Staphylococcus aureus alpha toxin activates Notch in vascular cells.

Area of Science:

• Vascular Biology
• Microbiology
• Cell Signaling

Background:

• Staphylococcus aureus infections cause significant morbidity, exacerbated by antibiotic resistance.
• The toxin hemolysin alpha toxin (Hla) uses ADAM10 to mediate effects and is linked to Notch signaling.
• Notch signaling regulates angiogenesis and is crucial in vascular and perivascular cells.

Purpose of the Study:

• To investigate if Staphylococcus aureus Hla activates Notch signaling in vascular cells.
• To elucidate the role of ADAM10 and γ-secretase in Hla-mediated Notch activation.
• To explore the in vivo relevance of Hla-induced Notch activation during S. aureus infection.

Main Methods:

• In vitro studies using human umbilical vein endothelial cells treated with recombinant Hla.
• Luciferase assays, immunocytochemistry, and Western blotting to assess Notch activation.
• In vivo studies using Notch reporter mice (retinal EC, aortic rings, skin inoculation) and human liver tissue analysis.

Main Results:

• Recombinant Hla significantly increased Notch activation in endothelial cells, dependent on ADAM10 and γ-secretase.
• Hla induced Notch activation in mouse retinal EC, aortic tip cells during sprouting, and skin post-infection.
• Human liver tissue from S. aureus infected patients showed elevated Notch expression in vascular and perivascular cells.

Conclusions:

• Staphylococcus aureus Hla toxin potently activates Notch signaling in vascular cells.
• This Hla-mediated Notch activation may play a role in the pathobiology of S. aureus infections.
• The findings suggest a novel mechanism linking bacterial toxins to host vascular signaling pathways.