The endothelium plays a critical role in the host response to infection and has been a focus of investigation in sepsis. While it is appreciated that intravascular thrombus formation, severe inflammation, and loss of endothelial integrity impair tissue oxygenation during sepsis, the precise molecular mechanisms that lead to endothelial injury remain poorly understood. We demonstrate here that endothelial ADAM10 was essential for the pathogenesis of Staphylococcus aureus sepsis, contributing to α-toxin–mediated (Hla-mediated) microvascular thrombus formation and lethality. As ADAM10 is essential for endothelial development and homeostasis, we examined whether other major human sepsis pathogens also rely on ADAM10-dependent pathways in pathogenesis. Mice harboring an endothelium-specific knockout of ADAM10 were protected against lethal Pseudomonas aeruginosa and Streptococcus pneumoniae sepsis, yet remained fully susceptible to group B streptococci and Candida albicans sepsis. These studies illustrate a previously unknown role for ADAM10 in sepsis-associated endothelial injury and suggest that understanding pathogen-specific divergent host pathways in sepsis may enable more precise targeting of disease.

中文翻译：

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内皮 ADAM10 的利用定义了细菌性脓毒症小鼠血管损伤的分子途径

内皮细胞在宿主对感染的反应中发挥着关键作用，并且一直是脓毒症研究的焦点。尽管人们认识到脓毒症期间血管内血栓形成、严重炎症和内皮完整性丧失会损害组织氧合，但导致内皮损伤的精确分子机制仍知之甚少。我们在此证明，内皮 ADAM10 对于金黄色葡萄球菌败血症的发病机制至关重要，有助于 α-毒素介导（Hla 介导）的微血管血栓形成和致死。由于 ADAM10 对于内皮发育和体内平衡至关重要，因此我们研究了其他主要人类脓毒症病原体在发病机制中是否也依赖 ADAM10 依赖性途径。内皮特异性敲除 ADAM10 的小鼠可以免受致命的铜绿假单胞菌和肺炎链球菌败血症的影响，但仍然完全易受 B 族链球菌和白色念珠菌败血症的影响。这些研究说明了 ADAM10 在脓毒症相关内皮损伤中的先前未知的作用，并表明了解脓毒症中病原体特异性的不同宿主途径可能有助于更精确地针对疾病。