Abstract
Vascular leakage frequently occurs in patients with severe Staphylococcus aureus infection. However, the mechanism underlying S. aureus infection-induced vascular leakage remains unclear. Here, we identified the S. aureus virulence factor phenol-soluble modulin (PSM)α4 from the culture supernatant of strain USA300 as a stimulator of heparin-binding protein (HBP) release from polymorphonuclear neutrophils (PMNs) and demonstrated that PSMα4-induced HBP release from PMNs leads to vascular leakage. PSMα4 appeared less cytolytic than PSMα1–3 and was insensitive to lipoproteins; it significantly increased myeloperoxidase and elastase release from PMNs and cell surface CD63 expression in PMNs. PSMα4-induced HBP release required formyl peptide receptor 2 (FPR2) and phosphoinositide 3-kinase (PI3K) and depended on Ca2+ influx and cytoskeleton rearrangement. Thus, PSMα4 may stimulate HBP release by activating FPR2 and PI3K to initiate PMN degranulation. PSMα4-induced HBP release from PMNs increased endothelial cell monolayer permeability in vitro and induced vascular leakage in mice. This novel function of PSMα4 may contribute to the pathogenesis of S. aureus and may be a potential therapeutic target.
Highlights
In addition to these well-recognized virulence factors, phenol-soluble modulin (PSM)α,which was originally identified from Staphylococcus epidermidis[12], is an important virulence factor of S. aureus
Heparin-binding protein (HBP) is stored in secretory vesicles and primary granules of human polymorphonuclear neutrophils (PMNs)[23,24], and its release is stimulated by multiple mediators, including lipid leukotriene B4 (LTB4)[25], M protein[26,27], and streptolysin O (SLO)[28], and results in vascular leakage
The current study revealed that PSMα4 secreted by S. aureus stimulated HBP release from PMNs and caused vascular leakage in vivo in a mouse model
Summary
In addition to these well-recognized virulence factors, phenol-soluble modulin (PSM)α,which was originally identified from Staphylococcus epidermidis[12], is an important virulence factor of S. aureus. Heparin-binding protein (HBP) is an early diagnostic marker for severe sepsis or septic shock caused by invasive bacterial infection[18,19,20,21]. It mediates neutrophil-evoked vascular leakage by inducing Ca2+-dependent cytoskeleton rearrangement in endothelial cells and promoting intercellular gap formation between endothelial cells[22]. HBP is stored in secretory vesicles and primary granules of human polymorphonuclear neutrophils (PMNs)[23,24], and its release is stimulated by multiple mediators, including lipid leukotriene B4 (LTB4)[25], M protein[26,27], and streptolysin O (SLO)[28], and results in vascular leakage.
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