Immunological Mechanisms in Mycobacterial Infections

The host response to Mycobacterium tuberculosis and related mycobacteria is orchestrated by a complex interplay between innate and adaptive immunity. After inhalation, mycobacteria are phagocytosed by macrophages and dendritic cells, which deploy reactive oxygen and nitrogen intermediates within the phagosome to limit bacterial growth. Successful pathogens subvert phagosome maturation and acidification, in part through secretion of cell‐envelope lipids such as lipoarabinomannan, thereby evading intracellular killing. In parallel, infected antigen‐presenting cells release interleukin‐12 and other cytokines, activating T helper 1 cells to produce interferon-gamma (IFN-γ) and tumour necrosis factor (TNF), both essential for macrophage activation and granuloma formation. The granuloma, a structured aggregate of macrophages, epithelioid cells and lymphocytes, serves to contain bacillary spread yet can provide a niche for long-term persistence. CD8+ T cells contribute to control via cytotoxicity and IFN-γ production, while regulatory pathways, including inhibitory receptors on T cells, can dampen protective immunity and lead to chronic infection. Advances in understanding metabolic cross-talk have revealed that mycobacteria exploit host signalling pathways such as mTORC1 to suppress T-cell effector function. Together, these mechanisms define a dynamic host–pathogen contest with direct implications for vaccine design, host-directed therapies and novel diagnostics.

Research from Nature Portfolio

Recent studies have uncovered pathogen-driven suppression of adaptive immunity through metabolic adaptation. Under hypoxic conditions, Mycobacterium tuberculosis induces a phosphoserine aminotransferase that produces d-serine, which interacts with host WDR24 to inhibit mTORC1 activation in CD8+ T cells. This downregulates T-bet expression and reduces IFN-γ secretion, indirectly impairing macrophage microbicidal activity. In parallel, structural analysis of mycobacterial glycoside hydrolases has identified LamH, an enzyme that cleaves lipoarabinomannan and lipomannan to release arabinomannan from the capsule. This release drives bacterial exit from stationary phase, influences host-cell entry and enhances intracellular survival. Together, these findings illuminate specific virulence factors that modulate host signalling and antigen presentation pathways, highlighting potential targets for therapeutic blockade or vaccine antigens.

Immunological Mechanisms in Mycobacterial Infections publication trend

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

Technical terms

Macrophage: Innate immune cell that engulfs pathogens and presents antigens to T cells.

Phagosome: Intracellular vesicle in which pathogens are sequestered and exposed to antimicrobial effectors.

Interferon-gamma (IFN-γ): Cytokine produced by T cells and natural killer cells that activates macrophage microbicidal functions.

Granuloma: Structured aggregate of immune cells that walls off persistent pathogens in tissue.

Lipoarabinomannan (LAM): Complex glycolipid of the mycobacterial cell envelope that modulates host immune signalling.

mTORC1: Host signalling complex that regulates cell growth and effector T-cell differentiation.

References

1. Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria. Cell (2023).
2. Mycobacterium tuberculosis produces d-serine under hypoxia to limit CD8+ T cell-dependent immunity in mice. Nature Microbiology (2024).
3. The mycobacterial glycoside hydrolase LamH enables capsular arabinomannan release and stimulates growth. Nature Communications (2024).
4. The Immune Escape Mechanisms of Mycobacterium Tuberculosis. International Journal of Molecular Sciences (2019).
5. The Granuloma in Tuberculosis: Dynamics of a Host–Pathogen Collusion. Frontiers in Immunology (2013).
6. TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection. PLOS Pathogens (2016).