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Tuberculosis: a problem with persistence

Key Points

  • With 8 million new infections each year and 2 million deaths, tuberculosis is a serious problem; this problem is compounded by the 2 billion people who have been infected and now carry latent infection that might reactivate later in life.

  • Evidence for persistent infection.

  • Epidemiological evidence of persistent infection shows that reactivation occurs where there is a low risk of reinfection and is related to both age and immune status; in endemic areas both reactivation and reinfection occur. Autopsy studies have detected viable bacteria in asymptomatic individuals, and provide evidence that bacteria can be found where there are no visible lesions. Animal models of persistence, particularly mice, provide a means of dissecting the interaction between host and bacteria. The murine model provides evidence that, during the persistent plateau phase of infection, mycobacteria are dividing very slowly or not at all. Mycobacterial mutants with persistence phenotypes have been constructed by inactivating a wide range of genes, providing clues to the mechanisms that mycobacteria use.

  • The immune response.

  • Having controlled initial infection, why does the immune response not clear the bacteria? Having coped with persistent infection, what triggers breakdown to active disease? Containment uses both the adaptive and innate immune responses, including macrophages and dendritic cells signalling through several receptors. CD4+ T cells and cytokines have a central role in containment, with other cell types (including CD8+ T cells) being involved in the control of persistence.

  • Targeting persistent infection.

  • Present therapies seek to break transmission by treating patients with active disease — an intervention that prevents the progression of patients with latent infection to active disease. This could be achieved by targeted drugs against persistent bacteria, or by post-exposure vaccination.

Abstract

Mycobacterium tuberculosis is one of most successful pathogens of mankind, infecting one-third of the global population and claiming two million lives every year. The ability of the bacteria to persist in the form of a long-term asymptomatic infection, referred to as latent tuberculosis, is central to the biology of the disease. The persistence of bacteria in superficially normal tissue was recognized soon after the discovery of the tubercle bacillus, and much of our knowledge about persistent populations of M. tuberculosis dates back to the first half of the last century. Recent advances in microbial genetics and host immunity provide an opportunity for renewed investigation of this persistent threat to human health.

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Figure 1: The search for persistent M. tuberculosis.
Figure 2: A simple plateau model for persistent infection in mice.
Figure 3: Immune mechanisms of containment and persistence.

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We thank one of the referees for their stimulating and useful comments.

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Correspondence to Douglas B. Young.

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Glossary

MACROPHAGE

Cell of the mononuclear phagocyte system that can phagocytose foreign particulate material. Macrophages are present in many tissues and are important for nonspecific immune reactions.

PHAGOSOME

A membrane-bounded cytoplasmic vacuole formed around a particle ingested by phagocytosis.

DENDRITIC CELLS

Professional antigen-presenting cells that take up proteins and present peptide antigens to T cells in conjunction with accessory molecules that stimulate T-cell activation. Characterized by many long thin processes extending from them.

T CELLS

Lymphocytes that undergo maturation and differentiation in the thymus. They are responsible for immune reactions that involve cell–cell interactions.

FOAMY GIANT CELL

A giant, multinucleate macrophage loaded with lipid.

BCG

Bacille Calmette–Guérin, the attenuated M. bovis live vaccine.

CASEOUS GRANULOMAS

An encapsulated lesion, known as caseous owing to a supposed resemblance to crumbly cheese. The underlying cells and tissue are totally destroyed in the process of caseous necrosis.

HYPOXIA

A condition in which the concentration of oxygen is greater than 0% but less than 20%.

WHOLE-GENOME PROFILING

The use of microarrays to obtain a snapshot of an organism's response to stimuli in terms of gene expression or genetic recombination.

SIGMA FACTOR

A subunit of bacterial RNA polymerase that is required for initiation of transcription. Some sigma factors confer the ability to recognize and bind to a particular promoter, thereby changing the pattern of gene expression.

PERFORIN

A pore-forming protein present in the granules of cytotoxic T cells.

TOLL-LIKE RECEPTOR

A family of mammalian transmembrane receptors related to the Toll protein of Drosophila. They are involved in the recognition of pathogens and microbial products and activate antimicrobial effector pathways in phagocytes.

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Stewart, G., Robertson, B. & Young, D. Tuberculosis: a problem with persistence. Nat Rev Microbiol 1, 97–105 (2003). https://doi.org/10.1038/nrmicro749

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