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

Summary

Lower respiratory tract infections caused byStreptococcusOpneumoniae (Spn)are a leading cause of death globally. Here we investigate the bronchial epithelial response toSpninfection 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 andin vivoin rodents, leading to a reduced production of NAD⁺. Knockdown of NAD⁺salvage enzymes (NAMPT, NMNAT1) increased bacterial replication. NAD⁺treatment ofSpninhibited 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 ofSpndysregulated 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 inSpninfections, predicting a novel antibacterial mechanism of NAD⁺.