Type I Interferon Responses in Mycobacterial Infections

Type I interferons (IFN-I), encompassing IFN-α and IFN-β, occupy a pivotal position in innate immunity yet assume a complex, often dualistic role in infections caused by Mycobacterium tuberculosis and related species. Triggered by cytosolic sensors such as cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) and nucleotide-binding oligomerisation domain receptors, IFN-I responses emerge rapidly after pathogen entry. At controlled levels, these cytokines can support antimicrobial programmes; however, sustained or exaggerated IFN-I signalling disrupts interferon-γ-dependent activation of macrophages, fosters neutrophil recruitment, and drives tissue pathology. Within granulomas, this imbalance can tip the scales from bacterial containment to progressive disease. Recent advances in dissecting cell-type specificity, molecular drivers and host-directed interventions underscore the global importance of fine-tuning IFN-I pathways to enhance treatment outcomes for both tuberculosis and nontuberculous mycobacterial diseases.

Research from Nature Portfolio

Investigation into cytokine networks in genetically susceptible mice has revealed that elevated IFN-I signalling promotes neutrophil extracellular trap (NET) formation in pulmonary tissues, exacerbating Mycobacterium tuberculosis growth and lesion necrosis. Loss of granulocyte-macrophage colony-stimulating factor (GM-CSF) or presence of TB-susceptibility alleles amplifies IFN-I-driven NETosis. Analysis of necrotic lesions from patients with poor antibiotic responses confirmed abundant NETs, linking pathological neutrophil activation to unfavourable clinical outcomes. These findings highlight an innate immune effector network centred on IFN-I and neutrophils as a target for adjunctive therapies aimed at reducing tissue damage and improving cure rates.

Type I Interferon Responses in Mycobacterial Infections publication trend

The graph below shows the total number of articles in type i interferon responses in mycobacterial infections across all publications each year (not limited to Nature Index journals).

Technical terms

Type I interferon (IFN-I): A family of cytokines, including IFN-α and IFN-β, that coordinate early innate immune defences.

Plasmacytoid dendritic cell (pDC): A specialised immune cell uniquely capable of rapid and abundant IFN-I production in response to nucleic acid sensing.

Neutrophil extracellular traps (NETs): Meshes of DNA and antimicrobial proteins released by neutrophils to ensnare pathogens, which may also drive inflammation.

cGAS–STING pathway: A cytosolic mechanism in which cGAS detects double-stranded DNA and synthesises cGAMP, activating STING to induce IFN-I expression.

Lipid droplets: Intracellular organelles for lipid storage that pathogens can exploit as nutrient sources during infection.

References

1. Mycobacterium tuberculosis suppresses host DNA repair to boost its intracellular survival. Cell Host & Microbe (2023).
2. Poly(ADP)ribose polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production. Journal of Clinical Investigation (2023).
3. Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis. Nature Communications (2020).
4. Type I IFN Induces IL-10 Production in an IL-27–Independent Manner and Blocks Responsiveness to IFN-γ for Production of IL-12 and Bacterial Killing in Mycobacterium tuberculosis–Infected Macrophages. The Journal of Immunology (2014).
5. NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosis. PLOS Pathogens (2009).