Glucose selectively drives a rapid oxidative burst and immunometabolic reprogramming in human neutrophils during Mycobacterium tuberculosis infection

Chinta, K. C.; Naicker, D.; Nadeem, S.; Sevalkar, R. R.; Pillay, V.; Naidoo, T.; Wells, G.; Lumamba, K.; Nargan, K.; Govender, A.; Jones, J. J.; Pang, M.; Quan, B.; Wang, T.-Y.; Roukes, M. L.; Chen, D.; Pacl, H. T.; Agarwal, A.; Glasgow, J. N.; Steyn, A. J.

doi:10.64898/2026.05.05.722986

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bioRxiv · 10.64898/2026.05.05.722986

Glucose selectively drives a rapid oxidative burst and immunometabolic reprogramming in human neutrophils during Mycobacterium tuberculosis infection

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Abstract

Neutrophil functions have been linked to tuberculosis (TB)-associated tissue damage; however, the mechanisms driving immunopathology in the human TB lung remain poorly understood, due partly to the scarcity of human tissue for study. Here, we examine the metabolic and bioenergetic reprogramming of human neutrophils in response to Mycobacterium tuberculosis (Mtb) infection. In human necrotic TB granulomas, levels of NETosis-associated proteins are increased and co-localize with GLUT3, linking nutrient uptake to tissue damage. In vitro, Mtb elicits an immediate, contact-dependent oxidative burst in human neutrophils, and the magnitude of this response is carbon source-dependent. Glucose enables the most robust responses, indicating that glucose metabolism is a key driver of neutrophil-mediated inflammatory damage during TB. Mtb-induced responses are distinct from those induced by PMA, non-tuberculous mycobacteria, or other pathogenic intracellular bacteria, and are mediated through multiple neutrophil surface receptors. Notably, our data show that while the oxidative burst is carbon source-dependent, cytokine production is not. Further, Mtb infection reprograms neutrophil metabolism from glycolysis to the pentose phosphate pathway (PPP), generating NADPH required for the oxidative burst. Inhibiting G6PD, NADPH oxidase, or PAD4 significantly reduces this response, highlighting the PPP as a promising host target for mitigating TB immunopathology.

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Chinta, K. C., Naicker, D., Nadeem, S., Sevalkar, R. R., Pillay, V., Naidoo, T., Wells, G., Lumamba, K., Nargan, K., Govender, A., Jones, J. J., Pang, M., Quan, B., Wang, T.-Y., Roukes, M. L., Chen, D., Pacl, H. T., Agarwal, A., Glasgow, J. N., Steyn, A. J.. 2026-05-07. Glucose selectively drives a rapid oxidative burst and immunometabolic reprogramming in human neutrophils during Mycobacterium tuberculosis infection. https://doi.org/10.64898/2026.05.05.722986

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