NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections

Björn Klabunde, André Wesener, Wilhelm Bertrams, Isabell Beinborn, Nicole Paczia, Kristin Surmann, Sascha Blankenburg, Jochen Wilhelm, Javier Serrania, Kèvin Knoops, Eslam M. Elsayed, Katrin Laakmann, Anna Lena Jung, Andreas Kirschbaum, Sven Hammerschmidt, Belal Alshaar, Nicolas Gisch, Mobarak Abu Mraheil, Anke Becker, Uwe Völker, Evelyn Vollmeister, Birke J. Benedikter () and Bernd Schmeck ()
Additional contact information
Björn Klabunde: Philipps-Universität Marburg
André Wesener: Philipps-Universität Marburg
Wilhelm Bertrams: Philipps-Universität Marburg
Isabell Beinborn: Philipps-Universität Marburg
Nicole Paczia: Max Planck Institute for Terrestrial Microbiology
Kristin Surmann: University Medicine Greifswald
Sascha Blankenburg: University Medicine Greifswald
Jochen Wilhelm: Institute for Lung Health (ILH)
Javier Serrania: Philipps-Universität Marburg
Kèvin Knoops: Maastricht University
Eslam M. Elsayed: Philipps-Universität Marburg
Katrin Laakmann: Philipps-Universität Marburg
Anna Lena Jung: Philipps-Universität Marburg
Andreas Kirschbaum: University Hospital Gießen and Marburg (UKGM)
Sven Hammerschmidt: University of Greifswald
Belal Alshaar: Leibniz Lung Center
Nicolas Gisch: Leibniz Lung Center
Mobarak Abu Mraheil: Justus-Liebig Universität Giessen
Anke Becker: Philipps-Universität Marburg
Uwe Völker: University Medicine Greifswald
Evelyn Vollmeister: Philipps-Universität Marburg
Birke J. Benedikter: Philipps-Universität Marburg
Bernd Schmeck: Philipps-Universität Marburg

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Lower respiratory tract infections caused by Streptococcus pneumoniae (Spn) are a leading cause of death globally. Here we investigate the bronchial epithelial cellular response to Spn infection on a transcriptomic, proteomic and metabolic level. We found the NAD+ salvage pathway to be dysregulated upon infection in a cell line model, primary human lung tissue and in vivo in rodents, leading to a reduced production of NAD+. Knockdown of NAD+ salvage enzymes (NAMPT, NMNAT1) increased bacterial replication. NAD+ treatment of Spn inhibited its growth while growth of other respiratory pathogens improved. Boosting NAD+ production increased NAD+ levels in immortalized and primary cells and decreased bacterial replication upon infection. NAD+ treatment of Spn dysregulated the bacterial metabolism and reduced intrabacterial ATP. Enhancing the bacterial ATP metabolism abolished the antibacterial effect of NAD+. Thus, we identified the NAD+ salvage pathway as an antibacterial pathway in Spn infections, predicting an antibacterial mechanism of NAD+.

Date: 2023
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DOI: 10.1038/s41467-023-41372-w

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