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; Bernd Schmeck

doi:10.1038/s41467-023-41372-w

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 VölkerEvelyn Vollmeister, Birke J Benedikter^*, Bernd Schmeck^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 .

Original language	English
Article number	5818
Number of pages	16
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-41372-w
Publication status	Published - 2 Oct 2023

Keywords

Humans
NAD/metabolism
Proteomics
Cytokines/metabolism
Cell Line
Bacterial Infections
Adenosine Triphosphate
Respiratory Tract Infections
Nicotinamide-Nucleotide Adenylyltransferase/metabolism

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10.1038/s41467-023-41372-wLicence: CC BY

Cite this

Klabunde, B., Wesener, A., Bertrams, W., Beinborn, I., Paczia, N., Surmann, K., Blankenburg, S., Wilhelm, J., Serrania, J., Knoops, K., Elsayed, E. M., Laakmann, K., Jung, A. L., Kirschbaum, A., Hammerschmidt, S., Alshaar, B., Gisch, N., Abu Mraheil, M., Becker, A., ... Schmeck, B. (2023). NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections. Nature Communications, 14(1), Article 5818. https://doi.org/10.1038/s41467-023-41372-w

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title = "NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections",

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 .",

keywords = "Humans, NAD/metabolism, Proteomics, Cytokines/metabolism, Cell Line, Bacterial Infections, Adenosine Triphosphate, Respiratory Tract Infections, Nicotinamide-Nucleotide Adenylyltransferase/metabolism",

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doi = "10.1038/s41467-023-41372-w",

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Klabunde, B, Wesener, A, Bertrams, W, Beinborn, I, Paczia, N, Surmann, K, Blankenburg, S, Wilhelm, J, Serrania, J, Knoops, K, Elsayed, EM, Laakmann, K, Jung, AL, Kirschbaum, A, Hammerschmidt, S, Alshaar, B, Gisch, N, Abu Mraheil, M, Becker, A, Völker, U, Vollmeister, E, Benedikter, BJ & Schmeck, B 2023, 'NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections', Nature Communications, vol. 14, no. 1, 5818. https://doi.org/10.1038/s41467-023-41372-w

TY - JOUR

T1 - NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections

AU - Klabunde, Björn

AU - Wesener, André

AU - Bertrams, Wilhelm

AU - Beinborn, Isabell

AU - Paczia, Nicole

AU - Surmann, Kristin

AU - Blankenburg, Sascha

AU - Wilhelm, Jochen

AU - Serrania, Javier

AU - Knoops, Kèvin

AU - Elsayed, Eslam M

AU - Laakmann, Katrin

AU - Jung, Anna Lena

AU - Kirschbaum, Andreas

AU - Hammerschmidt, Sven

AU - Alshaar, Belal

AU - Gisch, Nicolas

AU - Abu Mraheil, Mobarak

AU - Becker, Anke

AU - Völker, Uwe

AU - Vollmeister, Evelyn

AU - Benedikter, Birke J

AU - Schmeck, Bernd

PY - 2023/10/2

Y1 - 2023/10/2

N2 - 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 .

AB - 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 .

KW - Humans

KW - NAD/metabolism

KW - Proteomics

KW - Cytokines/metabolism

KW - Cell Line

KW - Bacterial Infections

KW - Adenosine Triphosphate

KW - Respiratory Tract Infections

KW - Nicotinamide-Nucleotide Adenylyltransferase/metabolism

U2 - 10.1038/s41467-023-41372-w

DO - 10.1038/s41467-023-41372-w

M3 - Article

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5818

ER -