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  • Review Article
  • Published:

The spectrum of latent tuberculosis: rethinking the biology and intervention strategies

Nature Reviews Microbiology volume 7, pages 845–855 (2009)Cite this article

Key Points

  • Latent tuberculosis is defined by the presence of an antigen-specific T cell response in the absence of clinical symptoms. It includes conditions ranging from clearance of the pathogen, maintenance of quiescent infected foci to active subclinical disease, and can be viewed as part of a spectrum of outcomes to infection with Mycobacterium tuberculosis.

  • The pathogenesis of tuberculosis depends on localized granulomatous responses. Different types of granuloma can promote bacterial killing, persistence or replication.

  • Live imaging by positron emission tomography and computed tomography in humans and non-human primates provides powerful new opportunities to analyse tuberculosis lesions in terms of spatial distribution and dynamic behaviour in the presence and absence of drugs.

  • Different granulomas provide different microenvironments that can support heterogeneous subpopulations of bacteria differing in phenotypic adaptation and drug susceptibility. Systems biology approaches will be important in the molecular characterization of the microenvironment within lesions and the corresponding bacterial physiology.

  • Drug strategies based on simple inhibition of individual enzyme targets have proved largely ineffective for the discovery of novel antimicrobials. An improved understanding of actual bactericidal mechanisms will be important in rational targeting of new drugs against persistent bacterial phenotypes.

  • In addition to the development of drugs that are customized against different subpopulations of bacteria, the use of preventive therapy as an intervention for the control of global tuberculosis will benefit from further definition of the spectrum of latent disease. Imaging profiles and biomarkers will assist in clinical trials of new drugs and in the identification of individuals at highest risk disease progression.

Abstract

Immunological tests provide evidence of latent tuberculosis in one third of the global population, which corresponds to more than two billion individuals. Latent tuberculosis is defined by the absence of clinical symptoms but carries a risk of subsequent progression to clinical disease, particularly in the context of co-infection with HIV. In this Review we discuss the biology of latent tuberculosis as part of a broad range of responses that occur following infection with Mycobacterium tuberculosis, which result in the formation of physiologically distinct granulomatous lesions that provide microenvironments with differential ability to support or suppress the persistence of viable bacteria. We then show how this model can be used to develop a rational programme to discover effective drugs for the eradication of M. tuberculosis infection.

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Figure 1: Tuberculosis infection as a spectrum.
Figure 2: Positron emission tomography and computed tomography imaging.
Figure 3: Tuberculous granulomas.
Figure 4: A systems biology approach to the pathology of tuberculosis.
Figure 5: A lesion-based framework for the study of latent tuberculosis and drug development.

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Acknowledgements

We are grateful to colleagues in the Grand Challenges in Global Health project “Drugs for Treatment of Latent Tuberculosis” for stimulating discussion and to the Bill and Melinda Gates Foundation and the Wellcome Trust for financial support. This work was also funded (in part) by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) and by NIH RO1 HL075845 (J.L.F.). We also thank our Novartis colleagues in Singapore, Basel, Cambridge and La Jolla for discussions and collaboration.

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Authors and Affiliations

  1. Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Clifton E. Barry 3rd & Helena I. Boshoff

  2. Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore

    Véronique Dartois & Thomas Dick

  3. Department of Microbiology and Immunology, Weill Cornell Medical College, New York, 10065, New York, USA

    Sabine Ehrt & Dirk Schnappinger

  4. Department of Molecular Genetics and Biochemistry, Biomedical Science Tower, University of Pittsburgh School of Medicine, Pittsburgh, 15261, Pennsylvania, USA

    JoAnne Flynn

  5. Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Robert J. Wilkinson

  6. Division of Mycobacterial Research, Medical Research Council National Institute for Medical Research, London, NW7 1AA, UK

    Robert J. Wilkinson & Douglas Young

  7. Centre for Molecular Microbiology and Infection and Division of Medicine, Imperial College London, SW7 2AZ, UK

    Robert J. Wilkinson & Douglas Young

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Glossary

Tuberculin skin test

A method of diagnosing Mycobacterium tuberculosis infection by injecting tuberculosis antigens intradermally. A delayed type hypersensitivity response, dependent on the presence of sensitized T cells, is seen in those infected with M. tuberculosis. This does not distinguish latent infection from active tuberculosis.

Purified protein derivative

A precipitate of non-specific molecules from sterilized and filtered cultures of Mycobacterium tuberculosis.

Computed tomography

An imaging technique in which X-ray scans of a subject are compiled to generate a three-dimensional picture of various organs and structures (including brain and lungs).

Positron emission tomography

A nuclear medicine imaging technique using a positron-emitting probe that produces a three-dimensional image of biological processes within the scanned subject.

Granuloma

An organized structure comprising lymphocytes, macrophages, neutrophils and sometimes fibroblasts that often has a necrotic centre, which arises in response to continued antigenic stimulation in the presence of macrophages, for example in response to Mycobacterium tuberculosis infection.

Hypoxia

Low levels of oxygen in tissues.

Paucibacillary

Containing just a few bacilli, as is the case with granulomas that are caused by various mycobacterial diseases.

Caseation

Necrotic degeneration of bodily tissue into a soft crumbly cheese-like mass, where cellular outline is lost. In tuberculosis, this refers to the necrotic centre of a granuloma and is mainly driven by the immune response and is typical of tuberculosis pathogenesis.

Hypoxic response

Changes in gene expression induced by the incubation of Mycobacterium tuberculosis under anaerobic conditions. This comprises an initial transient response (by the DosR hypoxia regulon) followed by the enduring hypoxic response involving expression of a set of 230 genes.

Hypoxia regulon

A cluster of 48 genes that are controlled by the transcriptional regulator DosR, which is upregulated in response to hypoxia but also during exposure to nitric oxide, carbon monoxide, sodium dodecyl sulfate or low pH.

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Barry, C., Boshoff, H., Dartois, V. et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 7, 845–855 (2009). https://doi.org/10.1038/nrmicro2236

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