NATURE MEDICINE • VOLUME 8 • NUMBER 7 • JULY 2002 687 ARTICLES Staphylococcus aureus is a highly virulent pathogen posing an un- abated challenge both in community-acquired as well as nosoco- mial infections 1 . The advent of methicillin resistance, sporadically observed since the 1960s but increasing worldwide since 1990s (ref. 2), has only recently been topped by the discov- ery of isolates with reduced susceptibility to vancomycin 3 , which renders the pathogen potentially resistant to all available an- timicrobials. S. aureus is a frequent colonizer of the human skin and mucous membranes; the organism readily gains access to the tissue through various breaks of the skin barrier. Wound in- fection is frequently associated with impaired healing; however, interference of S. aureus with wound-healing mechanisms is poorly understood and is thought to rely on a variety of different virulence factors. These include exotoxins and exoenzymes (en- terotoxins A–H, epidermolytic toxin A and toxic shock syn- drome toxin-1 (TSST-1)) some of which act as superantigens by binding to major histocompatibility (MHC) class II protein and stimulate T-cell proliferation 4–6 . Moreover, bacterial cell wall–an- chored adhesins mediate the adherence of S. aureus to host ex- tracellular matrix components such as fibronectin (FN), fibrinogen (FBG), vitronectin (VN), collagen or elastin which thereby contribute to bacterial colonization of host tissues 7–13 . In particular, binding of S. aureus to FBG is predominantly me- diated by clumping factor and has been implicated in the devel- opment of endocarditis or the attachment of bacteria to implanted biomaterials 9,14 . Although FN-binding proteins en- hance bacterial invasion of various cell types such as endothelial cells, epithelial cells or fibroblasts 15,16 , S. aureus produces and se- cretes other FBG-binding proteins. These include coagulase (im- portant in the development of pulmonary infection 17,18 ), the extracellular FBG-binding protein (Efb) 19 , as well as a 60-kD pro- tein with a broad repertoire of binding interactions to host ex- tracellular matrix components. This latter protein was designated Map (MHC class II analogous protein) or Eap (extra- cellular adherence protein) because of its ability to enhance bac- terial adherence 20–22 . However, the possibility that these secreted bacterial proteins—especially Eap—interfere with the host-de- fense systems has not been thoroughly investigated. As an immediate response towards bacterial infection or in- jury, leukocytes migrate from the blood stream into extravascu- lar sites of inflammation. This coordinated sequence of adhesion and locomotion steps requires the expression and upregulation of various adhesion receptors on the surface of mobile and sta- tionary vascular cells. Although leukocyte rolling depends on se- lectins, the firm adhesion to and transmigration through the endothelium is predominantly mediated by the β 2 -integrins Mac-1 (CD11b/CD18, αMβ2, CR3) and lymphocyte function-as- sociated antigen-1 (LFA-1) (CD11α/CD18, α L β 2 ) that interact with their major counter-receptor intercellular adhesion mole- cule 1 (ICAM-1) on endothelial cells. Mac-1 also regulates leuko- cyte adhesion to provisional matrix substrates including FBG, which is deposited at sites of inflammation and injury upon in- Staphylococcus aureus extracellular adherence protein serves as anti-inflammatory factor by inhibiting the recruitment of host leukocytes TRIANTAFYLLOS CHAVAKIS 1,2 , MUZAFFAR HUSSAIN 3 , SANDIP M. KANSE 1 , GEORG PETERS 3 , REINHARD G. BRETZEL 2 , JAN-INGMAR FLOCK 4 , MATHIAS HERRMANN 5 & KLAUS T. PREISSNER 1 1 Institute for Biochemistry and 2 Third Department of Internal Medicine, Justus-Liebig-Universität, Giessen, Germany 3 Institute of Medical Microbiology, University Hospital, Münster, Germany 4 Department of Microbiology, Pathology and Immunology, Karolinska Institutet, Huddinge University Hospital, Huddinge, Sweden 5 Department of Bacteriology and Hygiene, Institute of Medical Microbiology and Hygiene, Saarland University Hospital, Homburg/Saar, Germany Correspondence should be addressed to T.C.; email: triantafyllos.chavakis@innere.med.uni-giessen.de Published online: 24 June 2002, doi:10.1038/nm728 Staphylococcus aureus is a human pathogen that secretes proteins that contribute to bacterial col- onization. Here we describe the extracellular adherence protein (Eap) as a novel anti-inflamma- tory factor that inhibits host leukocyte recruitment. Due to its direct interactions with the host adhesive proteins intercellular adhesion molecule 1 (ICAM-1), fibrinogen or vitronectin, Eap dis- rupted β 2 -integrin and urokinase receptor–mediated leukocyte adhesion in vitro. Whereas Eap-ex- pressing S. aureus induced a 2–3-fold lower neutrophil recruitment in bacterial peritonitis in mice as compared with an Eap-negative strain, isolated Eap prevented β 2 -integrin-dependent neu- trophil recruitment in a mouse model of acute thioglycollate-induced peritonitis. Thus, the spe- cific interactions with ICAM-1 and extracellular matrix proteins render Eap a potent anti-inflammatory factor, which may serve as a new therapeutic substance to block leukocyte ex- travasation in patients with hyperinflammatory pathologies. © 2002 Nature Publishing Group http://medicine.nature.com