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Overexpression of heat-shock proteins reduces survival of Mycobacterium tuberculosis in the chronic phase of infection

Nature Medicine volume 7, pages 732–737 (2001)Cite this article

Abstract

Elevated expression of heat-shock proteins (HSPs) can benefit a microbial pathogen struggling to penetrate host defenses during infection, but at the same time might provide a crucial signal alerting the host immune system to its presence. To determine which of these effects predominate, we constructed a mutant strain of Mycobacterium tuberculosis that constitutively overexpresses Hsp70 proteins. Although the mutant was fully virulent in the initial stage of infection, it was significantly impaired in its ability to persist during the subsequent chronic phase. Induction of microbial genes encoding HSPs might provide a novel strategy to boost the immune response of individuals with latent tuberculosis infection.

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Figure 1: Structure, regulation and mutagenesis of the hsp70 (dnaK) operon.
Figure 2: Constitutive overexpression of hsp70 proteins in the HspR mutant.
Figure 3: Growth and survival of the wild type and ΔhspR mutant in stationary phase, heat stress conditions and bone marrow-derived macrophages.
Figure 4: Characterization of the ΔhspR mutant in a chronic infection model.
Figure 5: Lung morphology in mice infected with wild-type and mutant strains.
Figure 6: Infection with the ΔhspR mutant increases IFN-γ production by splenocytes.

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Acknowledgements

We thank B. Robertson for helpful discussions; H. Cooper and R. Shrimpton for assistance in protein purification; and D. Turner for help with macrophage preparations. Thanks also to the Hugget laboratory. This work was supported by a Wellcome Trust Programme Grant and an EMBO Fellowship (to P.T.).

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Authors and Affiliations

  1. Department of Infectious Diseases and Microbiology, Centre for Molecular Microbiology and Infection, Imperial College of Science Technology and Medicine, London, UK

    Graham R. Stewart, Valerie A. Snewin, Peter Tormay, Peadar O'Gaora, Ivor N. Brown & Douglas B. Young

  2. Department of Biochemistry, Centre for Molecular Microbiology and Infection, Imperial College of Science Technology and Medicine, London, UK

    Gerhard Walzl & Tracy Hussell

  3. Department of Biosciences, University of Hertfordshire, Hatfield, Hertfordshire, UK

    Madhu Goyal

  4. GlaxoSmithKline, Stevenage, Hertfordshire, UK

    Joanna Betts

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Correspondence to Graham R. Stewart.

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Stewart, G., Snewin, V., Walzl, G. et al. Overexpression of heat-shock proteins reduces survival of Mycobacterium tuberculosis in the chronic phase of infection. Nat Med 7, 732–737 (2001). https://doi.org/10.1038/89113

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