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Blood, 1 April 2006, Vol. 107, No. 7, pp. 2720-2727.
Prepublished online as a Blood First Edition Paper on November 29, 2005; DOI 10.1182/blood-2005-08-3140.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The extracellular adherence protein (Eap) of Staphylococcus aureus inhibits wound healing by interfering with host defense and repair mechanisms
Athanasios N. Athanasopoulos,
Matina Economopoulou,
Valeria V. Orlova,
Astrid Sobke,
Darius Schneider,
Holger Weber,
Hellmut G. Augustin,
Sabine A. Eming,
Uwe Schubert,
Thomas Linn,
Peter P. Nawroth,
Muzaffar Hussain,
Hans-Peter Hammes,
Mathias Herrmann,
Klaus T. Preissner, and
Triantafyllos Chavakis
From the Experimental Immunology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD; Department of Internal Medicine, University of Heidelberg, Germany; Fifth Medical Department, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany; Institute of Medical Microbiology, University of Saarland, Homburg/Saar, Germany; Department of Internal Medicine and Institute for Biochemistry, University of Giessen, Germany; Department of Vascular Biology and Angiogenesis, Research Tumor Biology Center, Freiburg, Germany; Department of Dermatology, University of Cologne, Germany; and Institute of Medical Microbiology, University Hospital, Münster, Germany.
Staphylococcus aureus is a major human pathogen interfering with host-cell functions. Impaired wound healing is often observed in S aureus–infected wounds, yet, the underlying mechanisms are poorly defined. Here, we identify the extracellular adherence protein (Eap) of S aureus to be responsible for impaired wound healing. In a mouse wound-healing model wound closure was inhibited in the presence of wild-type S aureus and this effect was reversible when the wounds were incubated with an isogenic Eap-deficient strain. Isolated Eap also delayed wound closure. In the presence of Eap, recruitment of inflammatory cells to the wound site as well as neovascularization of the wound were prevented. In vitro, Eap significantly reduced intercellular adhesion molecule 1 (ICAM-1)–dependent leukocyte-endothelial interactions and diminished the consequent activation of the proinflammatory transcription factor nuclear factor  B (NFB) in leukocytes associated with a decrease in expression of tissue factor. Moreover, Eap blocked  v-integrin–mediated endothelial-cell migration and capillary tube formation, and neovascularization in matrigels in vivo. Collectively, the potent anti-inflammatory and antiangiogenic properties of Eap provide an underlying mechanism that may explain the impaired wound healing in S aureus–infected wounds. Eap may also serve as a lead compound for new anti-inflammatory and antiangiogenic therapies in several pathologies.
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