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

我们先前已经证明，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在体外和体内介导了金黄色葡萄球菌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/神经酰胺系统是金黄色葡萄球菌败血症期间肺水肿发生所必需的，酸性鞘磷脂酶的遗传缺陷或药物抑制可以保护小鼠免受金黄色葡萄球菌引起的肺水肿、内皮紧密连接蛋白的破坏和中性粒细胞重新聚集到肺中。最重要的是，酸性鞘磷脂酶缺乏症还可以预防全身感染金黄色葡萄球菌的致命影响。利用一组金黄色葡萄球菌突变体和重组或纯化的毒素，我们将定义激活内皮细胞中的酸性鞘磷脂酶/神经酰胺系统从而导致肺水肿的细菌毒素；表征这些毒素刺激酸性鞘磷脂酶并触发神经酰胺释放的分子机制；以及确定在体外和体内金黄色葡萄球菌介导的酸性鞘磷脂酶/神经酰胺系统的激活上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.