Pneumococcal H₂O₂ Reshapes Mitochondrial Function and Reprograms Host Cell Metabolism

Area of Science:

• Microbiology
• Cellular Metabolism
• Infectious Diseases

Background:

• Streptococcus pneumoniae (Spn) causes pneumonia through a unique metabolic pathway generating hydrogen peroxide (H₂O₂).
• Spn-derived H₂O₂ is primarily produced by pyruvate oxidase (SpxB).
• Host cell metabolic reprogramming is crucial for pathogen survival.

Purpose of the Study:

• To elucidate the mechanism by which Spn-derived H₂O₂ affects host lung epithelial cell metabolism.
• To identify the specific metabolic pathways targeted by Spn-H₂O₂.
• To understand how these metabolic changes support Spn infection.

Main Methods:

• In vitro studies using lung epithelial cells and Spn.
• Measurement of TCA cycle enzyme activity.
• RNA sequencing to analyze gene expression.
• Analysis of mitochondrial membrane potential and apoptosis.

Main Results:

• Spn-derived H₂O₂ inhibits key TCA cycle enzymes (aconitase, glutamate dehydrogenase, α-ketoglutarate dehydrogenase).
• This inhibition leads to citrate accumulation and reduced NADH production.
• Host cells exhibit increased glucose consumption and lactate/acetate production, a Warburg-like metabolic shift.
• SpxB-dependent H₂O₂ upregulates glycolytic genes (HK2, PFKP).

Conclusions:

• Spn manipulates host cell metabolism via H₂O₂ to create a favorable environment for bacterial survival.
• Targeting Spn's metabolic pathway or the resulting host cell changes presents potential therapeutic strategies for pneumococcal diseases.
• Despite metabolic disruption, Spn infection induces minimal apoptosis and maintains mitochondrial function.