The extracellular adherence protein (Eap) of Staphylococcus aureus inhibits wound healing by interfering with host defense and repair mechanisms.
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 kappaB (NFkappaB) in leukocytes associated with a decrease in expression of tissue factor. Moreover, Eap blocked alphav-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.
Athanasopoulos
Athanasios N
AN
Experimental Immunology Branch, NCI, NIH, Center Dr, Rm 4B17, Bethesda, MD 20892, USA.
Economopoulou
Matina
M
Orlova
Valeria V
VV
Sobke
Astrid
A
Schneider
Darius
D
Weber
Holger
H
Augustin
Hellmut G
HG
Eming
Sabine A
SA
Schubert
Uwe
U
Linn
Thomas
T
Nawroth
Peter P
PP
Hussain
Muzaffar
M
Hammes
Hans-Peter
HP
Herrmann
Mathias
M
Preissner
Klaus T
KT
Chavakis
Triantafyllos
T
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D016384:Consensus Sequence; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000382:microbiology / Q000502:physiology*; D017353:Gene Deletion; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D007962:Leukocytes / Q000187:drug effects / Q000382:microbiology / Q000502:physiology; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000235:genetics / Q000472:pathogenicity*; D014471:Umbilical Veins; D014945:Wound Healing / Q000187:drug effects*; D014947:Wounds and Injuries / Q000382:microbiology / Q000503:physiopathology*
D001426:Bacterial Proteins; C444739:Eap-N protein, Staphylococcus aureus; D016328:NF-kappa B; D016601:RNA-Binding Proteins; D018799:Intercellular Adhesion Molecule-1