Microenvironmental acidification by pneumococcal sugar consumption fosters barrier disruption and immune suppression in the human alveolus.

IF 16.6 1区 医学 Q1 RESPIRATORY SYSTEM
European Respiratory Journal Pub Date : 2024-12-12 Print Date: 2024-12-01 DOI:10.1183/13993003.01983-2023
Diana Fatykhova, Verena N Fritsch, Keerthana Siebert, Karen Methling, Michael Lalk, Tobias Busche, Jörn Kalinowski, January Weiner, Dieter Beule, Wilhelm Bertrams, Thomas P Kohler, Sven Hammerschmidt, Anna Löwa, Mara Fischer, Maren Mieth, Katharina Hellwig, Doris Frey, Jens Neudecker, Jens C Rueckert, Mario Toennies, Torsten T Bauer, Mareike Graff, Hong-Linh Tran, Stephan Eggeling, Achim D Gruber, Haike Antelmann, Stefan Hippenstiel, Andreas C Hocke
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Abstract

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.

肺炎球菌耗糖造成的微环境酸化促进了人体肺泡屏障的破坏和免疫抑制。
肺炎链球菌(S.p. )是全球社区获得性肺炎最常见的致病菌。破坏肺泡-毛细血管屏障是加重疾病严重程度的一个关键致病机制。在本研究中,我们用 S.p.感染了活体人肺组织,观察到中心连接蛋白 occludin 和 VE-cadherin 显著降解,表明屏障被破坏。令人惊讶的是,肺炎溶素、细菌过氧化氢或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值显著下降(约6),导致肺泡微环境酸化,这与连接降解有关。对细菌代谢产物和 RNA 测序的进一步分析表明,糖的消耗和随后乳酸盐的产生是导致细菌诱导的肺泡酸化的主要因素,这也阻碍了关键免疫因子的释放。我们的研究结果突出表明,细菌代谢产物诱导的酸化是肺炎中屏障破坏和炎症失调的一种独立毒力机制。因此,我们的数据表明,在发酵细菌引起的感染期间,严格监控和缓冲肺泡 pH 值可作为一种辅助治疗策略,以维持屏障完整性和免疫反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
European Respiratory Journal
European Respiratory Journal 医学-呼吸系统
CiteScore
27.50
自引率
3.30%
发文量
345
审稿时长
2-4 weeks
期刊介绍: The European Respiratory Journal (ERJ) is the flagship journal of the European Respiratory Society. It has a current impact factor of 24.9. The journal covers various aspects of adult and paediatric respiratory medicine, including cell biology, epidemiology, immunology, oncology, pathophysiology, imaging, occupational medicine, intensive care, sleep medicine, and thoracic surgery. In addition to original research material, the ERJ publishes editorial commentaries, reviews, short research letters, and correspondence to the editor. The articles are published continuously and collected into 12 monthly issues in two volumes per year.
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