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  • Review Article
  • Published:

Who puts the tubercle in tuberculosis?

Nature Reviews Microbiology volume 5, pages 39–47 (2007)Cite this article

Key Points

  • Mycobacterium tuberculosis probably evolved from a founder strain similar to the TB-like strains found today in central Africa, and invaded mankind prior to the spread of humans out of Africa. Contrary to popular literature, TB did not evolve from Mycobacterium bovis that was acquired from cows during the evolution of animal husbandry in the Fertile Crescent.

  • Mycobacterium tuberculosis infections result in the formation of granulomas at the established infection site. The progression of these granulomas determines, locally, the outcome of the infection and not all granulomas in the same host progress in the same way.

  • Granulomas can resolve, mineralize, or progress to yield a productive infection. A productive infection is achieved when the centre of the granuloma caseates, degenerates and spills live infectious bacteria into the lung airways inducing a cough and transmission through aerosol droplets.

  • The peripheral cell-wall lipids from Mycobacterium tuberculosis are potent immunomodulating agents that, when inoculated into experimental animals, induce tissue pathology that is reminiscent of the granulomas produced in a viable infection.

  • Mycobacterium tuberculosis releases peripheral cell-wall lipids inside the infected host macrophage. The macrophage sequesters these lipids into the membranes of internal vesicles in the multi-vesicular lysosomes and releases these vesicles as exosomes.

  • The release and trafficking of bioactive lipids might be an active mechanism whereby Mycobacterium tuberculosis exacerbates the pathology of the infection, driving granuloma progression, and ultimately leading to caseation and spread.

Abstract

Tuberculosis (TB), an illness that mainly affects the respiratory system, is one of the world's most pernicious diseases. TB currently infects one-third of the world's population and kills approximately 1.7 million people each year. Most infected individuals fail to progress to full-blown disease because the TB bacilli are 'walled off' by the immune system inside a tissue nodule known as a granuloma. The granuloma's primary function is one of containment and it prevents the dissemination of the mycobacteria. But what is the role of the TB bacillus in the progression of the granuloma? This Review explores how Mycobacterium tuberculosis influences granuloma formation and maintenance, and ensures the spread of the disease.

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Figure 1: Trafficking of Mycobacterium tuberculosis bacilli in cells.
Figure 2: Release and trafficking of bacterial lipids.
Figure 3: The lipid-bead granuloma model.

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Acknowledgements

This work was supported by grants from the National Institute of Allergy and Infectious Diseases and the National Heart, Lung and Blood Institute of the National Institutes of Health, USA. The author would like to acknowledge the work of past and present members of the laboratory, most notably E. Rhoades, R. Geisel and K. Sakamoto.

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    David G. Russell

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Glossary

Founder strain

The ancestral species or strain that underwent divergent evolution to produce several new species or strains.

Caseation

The process by which a tuberculous granuloma decays into a structureless mass of cellular debris.

Chemokine

Cytokines involved in specific inflammatory responses. They are differentiated into CC or CXC chemokines on the basis of their primary sequence.

Natural killer (NK) T cell

An NK T cell is a T cell that expresses some NK cell receptors and has some NK-cell-like functions. They also express a T-cell receptor that recognizes CD1b (which binds glycolipids not peptides).

CD4+ cell

A subpopulation of T cells that express the CD4 receptor and respond to antigens presented on the surface of host cells that bear major histocompatibility complex class II molecules. Two distinct subsets of activated CD4+ T cells have been described. T-helper 1 (TH1) cells produce interferon γ, tumour-necrosis factor α and interleukin (IL-)12, and support cell-mediated immunity. TH2 cells produce IL-4, IL-5 and IL-13, support humoral immunity, and downregulate TH1 responses.

CD8+ cell

A subpopulation of T cells that express the CD8 receptor. CD8+ cells recognize antigens that are presented on the surface of host cells by major histocompatibility complex class I molecules, leading to their destruction, and are therefore also known as cytotoxic T cells.

Cytokine

Member of a large family of secreted proteins that bind immune cells through specific receptors. Cytokine production results in the activation of an intracellular-signalling cascade that commonly regulates processes such as immune function and inflammation.

Neovascularization

The formation of new blood vessels in a developing tissue. This process is stimulated by the production of vascular endothelial growth factor. The term is used most frequently in cancer biology in which the tumour develops its own blood supply through neovascularization.

Foamy macrophage

A macrophage loaded with lipid droplets. Such cells are often observed in tissues with chronic proinflammatory stimulus.

Giant cell

A giant, multinucleate macrophage.

Tuberculoma

The tuberculoma is the granuloma that is formed during tuberculosis infection. This term is most frequently used by clinicians and has replaced the more traditional 'tubercle'.

Phagosome

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

Homotypic fusion

The fusion of identical compartments or vesicles.

Autophagy

A pathway for the recycling of cellular contents, in which materials inside the cell are packaged into vesicles and are then targeted to the vacuole or lysosome for bulk turnover.

Fibrosis

Fibrosis is frequently seen at sites of chronic inflammatory stimulation. Cells lay down a fibrinogen/fibrin skeleton that is augmented with other extracellular matrix proteins like collagen.

Signature-tagged mutagenesis

A technique to screen large numbers of distinct mutants for those that fail to survive an animal infection. Each mutant is tagged with a unique DNA sequence (called a signature tag), which allows a specific mutant to be tracked within a large pool of bacteria.

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Russell, D. Who puts the tubercle in tuberculosis?. Nat Rev Microbiol 5, 39–47 (2007). https://doi.org/10.1038/nrmicro1538

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