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Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair

Nature Immunology volume 10, pages 899–906 (2009)Cite this article

Abstract

Induction of macrophage necrosis is a strategy used by virulent Mycobacterium tuberculosis (Mtb) to avoid innate host defense. In contrast, attenuated Mtb causes apoptosis, which limits bacterial replication and promotes T cell cross-priming by antigen-presenting cells. Here we show that Mtb infection causes plasma membrane microdisruptions. Resealing of these lesions, a process crucial for preventing necrosis and promoting apoptosis, required translocation of lysosomal and Golgi apparatus–derived vesicles to the plasma membrane. Plasma membrane repair depended on prostaglandin E2 (PGE2), which regulates synaptotagmin 7 (Syt-7), the calcium sensor involved in the lysosome-mediated repair mechanism. By inducing production of lipoxin A4 (LXA4), which blocks PGE2 biosynthesis, virulent Mtb prevented membrane repair and induced necrosis. Thus, virulent Mtb impairs macrophage plasma membrane repair to evade host defenses.

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Figure 1: Infection of human macrophages with virulent H37Rv inhibits lysosomal and Golgi-mediated plasma membrane repair.
Figure 2: Distinct calcium sensors regulate the recruitment of lysosomal and Golgi apparatus–derived membranes in Mtb-infected human macrophages.
Figure 3: PGE2 reconstitutes lysosomal repair in human macrophages infected with virulent Mtb.
Figure 4: Bacterial growth and the death modality of Mtb-infected mouse macrophages is regulated by eicosanoids.
Figure 5: The fate of Mtb-infected macrophages in vitro reflects the innate control of infection in vivo.
Figure 6: PGE2 regulates Syt-7 expression in mouse macrophages.
Figure 7: Syt-7 is essential for the induction of plasma membrane repair, prevention of necrosis and control of bacterial growth in mouse macrophages.

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Acknowledgements

We thank I-C. Ho for critical reading of the manuscript; and B. Koller (University of North Carolina) for Ptges−/− mice. Supported by the US National Institutes of Health (AI50216 and AI072143 to H.G.R.) and the Fonds de la Recherche en Santé du Québec (M.D.).

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Author notes

  1. Maziar Divangahi, Minjian Chen, Samuel M Behar and Heinz G Remold: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Rheumatology, Department of Medicine, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Maziar Divangahi, Minjian Chen, Huixian Gan, Danielle Desjardins, Tyler T Hickman, David M Lee, Samuel M Behar & Heinz G Remold

  2. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA

    Sarah Fortune

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Contributions

S.M.B., H.G.R. and M.D. conceived of and designed the experiments, analyzed the data and wrote the paper; M.D., M.C. and H.G. did the experiments with assistance from D.D.; T.T.H. did confocal microscopy; and D.M.L. and S.F. provided reagents and intellectual input.

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Correspondence to Samuel M Behar or Heinz G Remold.

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Divangahi, M., Chen, M., Gan, H. et al. Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair. Nat Immunol 10, 899–906 (2009). https://doi.org/10.1038/ni.1758

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