Review
Latent tuberculosis: mechanisms of host and bacillus that contribute to persistent infection

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Summary

Most people infected with Mycobacterium tuberculosis contain the initial infection and develop latent tuberculosis. This state is characterised by evidence of an immune response against the bacterium (a positive tuberculin skin test) but no signs of active infection. It can be maintained for the lifetime of the infected person. However, reactivation of latent infection occurs in about 10% of infected individuals, leading to active and contagious tuberculosis. An estimated 2 billion people worldwide are infected with M tuberculosis-an enormous reservoir of potential tuberculosis cases. The establishment and reactivation of latent infection depend on several factors, related to both host and bacterium. Elucidation of the host immune mechanisms that control the initial infection and prevent reactivation has begun. The bacillus is well adapted to the human host and has a range of evasion mechanisms that contribute to its ability to avoid elimination by the immune system and establish a persistent infection. We discuss here current understanding of both host and bacterial factors that contribute to latent and reactivation tuberculosis.

Section snippets

Immune response to M tuberculosis

The immune response to M tuberculosis is multifaceted and complex. T cells are an essential component of the protective response, and the interaction of these cells with infected macrophages is crucial for control of infection. The immune response is initiated when M tuberculosis arrives in the alveolar space, where it encounters alveolar macrophages. In response, at least partly through interactions of mycobacterial components with Toll-like receptors (TLR), the macrophages produce

Animal models for study of latent tuberculosis

Understanding of the various model systems available for study of acute and latent tuberculosis is useful. For studies of acute (primary) infection and vaccine testing, mice and guineapigs have been used extensively. Guineapigs are very susceptible to tuberculosis and can succumb to a very lowdose infection. This model has been used extensively to assess vaccine candidates. Mouse strains vary in susceptibility to M tuberculosis disease. An advantage of using mice for studies of infectious

T cells in latent tuberculosis

Interferon γ is a key cytokine in the immune response against M tuberculosis. This cytokine activates macrophages to kill the intracellular bacilli. Interferon γ probably has other roles in control of infection, since interferon-γ knockout mice are more susceptible to tuberculosis37, 38 than strains deficient in macrophage effector mechanisms, such as inducible nitric oxide synthase (NOS2)39, 40, 41 or in T cells.42, 43 Certain genetic mutations in human beings lead to deficiencies in

Modulation of antigen presentation: results of in-vitro studies

There is much evidence that M tuberculosis can interfere with the pathway for processing and presentation of MHC class II antigens. This pathway is crucial for the priming and effector function of CD4 T cells. Since CD4 T cells are an important component of the protective immune response against M tuberculosis, the ability of the tubercle bacillus to affect adversely the efficiency of MHC class II processing and presentation probably contributes to persistence.

In a study designed to

Avoidance of the toxic effects of RNI

The production of RNI by NOS2 therefore seems to be essential for the containment of M tuberculosis infection. Yet in both mice and human beings, many immunocompetent individuals, though able to contain infection with M tuberculosis, are unable to eliminate the bacterium completely. This feature suggests that M tuberculosis expresses genes that counteract the bactericidal or bacteriostatic effects of RNI; studies by various experimental approaches now support this hypothesis.

A selection

Remodelling the phagosome

Phagocytosis of pathogenic microorganisms by “professional” phagocytes such as macrophages and neutrophils is the first step in their eventual degradation, as the phagosome eventually matures into a phagolysosome rich in acid hydrolases with degradative and microbicidal capacity. The maturation of a pathogen-containing phagosome is a highly complex and ordered process that involves the interaction of the phagosome with several endocytic vesicles through fission and fusion events, the molecular

Cytokines and latent tuberculosis

Although a protective role for TNF against M tuberculosis is well established in mice,27, 146, 147, 148, 149 there was no evidence until recently that this cytokine is important for the control of tuberculosis in human beings. In fact, TNF was thought to contribute to the immunopathology of tuberculosis in both mice and human beings.150, 151, 152, 153 Administration of thalidomide (which suppresses TNF production) to individuals with M tuberculosis infection was reported to result in

Interleukin 10–regulation or dysfunction?

Interleukin 10 is an immunoregulatory cytokine produced by T cells, macrophages, and dendritic cells. It can deactivate macrophages and can dampen the immune response to prevent or limit pathology from an over-exuberant inflammatory response to a pathogen. In transgenic mice expressing interleukin 10 compared with control mice, BCG was present in slightly higher numbers in spleen and liver;169 this feature suggests that increased interleukin 10 could be detrimental to bacterial control.

Conclusion

Control of the initial phase of M tuberculosis infection is likely to be important to the downstream events of the disease. The immunological mechanisms involved in maintaining a latent infection are complex, but are clearly necessary to prevent reactivation. Although the host response is essential to control of infection, the tubercle bacillus participates in the establishment of latency by using various strategies to evade elimination by the host. The bacteria can wait for the immune response

Search strategy and selection criteria

Data for this review were identified though searches of Medline and PubMed, through references cited in relevant articles, and through searches of the authors' files. Search terms used were “mycobacterium”, “tuberculosis”, “latency”, “persistence”, “animal models”, “T cells”, “macrophage”, “nitric oxide”, “phagosome”, “antigen presentation”, “tumour necrosis factor”, and “IL-10”. Only papers published in English were reviewed.

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