Nitric Oxide Modulation in Mycobacterial Infections

Nitric oxide (NO) is a pivotal mediator of host defence against Mycobacterium species. Synthesised by the inducible nitric oxide synthase (iNOS) pathway in activated macrophages under the influence of interferon-gamma and other cytokines, NO and its secondary reactive nitrogen species (RNS) disrupt mycobacterial metabolism and integrity through direct nitrosative damage and modulation of phagosomal microenvironments. The balance of NO production is governed by competing arginine-metabolising enzymes (iNOS versus arginase), intracellular redox buffers such as glutathione, and transcriptional regulators that fine-tune antioxidant gene expression. Dysregulation of these pathways can tip the host response from microbial clearance toward tissue pathology or chronic infection. Non-invasive measurement of exhaled NO offers diagnostic and prognostic insights, while therapeutic strategies—including NO donor compounds and host-directed adjuvants that enhance nitrosative stress—are under exploration as adjuncts to conventional antimycobacterial regimens. Together, these insights underscore NO’s dual role as both an antimicrobial effector and a key regulator of immunometabolic networks in global efforts to control tuberculosis and related diseases.

Research from Nature Portfolio

Recent studies have uncovered host factors that modulate nitrosative responses during mycobacterial infection. One foundational investigation revealed that activation of the transcription factor STAT3 in human macrophages suppresses iNOS expression and downstream NO synthesis, thereby promoting intracellular persistence of Mycobacterium tuberculosis. Pharmacological or genetic inhibition of STAT3 restores robust nitrosative activity and restricts bacterial replication, positioning this axis as a candidate for host-directed therapy. In another study, deletion of the antioxidant regulator BACH1 in infected mice led to enhanced glutathione-dependent defences and altered tissue redox balance. Although centred on lipid peroxidation and ferroptosis, this work highlights how modulation of antioxidant gene networks influences reactive nitrogen species availability and mycobacterial control in vivo.

Nitric Oxide Modulation in Mycobacterial Infections publication trend

The graph below shows the total number of articles in nitric oxide modulation in mycobacterial infections across all publications each year (not limited to Nature Index journals).

Technical terms

Nitric oxide (NO): A diffusible free radical generated by immune cells that exerts antimicrobial and signalling roles.

Inducible nitric oxide synthase (iNOS): An enzyme upregulated by inflammatory cues that converts arginine into NO and citrulline.

Reactive nitrogen species (RNS): Nitrogen-derived derivatives of NO that contribute to microbial killing.

Macrophage polarisation: The functional state of macrophages shaped by cytokines, ranging from pro-inflammatory (M1) to anti-inflammatory (M2) phenotypes.

Arginase: An enzyme that competes with iNOS for arginine, diverting metabolism away from NO production.

References

1. BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility. Nature Microbiology (2023).
2. New insight into arginine and tryptophan metabolism in macrophage activation during tuberculosis. Frontiers in Immunology (2024).
3. Nitric Oxide in the Pathogenesis and Treatment of Tuberculosis. Frontiers in Microbiology (2017).
4. STAT3 Represses Nitric Oxide Synthesis in Human Macrophages upon Mycobacterium tuberculosis Infection. Scientific Reports (2016).