Infection by Staphylococcus aureus strain USA300 causes tissue injury, multiorgan failure, and high mortality. However, the mechanisms by which the bacteria adhere to, then stabilize on, mucosal surfaces before causing injury remain unclear. We addressed these issues through the first real-time determinations of USA300-alveolar interactions in live lungs. We found that within minutes, inhaled USA300 established stable, self-associated microaggregates in niches at curved, but not at flat, regions of the alveolar wall. The microaggregates released α-hemolysin toxin, causing localized alveolar injury, as indicated by epithelial dye loss, mitochondrial depolarization, and cytosolic Ca²⁺ increase. Spread of cytosolic Ca²⁺ through intercellular gap junctions to adjoining, uninfected alveoli caused pulmonary edema. Systemic pretreatment with vancomycin, a USA300-cidal antibiotic, failed to protect mice infected with inhaled WT USA300. However, vancomycin pretreatment markedly abrogated mortality in mice infected with mutant USA300 that lacked the aggregation-promoting factor PhnD. We interpret USA300-induced mortality as having resulted from rapid bacterial aggregation in alveolar niches. These findings indicate, for the first time to our knowledge, that alveolar microanatomy is critical in promoting the aggregation and, hence, in causing USA300-induced alveolar injury. We propose that in addition to antibiotics, strategies for bacterial disaggregation may constitute novel therapy against USA300-induced lung injury.

中文翻译：

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葡萄球菌聚集的破坏可防止致命的肺损伤

金黄色葡萄球菌菌株USA300的感染会导致组织损伤，多器官功能衰竭和高死亡率。然而，细菌在造成伤害之前粘附于粘膜表面然后稳定的机制尚不清楚。我们通过实时确定活肺中USA300-肺泡相互作用的方法解决了这些问题。我们发现，在几分钟内，吸入的USA300在弯曲但不是平坦的肺泡壁区域的壁ches中建立了稳定的，自缔合的微聚集体。微聚集体释放α-溶血素毒素，引起局部肺泡损伤，如上皮染料丢失，线粒体去极化和胞质Ca ²⁺增加所表明。胞质Ca ^2+的扩散通过细胞间隙间隙连接到相邻的，未感染的肺泡引起肺水肿。用万古霉素（一种对USA300具有杀伤力的抗生素）进行的全身预处理无法保护被吸入WT USA300感染的小鼠。但是，万古霉素预处理可显着降低感染了缺乏聚集促进因子PhnD的USA300突变小鼠的死亡率。我们将USA300诱导的死亡率解释为是由于肺泡壁ches中细菌的快速聚集导致的。这些发现首次表明，我们的知识是，肺泡微解剖结构对于促进聚集并因此导致USA300引起的肺泡损伤至关重要。我们建议，除抗生素外，细菌分解策略还可构成针对USA300诱导的肺损伤的新型疗法。