Opinion | Published:

Advancing host-directed therapy for tuberculosis

Nature Reviews Immunology volume 15, pages 255263 (2015) | Download Citation

This article has been updated

Abstract

Improved treatments are needed for nearly all forms of Mycobacterium tuberculosis infection. Adjunctive host-directed therapies have the potential to shorten tuberculosis treatment duration, prevent resistance and reduce lung injury by promoting autophagy, antimicrobial peptide production and other macrophage effector mechanisms, as well as by modifying specific mechanisms that cause lung inflammation and matrix destruction. The range of candidates is broad, including several agents approved for other clinical indications that are ready for evaluation in Phase II clinical trials. The promise of new and existing host-directed therapies that could accelerate response and improve tuberculosis treatment outcomes is discussed in this Opinion article.

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Change history

  • 17 March 2015

    In the version of this article that was originally published online, some of the information in the acknowledgements section was incorrect. This has been corrected online and was corrected for the print version of the article.

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Acknowledgements

The authors thank workshop participants for providing summaries of their presentations and the session chairs for their assistance in reviewing earlier versions of this document: L. S. Schlesinger (Ohio State University, USA), T. R. Hawn (University of Washington, USA), W. H. Boom (Case Western Reserve University, Ohio, USA), H. Kornfeld (University of Massachusetts, USA), G. Churchyard (Aurum Institute, South Africa), J. Ellner (Boston University, Massachusetts, USA) and G. Kaplan (Bill and Melinda Gates Foundation). They also acknowledge the editorial and administrative assistance of D. Johnson and S. Williams (Division of AIDS, US National Institute of Allergy and Infectious Disease (NIAID)). This publication and workshop have been funded in whole or in part with Federal funds from the Division of AIDS, NIAID, US National Institutes of Health, Department of Health and Human Services, under contract number HHSN272201200009C, entitled NIAID HIV and Other Infectious Diseases Clinical Research Support Services (CRSS).

Author information

Affiliations

  1. Aurum Institute, Johannesburg 2193, South Africa.

    • Robert S. Wallis
  2. Division of AIDS, National Institutes of Health, Bethesda, Maryland 20852, USA.

    • Richard Hafner

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Robert S. Wallis.

Glossary

Autophagy

A cellular process that delivers potentially harmful cytosolic macromolecules and organelles to lysosomes for degradation. In macro-autophagy, an isolation membrane fuses with itself to enclose the pathogen to form an autophagosome, which can then fuse with lysosomes.

C3HeB/FeJ mice

A strain of mice (also known as Kramnik mice) that develops granulomatous lesions with central necrosis and hypoxia following Mycobacterium tuberculosis infection. By contrast, lesions in BALB/c mice are non-necrotic and lack hypoxia.

Granulomas

Organized collections of tightly apposed epithelioid macrophages, lymphocytes and fibroblasts, with or without necrotic centres.

Immune reconstitution inflammatory syndrome

(IRIS). Paradoxical reactions that occur during combined antimicrobial and antiretroviral treatment in individuals with tuberculosis and AIDS.

Inflammasome

A molecular complex of several proteins that cleaves pro-interleukin-1 (IL-1) and pro-IL-18 following assembly, thereby producing active IL-1 and IL-18.

Latent M. tuberculosis infection

(LTBI). A clinical state in which there is evidence of T cell sensitization to Mycobacterium tuberculosis antigens (by tuberculin skin test or interferon-release assay) but no evidence of disease (by chest radiography and sputum culture). Individuals with LTBI are at risk of developing active tuberculosis if immunosuppressed by medical therapies or other infections.

Mammalian target of rapamycin

(mTOR). A conserved serine/threonine protein kinase that regulates cell growth and metabolism, as well as the expression of cytokines and growth factors, in response to environmental cues. mTOR receives stimulatory signals from RAS and phosphatidylinositol-3-OH kinase downstream of growth factors, as well as nutrients, such as amino acids, glucose and oxygen.

Paradoxical reactions

Exacerbation of clinical disease (worsened fever and increased lymph node and lung involvement) despite microbiological improvement (conversion of sputum cultures to negative) that occurs after antimicrobial treatment has commenced and is attributed to activation of inflammatory mechanisms.

Phagolysosome

A cytoplasmic body that is formed by the fusion of a phagosome (containing ingested particles at a neutral pH) and a lysosome (containing hydrolytic and other enzymes at an acidic pH). Fusion of the phagolysosome is inhibited by Mycobacterium tuberculosis as a mechanism for its intracellular survival.

S100 proteins

A family of low-molecular-weight proteins that participate in the inflammatory response by promoting leukocyte migration.

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