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

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Item Type:	Article
Title:	Microenvironmental acidification by pneumococcal sugar consumption fosters barrier disruption and immune suppression in the human alveolus
Creators Name:	Fatykhova, D., Fritsch, V.N., Siebert, K., Methling, K., Lalk, M., Busche, T., Kalinowski, J., Weiner, J., Beule, D., Bertrams, W., Kohler, T.P., Hammerschmidt, S., Löwa, A., Fischer, M., Mieth, M., Hellwig, K., Frey, D., Neudecker, J., Rueckert, J.C., Toennies, M., Bauer, T.T., Graff, M., Tran, H.L., Eggeling, S., Gruber, A.D., Antelmann, H., Hippenstiel, S. and Hocke, A.C.
Abstract:	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.
Keywords:	Streptococcus Pneumoniae, Glucose Metabolism, Lactate, Human Lung, Human Alveolus, Pneumonia, Barrier Disruption, VE-Cadherin, Occludin, PH, Acidification, Inflammation
Source:	European Respiratory Journal
ISSN:	0903-1936
Publisher:	European Respiratory Society
Page Range:	2301983
Date:	4 September 2024
Official Publication:	https://doi.org/10.1183/13993003.01983-2023
PubMed:	View item in PubMed

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