title: Phenol-soluble modulin α4 mediates Staphylococcus aureus-associated vascular leakage by stimulating heparin-binding protein release from neutrophils.
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 Ca(2+) 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.
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of infection and immunity, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Yaya
authors.initials: Y
authors.lastname: Pian
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Shaolong
authors.initials: S
authors.lastname: Chen
authors.affiliation: Institution of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Huaijie
authors.initials: H
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: National Center of Biomedical Analysis, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Keke
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of laboratory medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001427:Bacterial Toxins / Q000737:chemistry / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism*; D002199:Capillary Permeability / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D003470:Culture Media; D005089:Exocytosis / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013203:Staphylococcal Infections / Q000378:metabolism; D013211:Staphylococcus aureus / Q000472:pathogenicity / Q000502:physiology*; D037521:Virulence Factors / Q000502:physiology*
chemical_list: C062991:AZU1 protein, human; D023181:Antimicrobial Cationic Peptides; D001427:Bacterial Toxins; D001798:Blood Proteins; D002352:Carrier Proteins; D003470:Culture Media; D037521:Virulence Factors; C025971:staphylococcal delta toxin