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

溶血素 免疫系统 微生物学 封堵器 肺炎链球菌 毒力 势垒函数 肺炎球菌肺炎 病菌 免疫学 医学 生物 细胞生物学 紧密连接 生物化学 抗生素 基因
作者
Diana Fatykhova,Verena Nadin 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 Bauer,Mareike Graff,Hong-Linh Tran,Stephan Eggeling,Achim D. Gruber,Haike Antelmann,Stefan Hippenstiel,Andreas C. Hocke
出处
期刊:The European respiratory journal [European Respiratory Society]
卷期号:: 2301983-2301983
标识
DOI:10.1183/13993003.01983-2023
摘要

Streptococcus pneumoniae ( S.p. ) 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 S.p. and observed a significant degradation of the central junctional proteins occludin and VE-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 (approximately 6), resulting in 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 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.
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