title: ADAM10 mediates vascular injury induced by Staphylococcus aureus α-hemolysin.
abstract: Staphylococcus aureus is a leading cause of bacteremia and sepsis. The interaction of S. aureus with the endothelium is central to bloodstream infection pathophysiology yet remains ill-understood. We show herein that staphylococcal α-hemolysin, a pore-forming cytotoxin, is required for full virulence in a murine sepsis model. The α-hemolysin binding to its receptor A-disintegrin and metalloprotease 10 (ADAM10) upregulates the receptor's metalloprotease activity on endothelial cells, causing vascular endothelial-cadherin cleavage and concomitant loss of endothelial barrier function. These cellular injuries and sepsis severity can be mitigated by ADAM10 inhibition. This study therefore provides mechanistic insight into toxin-mediated endothelial injury and suggests new therapeutic approaches for staphylococcal sepsis.
authors.affiliation: Department of Microbiology, The University of Chicago, Illinois 60637, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Powers
authors.forename: Hwan Keun
authors.initials: HK
authors.lastname: Kim
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Juliane
authors.initials: J
authors.lastname: Bubeck Wardenburg
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006460:Hemolysin Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D011485:Protein Binding; D034741:RNA, Small Interfering; D013211:Staphylococcus aureus / Q000378:metabolism* / Q000472:pathogenicity; D014774:Virulence
chemical_list: D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C021091:staphylococcal alpha-toxin; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human