NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections
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Date
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Philipps-Universität Marburg
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+.