Role of the acid sphingomyelinase/ceramide system in lung edema induced by Staphylococcus aureus toxin

我们以前已经表明，酸性鞘磷脂酶/神经酰胺系统是细菌感染的重要介质。最近，我们发现酸性鞘磷脂酶和神经酰胺介导了金黄色葡萄球菌（S. aureus）感染后内皮细胞紧密连接的破坏。我们进一步证明，酸性鞘磷脂酶/神经酰胺系统对于金黄色葡萄球菌脓毒症期间肺水肿的发展是必要的，并且酸性鞘磷脂酶的遗传缺陷或药理抑制可以保护小鼠免受金黄色葡萄球菌诱导的肺水肿、内皮紧密连接蛋白的破坏和中性粒细胞进入肺的募集。最重要的是，酸性鞘磷脂酶缺乏也可以防止金黄色葡萄球菌全身感染的致命影响。使用一组金黄色葡萄球菌突变体和重组或纯化的毒素，我们将确定激活内皮细胞中的酸性鞘磷脂酶/神经酰胺系统并从而诱导肺水肿的细菌毒素；表征这些毒素刺激酸性鞘磷脂酶和触发神经酰胺释放的分子机制；并确定在体外和体内金黄色葡萄球菌介导的酸性鞘磷脂酶/神经酰胺系统激活过程中破坏内皮紧密连接的细胞靶点。

We have previously shown that the acid sphingomyelinase/ceramide system is an important mediator of bacterial infections. Recently, we showed that acid sphingomyelinase and ceramide mediate the disruption of tight junctions of endothelial cells in vitro and in vivo upon infection with Staphylococcus aureus (S. aureus). We further demonstrated that the acid sphingomyelinase/ceramide system is necessary for the development of lung edema during S. aureus sepsis and that genetic deficiency or pharmacological inhibition of acid sphingomyelinase protects mice from S. aureus-induced lung edema, disruption of endothelial tight junction proteins, and recruitment of neutrophils into the lung. Most importantly, acid sphingomyelinase deficiency also prevents the lethal effects of systemic infection with S. aureus. Using a panel of S. aureus mutants and recombinant or purified toxins, we will define the bacterial toxins that activate the acid sphingomyelinase/ceramide system in endothelial cells and thereby induce lung edema; characterize the molecular mechanisms by which these toxins stimulate acid sphingomyelinase and trigger the release of ceramide; and define the cellular targets that disrupt endothelial tight junctions upon S. aureus-mediated activation of the acid sphingomyelinase/ceramide system in vitro and in vivo.