Identification of Residues in the Staphylococcus aureus Fibrinogen-binding MSCRAMM Clumping Factor A (ClfA) That Are Important for Ligand Binding

Hartford, Orla; Wann, Elisabeth R.; Höök, Magnus; Foster, Timothy J.

doi:10.1074/jbc.m007979200

Cited by 70 publications

(59 citation statements)

References 38 publications

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“…S. aureus mutants lacking fibronectin binding proteins or lacking fibrinogen binding were unable to stimulate GM-CSF production, suggesting a more specific ligand-receptor interaction in the GM-CSF response. The fibrinogen binding domain of this adhesin has been mapped (13), and it is possible that a similar locus is available on respiratory cells. Alternatively, staphylococcal "clumping," a property conferred by clfA, may be necessary to provide a sufficient bacterial stimulus to activate epithelial signaling.…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureusagrandsarAFunctions Are Required for Invasive Infection but Not Inflammatory Responses in the Lung

et al. 2002

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Staphylococcus aureus strains lacking agr-and sarA-dependent gene products or specific MSCRAMM (microbial surface components recognizing adhesive matrix molecules) adhesins were compared for the ability to activate inflammatory responses in the lung. The mutants were evaluated for virulence in a mouse model of pneumonia and by quantifying their ability to stimulate interleukin-8 (IL-8) and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in respiratory epithelial cells. In a neonatal mouse, only strains with intact agr and sarA loci were consistently associated with invasive, fatal pulmonary infection (P < 0.001) and sarA was specifically required to cause bacteremia (P < 0.001). The agr and/or sarA mutants were, nonetheless, fully capable of producing pneumonia and were as proficient as the wild-type strain in stimulating epithelial IL-8 expression, a polymorphonuclear leukocyte chemokine, in airway cells. In contrast, agr and especially sarA mutants induced less epithelial GM-CSF expression, and MSCRAMM mutants lacking fibronectin binding proteins or clumping factor A, a ligand for fibrinogen, were unable to stimulate epithelial GM-CSF production. The ability to induce IL-8 expression was independent of the adherence properties of intact bacteria, indicating that shed and/or secreted bacterial components activate epithelial responses. While conserved staphylococcal components such as peptidoglycan are sufficient to evoke inflammation and cause pneumonia, the agr and sarA loci of S. aureus are critical for the coordination of invasive infection of the lungs.

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Section: Discussionmentioning

confidence: 99%

Staphylococcus aureusagrandsarAFunctions Are Required for Invasive Infection but Not Inflammatory Responses in the Lung

et al. 2002

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“…Previous studies into the crystal structures of ClfA, ClfB and SdrG have revealed the molecular mechanism underlying ligand-binding by A region in these MSCRAMMs (Ponnuraj et al, 2003;Ganesh et al, 2008). Typically, MSCRAMMs have been reported to bind to fi brinogen, fi bronectin, neurexin and IgGs (Hartford et al, 2001;Deivanayagam et al, 2002;Barbu et al, 2010;Ganesh et al, 2011). Our recent work has also revealed a multi-ligand binding mechanism of ClfB, thus raising the possibility that multi-ligand binding might be a common characteristic shared by multiple MSCRAMMs (Xiang et al, 2012).…”

Section: Introductionmentioning

confidence: 95%

“…In the structure, B1 domain interacts with N2 domain, further opening the groove between N2 and N3 for potential ligands to fi t in. The identification of the conserved ligand binding groove between SdrD and ClfB provides important insights into the features of the potential ligands that SdrD binds to (Hartford et al, 2001;Ponnuraj et al, 2003;Ganesh et al, 2011;Xiang et al, 2012). The conserved residues in ClfB mentioned above have been reported to specifi cally recognize a GSR motif derivative of the ligands (Xiang et al, 2012), with the sequence GSSGXGXXG.…”

Section: Structural Comparison Of Sdrd B1 Domain With Cnamentioning

confidence: 99%

Structures of SdrD from Staphylococcus aureus reveal the molecular mechanism of how the cell surface receptors recognize their ligands

Wang

Liu

et al. 2013

Protein Cell

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“…For a ClfA-containing vaccine, elicitation of functional antibodies that prevent the binding of S. aureus cells to immobilized Fg constitutes a critical measure of the neutralization of this virulence factor. Enzyme-linked immunosorbent assay (ELISA)-based whole-cell S. aureus ClfA-Fg binding assays have previously been used to define Fg ␥-chain peptide and ClfA sequences responsible for S. aureus Fg binding and to identify a monoclonal antibody (MAb) that can interfere with this interaction (14,15,27). A radiometric assay to measure ClfA immune serum titers in response to a DNA vaccine has also been described (4).…”

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confidence: 99%

A Recombinant Clumping Factor A-Containing Vaccine Induces Functional Antibodies to Staphylococcus aureus That Are Not Observed after Natural Exposure

Hawkins

Kodali

Matsuka

et al. 2012

Clin Vaccine Immunol

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Staphylococcus aureus is a Gram-positive pathogen that causes devastating disease and whose pathogenesis is dependent on interactions with host cell factors. Staphylococcal clumping factor A (ClfA) is a highly conserved fibrinogen (Fg)-binding protein and virulence factor that contributes to host tissue adhesion and initiation of infection. ClfA is being investigated as a possible component of a staphylococcal vaccine. We report the development of an Fg-binding assay that is specific for ClfA-mediated binding. Using the assay, we show that despite the presence of anti-ClfA antibodies, human sera from unvaccinated subjects are unable to prevent the binding of S. aureus to an Fg-coated surface. In contrast, antibodies elicited by a recombinant ClfA-containing vaccine were capable of blocking the ClfA-dependent binding of a diverse and clinically relevant collection of staphylococcal strains to Fg. These functional antibodies were also able to displace S. aureus already bound to Fg, suggesting that the ligand-binding activity of ClfA can be effectively neutralized through vaccination.

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Identification of Residues in the Staphylococcus aureus Fibrinogen-binding MSCRAMM Clumping Factor A (ClfA) That Are Important for Ligand Binding

Cited by 70 publications

References 38 publications

Staphylococcus aureusagrandsarAFunctions Are Required for Invasive Infection but Not Inflammatory Responses in the Lung

Staphylococcus aureusagrandsarAFunctions Are Required for Invasive Infection but Not Inflammatory Responses in the Lung

Structures of SdrD from Staphylococcus aureus reveal the molecular mechanism of how the cell surface receptors recognize their ligands

A Recombinant Clumping Factor A-Containing Vaccine Induces Functional Antibodies to Staphylococcus aureus That Are Not Observed after Natural Exposure

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