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Toxins 2017, 9(10), 332; doi:10.3390/toxins9100332

P2X-Receptor Antagonists Inhibit the Interaction of S. aureus Hemolysin A with Membranes

1
Institute for Molecular Biophysics, Jakob-Welder-Weg 26, University of Mainz, 55128 Mainz, Germany
2
Institute of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg-University Mainz, Hochhaus am Augustusplatz, 55131 Mainz, Germany
Current affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Johann-Joachim-Becher-Weg 30, 55128 Mainz, Germany.
*
Author to whom correspondence should be addressed.
Academic Editors: Evelyne Benoit and Jordi Molgo
Received: 7 September 2017 / Revised: 8 October 2017 / Accepted: 15 October 2017 / Published: 19 October 2017
(This article belongs to the Special Issue Toxins and Ion Channels)
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Abstract

The pore forming hemolysin A, Hla, is a major virulence factor of Staphylococcus aureus. Apparently, 1–2 pore(s) per cell suffice(s) to cause cell death. Accumulated experimental evidence points towards a major role of ATP-gated purinergic receptors (P2XR) for hemolysis caused by Hla, complement and other pore forming proteins, presumably by increasing membrane permeability. Indeed, in experiments employing rabbit erythrocytes, inhibitory concentrations of frequently employed P2XR-antagonists were in a similar range as previously reported for erythrocytes of other species and other toxins. However, Hla-dependent hemolysis was not enhanced by extracellular ATP, and oxidized adenosinetriphosphate (oxATP) had only a minor inhibitory effect. Unexpectedly, P2XR-inhibitors also prevented Hla-induced lysis of pure lipid membranes, demonstrating that the inhibition did not even depend on the presence of P2XR. Fluorescence microscopy and gel-electrophoresis clearly revealed that P2XR-inhibitors interfere with binding and subsequent oligomerisation of Hla with membranes. Similar results were obtained employing HaCaT-cells. Furthermore, calorimetric data and hemolysis experiments with Hla pre-treated with pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) showed that this compound directly binds to Hla. Our results call for a critical re-assessment of the appealing concept, which suggests that P2XR are general amplifiers of damage by pore-forming proteins. View Full-Text
Keywords: hemolysin; pore forming toxin; Staphylococcus aureus; P2XR; P2XR-antagonists; erythrocytes; HaCaT-cells; liposomes; oligomerisation hemolysin; pore forming toxin; Staphylococcus aureus; P2XR; P2XR-antagonists; erythrocytes; HaCaT-cells; liposomes; oligomerisation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Schwiering, M.; Husmann, M.; Hellmann, N. P2X-Receptor Antagonists Inhibit the Interaction of S. aureus Hemolysin A with Membranes. Toxins 2017, 9, 332.

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