Pneumococcal H2O2 Reshapes Mitochondrial Function and Reprograms Host Cell Metabolism

Streptococcus pneumoniae (Spn), a primary cause of pneumonia, induces acute lung parenchymal damage through a unique metabolic pathway generating hydrogen peroxide (H2O2) as a byproduct. This study demonstrates that Spn-derived H2O2, primarily produced by pyruvate oxidase (SpxB), inhibits key tricarboxylic acid (TCA) cycle enzymes (aconitase, glutamate dehydrogenase, and a-ketoglutarate dehydrogenase) in lung epithelial cells, leading to citrate accumulation and diminished NADH production for oxidative phosphorylation. RNA sequencing reveals SpxBdependent upregulation of glycolytic genes (HIF1A, IER3, HK2, PFKP), restricting pyruvate entry into the TCA cycle and increasing glucose consumption and lactate/acetate production, indicative of a Warburg-like metabolic shift that enhances bacterial survival. Notably, mitochondrial membrane potential remains largely preserved, with minimal apoptosis despite Spn-induced stress. These findings uncover a novel mechanism of Spn-driven host metabolic reprogramming, highlighting potential therapeutic targets for pneumococcal diseases. Overall design: Comparative transcriptomic analysis of RNA-seq data from human Calu-3 bronchial epithelial cells, either mock-infected or infected with Streptococcus pneumoniae strain TIGR4 and its isogenic mutant derivatives.