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How macrophage heterogeneity affects tuberculosis disease and therapy

Nature Reviews Immunology (2025)Cite this article

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Abstract

Macrophages are the primary host cell type for infection by Mycobacterium tuberculosis in vivo. Macrophages are also key immune effector cells that mediate the control of bacterial growth. However, the specific macrophage phenotypes that are required for optimal immune control of M. tuberculosis infection in vivo remain poorly defined. There are two distinct macrophage lineages in the lung, comprising embryonically derived, tissue-resident alveolar macrophages and recruited, blood monocyte-derived interstitial macrophages. Recent studies have shown that these lineages respond divergently to similar immune environments within the tuberculosis granuloma. Here, we discuss how the differing responses of macrophage lineages might affect the control or progression of tuberculosis disease. We suggest that the ability to reprogramme macrophage responses appropriately, through immunological or chemotherapeutic routes, could help to optimize vaccines and drug regimens for tuberculosis.

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Fig. 1: Tuberculosis granulomas are heterogeneous in both structure and disease outcome.
Fig. 2: Main features of the macrophage populations in non-infected mouse lung.
Fig. 3: Host macrophage populations in Mycobacterium tuberculosis-infected mouse lung.
Fig. 4: Differential distribution of Mycobacterium tuberculosis associated with host cell phenotype and drug susceptibility.

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Acknowledgements

The authors’ work highlighted in this article was supported by funding from the National Institutes of Health (AI155319, AI162598, OD032135 and AI176575 to D.G.R.; AI167710 and AI164970 to J.T.M.), with additional support from the Bill and Melinda Gates Foundation, and the Mueller Health Foundation to D.G.R. The authors thank Shumin Tan for discussions surrounding the development of Fig. 4.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA

    David G. Russell, Nelson V. Simwela & Davide Pisu

  2. Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Joshua T. Mattila

  3. Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Joshua T. Mattila & JoAnne Flynn

  4. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    JoAnne Flynn

  5. Malawi Liverpool Wellcome Research Programme, Kamuzu University of Health Sciences, Blantyre, Malawi

    Henry C. Mwandumba

  6. Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK

    Henry C. Mwandumba

  7. Department of Microbial Pathogenesis and Immunology, Texas A&M School of Medicine, Bryan, TX, USA

    Davide Pisu

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Glossary

Caseum

The lipid-rich acellular material that derives from dead foamy macrophages and accumulates in the centre of many human TB granulomas.

Cavitation

The process by which the centre of a caseous human TB granuloma collapses into the lung airway, releasing viable Mycobacterium tuberculosis bacilli that can transmit infection to new, susceptible hosts.

Extrinsic apoptosis

A regulated cell death pathway that is triggered either by extracellular mediators that activate a death receptor such as Fas (also known as CD95) or by granzyme B and perforin released from cytotoxic lymphocytes.

Fatty acid oxidation

(FAO). The mitochondrial aerobic process of breaking down long-chain fatty acids into individual acetyl-CoA units.

Fitness reporter strains

Fluorescent Mycobacterium tuberculosis strains that express one fluorochrome constitutively (frequently, mCherry) and another fluorochrome (usually GFP or mkOrange) either in response to specific environmental stimuli, such as nitric oxide, or upon induction with tetracycline.

Glycolysis

The metabolic pathway that converts glucose into pyruvate or lactate, the energy from which is used to generate ATP and nicotinamide adenine dinucleotide (NAD).

Gluconeogenesis

The metabolic pathway that enables the biosynthesis of glucose from non-hexose carbon substrates, such as glycerol, lactate, pyruvate and propionate.

Granuloma

A cluster of immune cells, most frequently macrophages, but also including other cell types such as neutrophils, dendritic cells and lymphocytes, that forms around a site of infection or inflammation.

Intrinsic apoptosis

A programmed cell death pathway that is triggered by intracellular damage or stress, usually associated with permeabilization of the mitochondrial outer membrane.

Necrosis

A programmed cell death pathway that usually occurs in response to excessive cellular stress. In contrast to apoptosis, necrosis is extremely inflammatory and can result in extensive tissue damage.

Oxidative phosphorylation

(OXPHOS). The set of oxygen-dependent metabolic reactions that take place in the mitochondria and convert the energy in macronutrients to ATP.

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Russell, D.G., Simwela, N.V., Mattila, J.T. et al. How macrophage heterogeneity affects tuberculosis disease and therapy. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-024-01124-3

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