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p47 GTPases: regulators of immunity to intracellular pathogens

Nature Reviews Immunology volume 4, pages 100–109 (2004)Cite this article

Key Points

  • The 47-kDa GTP-binding proteins constitute a family of structurally related genes that are upregulated by stimulation with type I and type II interferons (IFNs). Most of these molecules seem to have GTPase enzyme activity.

  • Mice that are deficient in two of the p47 GTPase family members, Igtp and Lrg47, have been shown to be acutely susceptible to various infections with intracellular protozoa and bacteria that are normally controlled by IFN-dependent host-resistance mechanisms. By contrast, the same animals are resistant to infection with viruses.

  • Whereas Igtp-deficient mice are highly susceptible to several protozoan pathogens, they are resistant to all bacterial infections that have been tested so far. By contrast, Lrg47-deficient animals fail to control both protozoan and bacterial infections.

  • In the case of Mycobacterium tuberculosis, Lrg47 has been shown to affect intracellular survival of the pathogen by regulating phagosome maturation and acidification.

  • Additional studies indicate that Lrg47 and Igtp can regulate lymphocyte dynamics and therefore influence host resistance by controlling the generation of effector T cells.

Abstract

Activation of the innate immune system by interferon-γ(IFN-γ) is crucial for host resistance to infection. IFN-γ induces the expression of a wide range of mediators that undermine the ability of pathogens to survive in host cells, including a newly discovered family of 47-kDa GTPases. Elimination of different p47 GTPases in mice by gene targeting severely cripples IFN-γ-regulated defence against Toxoplasma gondii, Listeria monocytogenes, Mycobacterium spp. and other pathogens. In this article, we review our understanding of the role of p47 GTPases in resistance to intracellular infection and discuss the present evidence concerning their mode of action.

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Figure 1: Selected intracellular anti-microbial mediators induced by interferon-γ(IFN-γ).
Figure 2: Dendrogram of the p47 GTPase family.
Figure 3: Mechanisms implicated in p47 GTPase regulation of host resistance to infection.

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Acknowledgements

We are grateful to Y. Belkaid, G. Yap, J. MacMicking, J. McKinney, D. Sacks, H. Young and C. Collazo for helpful discussions and intellectual contributions to this work.

Author information

Authors and Affiliations

  1. Departments of Medicine and Immunology, Division of Geriatrics, and the Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Gregory A. Taylor

  2. GRECC, VA Medical Center, Durham, 27705, North Carolina, USA

    Gregory A. Taylor

  3. Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, 20892, Maryland, USA

    Carl G. Feng & Alan Sher

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DATABASES

LocusLink

CD4

CD8

Gbp1

GBP1

Gbp2

GBP2

Gbp3

Gbp4

Gbp5

GM-CSF

gp91-phox

Gtpi

IDO

IFN-α

IFN-β

IFN-γ

Igtp

Iigp

IL-1α

IL-1β

IL-2

IL-6

IRF1

Lrg47

Mx1

Mx2

MxA

MxB

NOS2

NRAMP1

RAB5A

RAB5B

RAB5C

RAB7

Stat1

Tgtp

TNF

FURTHER INFORMATION

Alan Sher's laboratory

Glossary

NITRIC OXIDE SYNTHASE 2

(NOS2). The inducible form of nitric oxide synthase — an important enzyme in the production of nitric oxide — which is produced in response to lipopolysaccharide and interferon-γ by macrophages and other cells. NOS2 has a crucial role in host resistance to infection.

ISOPRENYLATED PROTEINS

Proteins that are post-translationally modified by the covalent addition of an isoprenoid lipid moiety (either a farnesyl or geranylgeranyl group) to a cysteine near the carboxyl terminus of the protein, usually in a Cys-Ala-Ala-Xaa motif. This modification often allows association of the protein with a lipid membrane in the cell.

OLIGOMERIZATION

The association of polypeptide monomers to form a multi-subunit protein.

GENE KNOCKOUT

A technique, also referred to as gene targeting, by which a specific gene is inactivated, usually through the disruption, mutation or removal of a portion of the protein-coding segments of the gene.

PARASITOPHOROUS VACUOLE

An intracellular, membrane-bound vacuole that contains a parasite that has infected a host cell. The vacuole is initially formed from host-cell lipid and protein components, but, subsequently, the character of the vacuole is greatly influenced by the parasite that it contains.

BONE-MARROW CHIMAERAS

Animals in which the endogenous immune system has been inactivated and replaced with the immune system from an allogeneic donor. To accomplish this, the haematopoietic cells of the recipient are lethally irradiated, after which the immune system is reconstituted by intravenous injection of bone-marrow cells from the donor.

PARTIAL CHEMOTHERAPY

The use of antimicrobial agents to allow an otherwise susceptible host to survive through a particular period of infection.

LYSOSOMES

Membrane-bound organelles in the cytoplasm of cells that contain a high concentration of hydrolytic enzymes that are responsible for the degradation of macromolecules. The contents of lysosomes are acidic due to the actions of a vacuolar ATPase.

T HELPER 1/2 (TH1/2) CELLS

Two subsets of T helper cells that are defined by the different spectra of cytokines that they secrete, and, consequently, the different biological functions that they carry out. TH1 cells secrete interferon-γ and are involved in cell-mediated functions such as macrophage activation, whereas TH2 cells function as helpers for B-cell activation and antibody production.

GRANULOMA

A mass of inflammatory cells that arises due to the persistence of an antigen or infectious agent in host tissue. The granuloma contains various cells, including lymphocytes, macrophages, giant cells and fibroblasts.

ENDOSOMES

Membrane-bound vesicles in the cytoplasm of cells that are formed by the fusion of small endocytic vesicles that result from endocytosis. A network of endosomes extends from the plasma membrane of the cell to the perinuclear region.

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Taylor, G., Feng, C. & Sher, A. p47 GTPases: regulators of immunity to intracellular pathogens. Nat Rev Immunol 4, 100–109 (2004). https://doi.org/10.1038/nri1270

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