Abstract
Staphylococcus aureus causes severe, life-threatening infections that often are complicated by severe local and systemic pathologies with non-healing lesions. A classic example is S. aureus infective endocarditis (IE), where the secreted hemolysin β-toxin potentiates the disease via its sphingomyelinase and biofilm ligase activities. Although these activities dysregulate human aortic endothelial cell activation, β-toxin effect on endothelial cell function in wound healing has not been addressed. With the use of the ex vivo rabbit aortic ring model, we provide evidence that β-toxin prevents branching microvessel formation, highlighting its ability to interfere with tissue re-vascularization and vascular repair. We show that β-toxin specifically targets both human aortic endothelial cell proliferation and cell migration and inhibits human umbilical vein endothelial cell rearrangement into capillary-like networks in vitro. Proteome arrays specific for angiogenesis-related molecules provided evidence that β-toxin promotes an inhibitory profile in endothelial cell monolayers, specifically targeting production of TIMP-1, TIMP-4, and IGFBP-3 to counter the effect of a pro-angiogenic environment. Dysregulation in the production of these molecules is known to result in sprouting defects (including deficient cell proliferation, migration, and survival), vessel instability and/or vascular regression. When endothelial cells are grown under re-endothelialization/wound healing conditions, β-toxin decreases the pro-angiogenic molecule MMP-8 and increases the anti-angiogenic molecule endostatin. Altogether, the data indicate that β-toxin is an anti-angiogenic virulence factor and highlight a mechanism where β-toxin exacerbates S. aureus invasive infections by interfering with tissue re-vascularization and vascular repair.
Highlights
Staphylococcus aureus is the causative agent of numerous diseases including skin and soft-tissue infections, bacteremia, toxic shock syndrome, pneumonia, and infective endocarditis (IE) (SalgadoPabón and Schlievert, 2014)
The cytolysin β-toxin is encoded by a majority of S. aureus strains and shown to be expressed in S. aureus isolates causing chronic infections in humans as well as in isolates recovered from the heart, lung, kidneys, and liver in experimental IE in rabbits (Hedstrom and Malmqvist, 1982; Goerke et al, 2004; Salgado-Pabón et al, 2014). β-toxin expression is conditional, as the hlb gene is disrupted by the φSa3int prophage in most S. aureus strains (Winkler et al, 1965; Mason and Allen, 1975)
While β-toxin can diminish the complexity of capillary-like structures formed in vitro, conclusive evidence comes from ex vivo studies that demonstrate β-toxin prevents branching microvessel formation, highlighting its ability to interfere with tissue re-vascularization and vascular repair
Summary
Staphylococcus aureus is the causative agent of numerous diseases including skin and soft-tissue infections, bacteremia, toxic shock syndrome, pneumonia, and infective endocarditis (IE) (SalgadoPabón and Schlievert, 2014). Β-toxin expression is conditional, as the hlb gene is disrupted by the φSa3int prophage in most S. aureus strains (Winkler et al, 1965; Mason and Allen, 1975) It means that β-toxin production is controlled by phage excision, where the φSa3int prophage functions as a phageregulatory switch that allows expression in response to host signals (Salgado-Pabón et al, 2014; Tran et al, 2019). In human aortic endothelial cells, β-toxin decreases expression of the chemokine IL-8 and upregulates expression of VCAM-1, both of which are important angiogenic molecules (Heidemann et al, 2003; Tajima et al, 2009; Herrera et al, 2017; Kong et al, 2018) These studies indicate that a central process may exist where β-toxin targets angiogenesis as a pathogenesis mechanism that enhances S. aureus infections. While β-toxin can diminish the complexity of capillary-like structures formed in vitro, conclusive evidence comes from ex vivo studies that demonstrate β-toxin prevents branching microvessel formation, highlighting its ability to interfere with tissue re-vascularization and vascular repair
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