Streptococcus pneumoniae is the most common causative agent of community-acquired pneumonia worldwide. A key pathogenic mechanism that exacerbates severity of disease is the disruption of the alveolar-capillary barrier. However, the specific virulence mechanisms responsible for this in the human lung are not yet fully understood. In this study, we infected living human lung tissue with Strep. pneumoniae and observed a significant degradation of the central junctional proteins occludin and vascular endothelial cadherin, indicating barrier disruption. Surprisingly, neither pneumolysin, bacterial hydrogen peroxide nor pro-inflammatory activation were sufficient to cause this junctional degradation. Instead, pneumococcal infection led to a significant decrease of pH (∼6), resulting in the acidification of the alveolar microenvironment, which was linked to junctional degradation. Stabilising the pH at physiological levels during infection reversed this effect, even in a therapeutic-like approach. Further analysis of bacterial metabolites and RNA sequencing revealed that sugar consumption and subsequent lactate production were the major factors contributing to bacterially induced alveolar acidification, which also hindered the release of critical immune factors. Our findings highlight bacterial metabolite-induced acidification as an independent virulence mechanism for barrier disruption and inflammatory dysregulation in pneumonia. Thus, our data suggest that strictly monitoring and buffering alveolar pH during infections caused by fermentative bacteria could serve as an adjunctive therapeutic strategy for sustaining barrier integrity and immune response.

中文翻译：

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肺炎球菌糖消耗引起的微环境酸化会促进人肺泡中的屏障破坏和免疫抑制。


肺炎链球菌是全世界社区获得性肺炎最常见的病原体。加剧疾病严重程度的一个关键致病机制是肺泡毛细血管屏障的破坏。然而，在人肺中导致这种情况的特定毒力机制尚不完全清楚。在这项研究中，我们用 Strep 感染了活体人类肺组织。肺炎，并观察到中央连接蛋白 occludin 和血管内皮钙粘蛋白的显着降解，表明屏障被破坏。令人惊讶的是，溶肺素、细菌过氧化氢和促炎激活都不足以导致这种连接降解。相反，肺炎球菌感染导致 pH 值 （∼6） 显着降低，导致肺泡微环境酸化，这与连接降解有关。在感染期间将 pH 值稳定在生理水平可以逆转这种影响，即使是在类似治疗方法的情况下也是如此。细菌代谢物和 RNA 测序的进一步分析表明，糖消耗和随后的乳酸产生是导致细菌诱导肺泡酸化的主要因素，这也阻碍了关键免疫因子的释放。我们的研究结果强调了细菌代谢物诱导的酸化是肺炎屏障破坏和炎症失调的独立毒力机制。因此，我们的数据表明，在发酵细菌引起的感染期间严格监测和缓冲肺泡 pH 值可以作为维持屏障完整性和免疫反应的辅助治疗策略。