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Staphylococcus aureus alpha toxin mediates polymorphonuclear leukocyte-induced vasocontraction and endothelial
Michael Buerke1, Ulf Sibelius, Ulrich Grandel
1Department of Medicine, Johannes Gutenberg-University, Mainz, Germany.
Abstract:
The effect of Staphylococcus aureus alpha toxin (alpha-toxin) on selectin-mediated neutrophil adhesion was investigated in polymorphonuclear leukocyte- (PMN) induced vasocontraction and endothelial dysfunction. Adherence of human PMNs to rat aortic endothelium increased significantly following stimulation of the endothelium with alpha-toxin (0.1, 0.5, and 1 microg/mL). This effect could be significantly attenuated by monoclonal antibodies directed against P-selectin or fucoidin, a carbohydrate known to block selectins. Unstimulated human PMNs (10(6)cells/mL) were added to organ chambers containing rat aortic rings stimulated with alpha-toxin (0.5 microg/mL). PMNs elicited a significant vasocontraction in alpha-toxin-stimulated, but not in control aortic, rings (142+/-12 mg versus 12+/-4 mg, P < 0.05). This PMN-induced vasocontraction was virtually blunted by pretreatment with MAb directed against P-selectin or fucoidin (P < 0.05). Endothelial function as assessed by endothelium-dependent vasorelaxation to acetylcholine was substantially inhibited after induction of PMN-induced vasocontraction in alpha-toxin-stimulated aortic rings. This endothelial dysfunction was reduced by P-selectin MAb or fucoidin. In contrast, endothelium-independent relaxation to sodium nitrite was not altered by PMN incubation, indicating that vascular smooth muscle function was unaffected. Thus, PMN-endothelial interaction following S. aureus a-toxin activation of the vascular endothelium is at least, in part, mediated by selectins. As a consequence, PMN-induced vasocontraction and endothelial dysfunction occur. Such mechanisms may be involved in microcirculation abnormalities encountered in sepsis or septic shock due to S. aureus infection.
Insights
Staphylococcus aureus alpha-toxin promotes neutrophil adhesion and vascular dysfunction by activating selectins. This interaction leads to vasocontraction and impaired endothelial function, potentially contributing to sepsis complications.
Area of Science:
- Vascular Biology
- Microbiology
- Immunology
Background:
- Staphylococcus aureus alpha-toxin is a key virulence factor.
- Neutrophil (PMN) interactions with endothelium contribute to vascular dysfunction in sepsis.
- The role of selectins in alpha-toxin-induced PMN adhesion and vascular effects is not fully understood.
Purpose of the Study:
- To investigate the effect of Staphylococcus aureus alpha-toxin on selectin-mediated neutrophil adhesion.
- To determine the role of PMN-endothelial interactions in alpha-toxin-induced vasocontraction and endothelial dysfunction.
- To elucidate the mechanisms underlying microcirculation abnormalities in S. aureus infections.
Main Methods:
- Human PMNs were incubated with alpha-toxin-stimulated rat aortic endothelium.
- Vasocontraction was measured in rat aortic rings exposed to alpha-toxin and PMNs.
- Monoclonal antibodies against P-selectin and fucoidin were used to block selectin interactions.
- Endothelial function was assessed by vasorelaxation responses to acetylcholine and sodium nitrite.
Main Results:
- Alpha-toxin significantly increased human PMN adherence to rat aortic endothelium.
- This adherence was attenuated by P-selectin antibodies and fucoidin.
- PMNs induced significant vasocontraction in alpha-toxin-stimulated aortic rings, which was blocked by P-selectin inhibition.
- Endothelium-dependent vasorelaxation was impaired, while endothelium-independent relaxation was unaffected.
Conclusions:
- PMN-endothelial interactions, mediated by selectins, are crucial in alpha-toxin-induced vasocontraction and endothelial dysfunction.
- These findings highlight a potential mechanism for microcirculatory disturbances in S. aureus sepsis.
- Targeting selectin-mediated interactions may offer therapeutic strategies for sepsis-related complications.