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Mycobacterium tuberculosis: here today, and here tomorrow

Nature Reviews Molecular Cell Biology volume 2, pages 569–578 (2001)Cite this article

Key Points

  • Pathogenic Mycobacterium spp. survive within the macrophages of their host. One of these, Mycobacterium tuberculosis, is a highly successful pathogen that subverts two pathways of its host. First, it stops the normal progression of the phagosome into an acidic, hydrolytically active compartment; and second, it avoids the development of a localized, productive immune response that could activated the host cell.

  • The bacilli gain entry to macrophages through binding to one of several phagocytic receptors. Once in the cell, Mycobacterium are retained in a phagocytic vacuole until the host cell dies by necrosis or apoptosis. These vacuoles fail to fuse with lysosomes, but they remain fusion-competent, acquire some 'lysosomal' proteins from the synthetic pathway of the host cell, and undergo fusion with other vesicles of the endosomal system.We are beginning to understand the molecular mechanisms that Mycobacterium use to prevent maturation of the phagosomes after uptake by the macrophage.

  • Host cells have also developed means of protection against intracellular parasites such as Mycobacterium. For example, NRAMP1 ( natural-resistance-associated macrophage 1) confers innate resistance for macrophages against the growth of certain intracellular microorganisms, and might influence vacuolar pH.

  • It is hoped that new genetic screens will shed light on the molecules that Mycobacterium uses to maintain the host as a habitable environment.

  • Mycobacterium avoid or minimize the induction of a productive immune response and suppress the effector cascade once such a response has developed. It is thought that mycobacteria do this by sequestering vacuoles away from the normal antigen-processing and -presentation machinery, and by modulating the environment in the immediate vicinity of the infected macrophage.

  • Understanding the position of infected vacuoles in the endosomal pathway should help us to develp improved drug delivery. For this, a much greater understanding of the endosomal-lysosomal environment is required.

Abstract

Mycobacterium tuberculosis is a highly successful pathogen that parasitizes the macrophages of its host. Its success can be attributed directly to its ability to manipulate the phagosome that it resides in and to prevent the normal maturation of this organelle into an acidic, hydrolytic compartment. As the macrophage is key to clearing the infection, the interplay between the pathogen and its host cell reflects a constant battle for control.

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Figure 1: Electron micrograph of a mouse bone-marrow-derived macrophage infected eight days previously with Mycobacterium tuberculosis.
Figure 2: The vacuole containing pathogenic Mycobacterium.
Figure 3: The relationship between the Mycobacterium-containing vacuole and the host cell's antigen-presentation machinery.

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Author information

Authors and Affiliations

  1. Microbiology and Immunology, 5173 Veterinary Medical Center, Cornell University, Ithaca, 14853, New York, USA

    David G. Russell

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Supplementary information

Movie 1

J774 macrophages transfected with Rab5–GFP show the transient association of the GTPase with phagosomes during formation around heat-killed Mycobacterium avium (labelled with Texas red dextran).

Courtesy of Joachim Ullrich and Rick Roberts.

Movie 2

J774 macrophages transfected with Rab5–GFP. In this rab5 mutant, amino-acid residue 79 is mutated from Q to L, causing the GTPase to be stably GDP-bound and remain membrane associated. These phagosomes retain the GTPase and exhibit homotypic fusion with other Rab5–GFP-positive endosomal compartments.

Courtesy of Joachim Ullrich and Rick Roberts.

Movie 3

Murine bone-marrow-derived macrophages infected 24 hr previously with Mycobacterium bovis BCG (labelled with Texas red hydrazide after mild periodate treatment). Most of the label is incorporated into lipidoglycans exposed on the bacterial surface. The glycoconjugates are released into the host cell in copious amounts and traffic through the cell as membraneous components of the host cell's endosomal system. This movie was made in collaboration with John Heuser Washington University (see Ref 53).

Related links

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DATABASE LINKS

LAMP1

cholera toxin B subunit

transferrin receptor

transferrin

cathepsin D

Rab5

Rab7

calmodulin

CaMKII

coronin I

NRAMP1

NRAMP2

urease

IFN-γ

NOS2

HLA-DR

neuraminidase

H2-M

IL-1

tumour necrosis factor-α

IL-6

STAT1

CREB-binding protein

isocitrate lyase

early endosomal antigen 1

CLIP peptide

isocitrate dehydrogenase

FURTHER INFORMATION

Russell lab

Glossary

ACTINOMYCETE

A diverse group of filamentous Gram-positive bacteria.

SAPROPHYTIC

Lives on dead or decaying organic matter.

GRAM-POSITIVE BACTERIA

Bacteria with cell walls that retain a basic blue dye during the Gram-stain procedure. These cell walls are relatively thick, consisting of a network of peptidoglycan.

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.

PHAGOCYTOSIS

Actin-dependent process, by which cells engulf external particulate material by extension and fusion of pseudopods.

VACUOLAR ATPASE

An enzyme that uses ATP as an energy source to pump protons into intracellular compartments and acidify them.

FOAMY GIANT CELL

A giant, multinucleate macrophage loaded with lipid.

LYMPHOCYTE

A type of leukocyte with functions in specific immunity.

MANNOSE 6-PHOSPHATE

Sugar modification required for lysosomal sorting of soluble hydrolases. Transmembrane mannose 6-phosphate receptors bind to these sugars and are sorted to late endosomes and lysosomes through their cytoplasmic targeting sequences.

OPSONIZED

Covered with blood-serum proteins — complement, or immunoglobulin-G antibodies — that enhance uptake by phagocytosis.

ZYMOSAN

Crude preparation of yeast cell walls that is used experimentally to activate complement-dependent phagocytosis.

COMPLEMENT RECEPTOR C3

(CR3). Receptor found on the cell surface of phagocytic cells, which recognizes particles opsonized with a fragment of the third component of complement, C3bi.

MEL JUSO CELLS

Nonphagocytic melanoma cell line.

MONOCYTE

Large leukocyte of the mononuclear phagocyte system. Monocytes are derived from pluripotent stem cells and become macrophages when they enter the tissues.

ANTIGEN-PRESENTING CELL

A cell, most often a macrophage or dendritic cell, that presents an antigen to activate a T cell.

T CELLS

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

GRANULOMA

The cellular aggregate, or tubercle, that forms around an inflammatory stimulus such as Mycobacterium.

SIGNATURE-TAGGED MUTAGENESIS

A negative selection method for the identification of virulence genes. The technique involves mutation of microbial genes by random insertion of a tagged transposon. After growth of a mixed population in a host, mutated genes that are absent and hence required for virulence are identified with the help of the tag.

MICROAEROPHILIC ENVIRONMENT

An environment in which the partial pressure of dioxygen is lower than under normal atmospheric conditions.

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Russell, D. Mycobacterium tuberculosis: here today, and here tomorrow. Nat Rev Mol Cell Biol 2, 569–578 (2001). https://doi.org/10.1038/35085034

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