Publikationsdatenbank

Microenvironmental acidification by pneumococcal sugar consumption fosters barrier disruption and immune suppression in the human alveolus (2024)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Fatykhova, Diana

Fritsch, Verena N.

Siebert, Keerthana

Methling, Karen

Lalk, Michael

Busche, Tobias

Kalinowski, Jörn

Weiner, January

Beule, Dieter

Bertrams, Wilhelm

Kohler, Thomas P.

Hammerschmidt, Sven

Löwa, Anna

Fischer, Mara

Mieth, Maren

Hellwig, Katharina

Frey, Doris

Neudecker, Jens

Rueckert, Jens C.

Toennies, Mario

Bauer, Torsten T.

Graff, Mareike

Tran, Hong-Linh

Eggeling, Stephan

Gruber, Achim D. (WE 12)

Antelmann, Haike

Hippenstiel, Stefan

Hocke, Andreas C.

Quelle

The European respiratory journal

Bandzählung: 64

Heftzählung: 6

Seiten: Artikelnummer 2301983

ISSN: 0903-1936

Sprache

Englisch

Verweise

URL (Volltext): https://publications.ersnet.org/content/erj/64/6/2301983

DOI: 10.1183/13993003.01983-2023

Pubmed: 39231629

Kontakt

Institut für Tierpathologie

Robert-von-Ostertag-Str. 15
14163 Berlin
+49 30 838 62450
pathologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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.