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

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