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

<i>Streptococcus pneumoniae</i> 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 <i>Strep. pneumoniae</i> 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.

Authors

Institutions

Publication Details

Journal
European Respiratory Journal
Published
2024-09-04
DOI
https://doi.org/10.1183/13993003.01983-2023
Citations
6
Primary Topic
Pneumonia and Respiratory Infections
Type
article
Field-Weighted Citation Impact
2.32

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Mario Toennies, Mara Fischer, Achim D. Gruber, Torsten Bauer et al.
6 citations
European Respiratory Journal
Pneumonia and Respiratory Infections
2.32
article

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

Mario Toennies, Mara Fischer, Achim D. Gruber, Torsten Bauer, Stefan Hippenstiel, Haike Antelmann, Andreas C. Hocke, Verena Nadin Fritsch, Jörn Kalinowski, Karen Methling, January Weiner, Tobias Busche, Anna Löwa, Hong-Linh Tran, Michael Lalk, Diana Fatykhova, Mareike Graff, Katharina Hellwig, Sven Hammerschmidt, Thomas P. Kohler, Maren Mieth, Dieter Beule, Stephan Eggeling, Jens Neudecker, Keerthana Siebert, Doris Frey, Wilhelm Bertrams, Jens C. Rueckert
article en
6 citations

Abstract

<i>Streptococcus pneumoniae</i> 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 <i>Strep. pneumoniae</i> 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.

European Respiratory JournalVol. 64(6)
Bielefeld University (DE), Hochschule Bielefeld (DE), Max Delbrück Center (DE), Universitätsmedizin Greifswald (DE), Universität Greifswald (DE), Humboldt-Universität zu Berlin (DE), Helios Klinikum Emil von Behring (DE), Vivantes Klinikum (DE), German Center for Lung Research (DE), Universities of Giessen and Marburg Lung Center (DE), DRK Kliniken Berlin (DE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Freie Universität Berlin (DE), Charité - Universitätsmedizin Berlin (DE)
Yale University, University of Leicester, Deutsche Forschungsgemeinschaft, Einstein Stiftung Berlin
Openalex Percentile: Top 11%
Pneumonia and Respiratory Infections
2.32
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.