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Evasion of innate immunity by Mycobacterium tuberculosis: is death an exit strategy?

Nature Reviews Microbiology volume 8, pages 668–674 (2010)Cite this article

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Abstract

Virulent Mycobacterium tuberculosis inhibits apoptosis and triggers necrosis of host macrophages to evade innate immunity and delay the initiation of adaptive immunity. By contrast, attenuated M. tuberculosis induces macrophage apoptosis, an innate defence mechanism that reduces bacterial viability. In this Opinion article, we describe how virulent M. tuberculosis blocks production of the eicosanoid lipid mediator prostaglandin E2 (PGE2). PGE2 production by infected macrophages prevents mitochondrial damage and initiates plasma membrane repair, two processes that are crucial for preventing necrosis and inducing apoptosis. Thus, M. tuberculosis-mediated modulation of eicosanoid production determines the death modality of the infected macrophage, which in turn has a substantial impact on the outcome of infection.

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Figure 1: The fate of infected macrophages affects host resistance to Mycobacterium tuberculosis infection.
Figure 2: The balance of prostaglandin E2 and lipoxin A4 determine the cellular fate of macrophages infected with Mycobacterium tuberculosis.
Figure 3: The antinecrotic action of prostaglandin E2 is mediated through the induction of membrane repair and the protection of mitochondria.

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Acknowledgements

H.R.G. and S.M.B. are supported by the US National Institutes of Health (grant R01 AI073774).

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Author notes

  1. Maziar Divangahi

    Present address: Present address: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada (M.D.).,

Authors and Affiliations

  1. Maziar Divangahi and Heinz Remold are at the Division of Rheumatology, Department of Medicine, Samuel M. Behar, Immunology, and Allergy, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.,

    Samuel M. Behar, Maziar Divangahi & Heinz G. Remold

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DATABASES

Entrez Genome Project

Coxiella burnetii

Danio rerio

Legionella pneumophila

Leishmania major

Listeria monocytogenes

Mycobacterium bovis bacille Calmette–Guérin

Mycobacterium marinum

Mycobacterium tuberculosis

Salmonella enterica subsp. enterica serovar Typhimurium

Shigella flexneri

Yersinia pestis

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Glossary

Apoptosis

A type of programmed cell death defined by chromatin condensation (pyknosis) and fragmentation, blebbing of the plasma membrane and formation of apoptotic bodies. The plasma membrane of an apoptotic cell remains intact and contains proteins that are cross-linked by transglutaminases such as annexin 1.

Efferocytosis

The uptake of apoptotic cells or apoptotic bodies by phagocytic cells.

Eicosanoid

A lipid mediator that is derived from arachidonic acid. Eicosanoids include prostaglandins, lipoxins, leukotrienes, prostacyclins, thromboxanes and hydroxyeicosatetraenoic acid compounds.

Mitochondrial membrane potential

The electrochemical gradient across the mitochondrial membranes, given the symbol ΔΨm. Complexes I, III and IV of the electron transport system in the inner mitochondrial membrane pump protons against their concentration gradient from the mitochondrial matrix into the inter-membrane space, making the matrix more negative.

Mitochondrial permeability transition

An increase in the permeability of the mitochondrial membranes to molecules of less than 1,500 daltons.

Necrosis

A form of cell death that is characterized by swelling of cytoplasmic organelles, including the mitochondria, and a loss of plasma membrane integrity.

Plasma membrane microdisruption

A pore formed by damage of the plasma membrane, as determined by measuring the diffusion of fluorescent dextran, an inert impermeant molecule.

Prostanoid

A lipid metabolite of arachidonic acid that is a product of the cyclooxygenase cascade and of specific prostanoid synthases.

sn-2 position

The second (that is, middle) carbon atom in the glycerol backbone of phospholipids, providing a link for fatty acids.

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Behar, S., Divangahi, M. & Remold, H. Evasion of innate immunity by Mycobacterium tuberculosis: is death an exit strategy?. Nat Rev Microbiol 8, 668–674 (2010). https://doi.org/10.1038/nrmicro2387

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