Myeloid HIF-1α Couples Glycolytic Energy Supply with NCF2-Dependent Oxidative Killing to Protect Against Klebsiella pneumoniae Pneumonia.

Summary

Using patient data and myeloid-specific knockout mice, the study shows HIF-1α directly drives NCF2 (p67-phox) transcription, coupling glycolytic ATP production to ROS-mediated bacterial killing against hypervirulent K. pneumoniae. Pharmacologic stabilization of HIF-1α with DMOG improved host resistance, positioning immunometabolic targeting as a therapeutic avenue.

Key Findings

• Monocyte HIF-1α inversely correlated with CRP, procalcitonin, ICU length of stay, and SOFA in K. pneumoniae pneumonia.
• Myeloid Hif-1α knockout mice had reduced survival and disseminated infection with impaired macrophage phagocytosis and ROS generation.
• HIF-1α directly transcriptionally upregulated NCF2, coupling glycolytic ATP production to NADPH oxidase-dependent ROS killing; DMOG improved host resistance.

Clinical Implications

HIF-1α levels may serve as a severity biomarker in Klebsiella pneumoniae pneumonia, and pharmacologic HIF-1α stabilization or NCF2 pathway augmentation could be explored as adjunctive therapies alongside antibiotics.

Limitations

• Preclinical mouse model with hypervirulent strain may not capture full clinical heterogeneity.
• DMOG has off-target effects and systemic HIF-1α stabilization could have safety trade-offs.

Future Directions

Validate HIF-1α/NCF2 axis in diverse pathogens and human cohorts; develop selective HIF-1α modulators or NCF2-targeted strategies and assess safety/efficacy in sepsis trials.