes the abundant surface-exposed Staphylococcal protein A (SpA). We find that galactosylation of 3F6-hIgG1 that favors C1q recruitment is indispensable for opsonophagocytic killing of staphylococci and for protection against bloodstream infection in animals. However, the simple removal of fucosyl residues, which results in reduced C1q binding and increased engagement with FcγR, maintains the opsonophagocytic killing and protective attributes of the antibody. We confirm these results by engineering 3F6-hIgG1 variants with biased binding toward C1q or FcγRs. While the therapeutic benefit of monoclonal antibodies against infectious disease agents may be debatable, the functional characterization of such antibodies represents a powerful tool for the development of correlates of protection that may guide future vaccine trials.

scholarly journals Staphylococcal Protein A Induces Leukocyte Necrosis by Complexing with Human Immunoglobulins

mBio ◽  
2021 ◽  
Author(s):  
Proinnsias G. Fox ◽  
Francesca Schiavetti ◽  
Rino Rappuoli ◽  
Rachel M. McLoughlin ◽  
Fabio Bagnoli
Keyword(s):  
Staphylococcus Aureus ◽  
Protein A ◽  
The United States ◽  
Staphylococcal Protein A ◽  
Human Pathogen ◽  
Content Type ◽  
Staphylococcal Protein ◽  
Human Immunoglobulins ◽  
Human Immune Response ◽  
Human Immune

Staphylococcus aureus is one of the largest health care threats faced by humankind, with a reported mortality rate within the United States greater than that of HIV/AIDS, tuberculosis, and viral hepatitis combined. One of the defining features of S. aureus as a human pathogen is its ability to evade and impair the human immune response through expression of staphylococcal protein A.

scholarly journals Quantification of platelet-bound IgG by 125I-Staphylococcal protein A in immune thrombocytopenic purpura and other thrombocytopenic disorders

Blood ◽  
1984 ◽  
Vol 63 (1) ◽  
pp. 154-161 ◽  
Author(s):  
GM Shaw ◽  
J Axelson ◽  
JG Maglott ◽  
AF LoBuglio
Keyword(s):  
Immune Thrombocytopenic Purpura ◽  
Protein A ◽  
Normal Subjects ◽  
Unknown Etiology ◽  
Staphylococcal Protein A ◽  
Thrombocytopenic Purpura ◽  
Clinical Criteria ◽  
Staphylococcal Protein ◽  
Wide Range ◽  
Immune Hemolytic Anemia

Abstract In this report we describe the use of an 125I-Staphylococcal protein A (SPA) assay to measure platelet-bound IgG in the evaluation of 62 thrombocytopenic patients. Platelets from 150 normal subjects were found to bind 146 +/- 112 molecules of SPA per platelet (mean +/- 2 SD). Nineteen of 20 patients with untreated immune thrombocytopenia had platelet IgG values above this range, with 15 of 20 having values above 1,000 molecules of SPA per platelet. Patients with immune thrombocytopenic purpura by clinical criteria, but who had failed conventional therapy (corticosteroids or splenectomy), had a wide range of platelet IgG levels: 4 of 20 had normal values, 6 of 20 had minimally elevated levels in the range seen with nonimmune thrombocytopenia, and 10 of 20 had much higher values. Fifteen patients with thrombocytopenia of apparent nonimmune origin and 7 others with chronic stable thrombocytopenia of unknown etiology were found to have platelet IgG levels within or only slightly above the normal range. Because of its simplicity, accuracy, and clinical correlation, the 125I- SPA assay provides an important new approach for studying platelet IgG in thrombocytopenic states. The data obtained with this technique are similar to those found in immune hemolytic anemia and suggest that the platelet-bound IgG so measured has pathophysiologic relevance in immune thrombocytopenic purpura.

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