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

<label>1.</label>

Summary

Lower respiratory tract infections caused by Streptococcus O pneumoniae (Spn) are a leading cause of death globally. Here we investigate the bronchial epithelial 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 cascade in Spn infections, predicting a novel antibacterial mechanism of NAD ⁺ .