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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ADAM Proteins / metabolism*
-
ADAM10 Protein
-
Amyloid Precursor Protein Secretases / metabolism*
-
Animals
-
Bacterial Toxins / genetics
-
Bacterial Toxins / metabolism
-
Bacterial Toxins / toxicity*
-
Cells, Cultured
-
Endothelial Cells / drug effects*
-
Endothelial Cells / pathology
-
Gene Expression Regulation, Bacterial / physiology
-
Gene Expression Regulation, Enzymologic
-
Hemolysin Proteins / genetics
-
Hemolysin Proteins / metabolism
-
Hemolysin Proteins / toxicity*
-
Humans
-
Membrane Proteins / metabolism*
-
Mice
-
Mice, Inbred BALB C
-
Mutation
-
Protein Binding
-
RNA, Small Interfering
-
Staphylococcus aureus / metabolism*
-
Staphylococcus aureus / pathogenicity
-
Virulence
Substances
-
Bacterial Toxins
-
Hemolysin Proteins
-
Membrane Proteins
-
RNA, Small Interfering
-
staphylococcal alpha-toxin
-
Amyloid Precursor Protein Secretases
-
ADAM Proteins
-
ADAM10 Protein
-
ADAM10 protein, human