Mycobacterial Diseases
Open Access

Molecular Mechanisms behind Bacterial Persistence in Leprosy Granulomas

Zabosta Lakhoi^{* *}Correspondence: Zabosta Lakhoi, Department of Microbiology, University of Warsaw, Warsaw, Poland, Email:

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Description

Leprosy, caused by Mycobacterium leprae and Mycobacterium lepromatosis, remains a global health challenge despite advancements in treatment. A characteristic of the disease is the formation of granulomas, organized structures of immune cells that form in response to infection. Granulomas play a dual role: Containing bacterial growth in some cases while providing a niche for bacterial persistence in others. Understanding the cellular and molecular factors that influence bacterial load within granulomas is important for developing improved therapeutic strategies. The composition of leprosy granulomas reflects the spectrum of immune responses, ranging from robust cellmediated immunity in tuberculoid leprosy to ineffective immune activation in lepromatous forms. Key players include macrophages, T cells, and cytokines like TNF-α and IFN-γ, which dictate the balance between bacterial control and immune tolerance. The persistence of M. leprae is often linked to its ability to modulate host immune pathways, such as suppressing antigen presentation or inducing regulatory T cells. Advanced imaging and molecular techniques are uncovering new aspects of granuloma biology, paving the way for targeted therapies aimed at enhancing bacterial clearance while minimizing tissue damage.

Cellular composition of leprosy granulomas

Granulomas in leprosy are composed of various immune cells, each contributing uniquely to bacterial containment or survival:

Macrophages: Central to granulomas, macrophages engulf M. leprae but often fail to eliminate it due to the bacterium's ability to resist intracellular killing. Infected macrophages may transform into foamy macrophages, characterized by lipid accumulation, which supports bacterial survival and replication.

T Lymphocytes: CD4+ T cells mediate the release of cytokines such as Interferon-gamma (IFN-γ), enhancing macrophage activation and bacterial killing. CD8+ T cells is more complex, as they can contribute to bacterial killing or, in some cases, exacerbate tissue damage.

Dendritic cells: These antigen-presenting cells orchestrate immune responses by activating T cells, influencing granuloma efficiency.

Neutrophils: While less prominent in granulomas, neutrophils can infiltrate during acute inflammatory responses, potentially contributing to bacterial killing or tissue damage.

Molecular determinants of bacterial burden

Several molecular factors regulate bacterial load within leprosy granulomas, influencing disease outcomes:

Cytokines and chemokines: Pro-inflammatory cytokines such as IFN-γ and Tumor Necrosis Factor-alpha (TNF-α) enhance bacterial control by activating macrophages. Anti-inflammatory cytokines such as Interleukin-10 (IL-10) and Transforming Growth Factor-beta (TGF-β) suppress immune responses, facilitating bacterial persistence. Chemokines such as CXCL10 and CCL2 recruit immune cells to granulomas, shaping their composition and function.

Immune checkpoints: Molecules such as PD-1 and its ligand PDL1 modulate T cell activity, often dampening immune responses within granulomas, which may contribute to bacterial survival.

Metabolic reprogramming: M. leprae manipulates host lipid metabolism, inducing foamy macrophages that provide nutrients and a protective niche. The hypoxic environment within granulomas alters immune cell metabolism, impairing effective bacterial clearance.

Cell death pathways: Apoptosis is a controlled cell death can limit bacterial spread and stimulate immune responses. Necrosis is an unregulated cell death releases bacteria into surrounding tissues, exacerbating disease. Autophagy cellular process can degrade intracellular bacteria, but M. leprae can evade or inhibit autophagy in infected cells.

Factors influencing granuloma efficacy

Variations in genes related to immune responses, such as those encoding cytokines or pattern recognition receptors, influence granuloma formation and function. M. leprae secretes virulence factors that modulate host immune responses, promoting its survival within granulomas. The cellular and molecular profile of granulomas varies along the leprosy spectrum, from tuberculoid leprosy (characterized by robust immune responses and low bacterial loads) to lepromatous leprosy (with weak immune responses and high bacterial loads). Understanding the cellular and molecular determinants of bacterial burden in leprosy granulomas provides insights into disease pathogenesis and therapeutic targets. Strategies to enhance granuloma efficacy include, modulating cytokine profiles to boost bacterial killing. Targeting lipid metabolism to disrupt bacterial niches. Developing immunotherapies to counteract immune evasion mechanisms.

Conclusion

Leprosy granulomas reflect the complex interplay between host immunity and bacterial survival strategies. By dissecting the cellular and molecular determinants of bacterial burden, researchers can identify novel interventions to improve disease control and patient outcomes. Understanding the dynamics within leprosy granulomas offers essential insights into the mechanisms of immune evasion and persistence of Mycobacterium leprae. By targeting these pathways, innovative therapeutic approaches can be developed to enhance bacterial clearance and modulate immune responses. Such advancements hold the potential to reduce transmission, improve treatment efficacy, and mitigate long-term complications.