Brosnahan Amanda J, Mantz Mary J, Squier Christopher A, Peterson Marnie L, Schlievert Patrick M
Department of Microbiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
J Immunol. 2009 Feb 15;182(4):2364-73. doi: 10.4049/jimmunol.0803283.
Staphylococcus aureus and Streptococcus pyogenes colonize mucosal surfaces of the human body to cause disease. A group of virulence factors known as superantigens are produced by both of these organisms that allows them to cause serious diseases from the vaginal (staphylococci) or oral mucosa (streptococci) of the body. Superantigens interact with T cells and APCs to cause massive cytokine release to mediate the symptoms collectively known as toxic shock syndrome. In this study we demonstrate that another group of virulence factors, cytolysins, aid in the penetration of superantigens across vaginal mucosa as a representative nonkeratinized stratified squamous epithelial surface. The staphylococcal cytolysin alpha-toxin and the streptococcal cytolysin streptolysin O enhanced penetration of toxic shock syndrome toxin-1 and streptococcal pyrogenic exotoxin A, respectively, across porcine vaginal mucosa in an ex vivo model of superantigen penetration. Upon histological examination, both cytolysins caused damage to the uppermost layers of the vaginal tissue. In vitro evidence using immortalized human vaginal epithelial cells demonstrated that although both superantigens were proinflammatory, only the staphylococcal cytolysin alpha-toxin induced a strong immune response from the cells. Streptolysin O damaged and killed the cells quickly, allowing only a small release of IL-1beta. Two separate models of superantigen penetration are proposed: staphylococcal alpha-toxin induces a strong proinflammatory response from epithelial cells to disrupt the mucosa enough to allow for enhanced penetration of toxic shock syndrome toxin-1, whereas streptolysin O directly damages the mucosa to allow for penetration of streptococcal pyrogenic exotoxin A and possibly viable streptococci.
金黄色葡萄球菌和化脓性链球菌定殖于人体黏膜表面从而引发疾病。这两种微生物都会产生一类被称为超抗原的毒力因子，这些毒力因子使它们能够从人体的阴道（葡萄球菌）或口腔黏膜（链球菌）引发严重疾病。超抗原与T细胞和抗原呈递细胞相互作用，导致大量细胞因子释放，从而介导统称为中毒性休克综合征的症状。在本研究中，我们证明另一类毒力因子——溶细胞素，有助于超抗原穿透阴道黏膜，阴道黏膜是一种典型的非角化复层鳞状上皮表面。在超抗原穿透的体外模型中，葡萄球菌溶细胞素α毒素和链球菌溶细胞素溶血素O分别增强了中毒性休克综合征毒素-1和化脓性链球菌外毒素A穿过猪阴道黏膜的能力。经组织学检查，两种溶细胞素均对阴道组织的最上层造成了损伤。使用永生化人阴道上皮细胞的体外证据表明，尽管两种超抗原都具有促炎作用，但只有葡萄球菌溶细胞素α毒素能诱导细胞产生强烈的免疫反应。溶血素O迅速损伤并杀死细胞，仅允许少量白细胞介素-1β释放。我们提出了两种不同的超抗原穿透模型：葡萄球菌α毒素诱导上皮细胞产生强烈的促炎反应，足以破坏黏膜，从而增强中毒性休克综合征毒素-1的穿透；而溶血素O直接损伤黏膜，以允许化脓性链球菌外毒素A以及可能的活链球菌穿透。
