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The immunity-related GTPases in mammals: a fast-evolving cell-autonomous resistance system against intracellular pathogens

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Abstract

The immunity-related GTPases (IRGs) belong to the family of large, interferon-inducible GTPases and constitute a cell-autonomous resistance system essential for the control of vacuolar pathogens like Toxoplasma gondii in mice. Recent results demonstrated that numerous IRG members accumulate collaboratively at the parasitophorous vacuole of invading T. gondii leading to the destruction of the vacuole and the parasite and subsequent necrotic host cell death. Complex regulatory interactions between different IRG proteins are necessary for these processes. Disturbance of this finely balanced system, e.g., by single genetic deficiency for the important negative regulator Irgm1 or the autophagic regulator Atg5, leads to spontaneous activation of the effector IRG proteins when induced by IFNγ. This activation has cytotoxic consequences resulting in a severe lymphopenia, macrophage defects, and failure of the adaptive immune system in Irgm1-deficient mice. However, alternative functions in phagosome maturation and induction of autophagy have been proposed for Irgm1. The IRG system has been studied primarily in mice, but IRG genes are present throughout the mammalian lineage. Interestingly, the number, type, and diversity of genes present differ greatly even between closely related species, probably reflecting intimate host-pathogen coevolution driven by an armed race between the IRG resistance proteins and pathogen virulence factors. IRG proteins are targets for polymorphic T. gondii virulence factors, and genetic variation in the IRG system between different mouse strains correlates with resistance and susceptibility to virulent T. gondii strains.

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Acknowledgments

JCH and JPH were supported by SFB635, SFB670, SFB680 and SPP1399 from the Deutsche Forschungsgemeinschaft; and CGF and AS were supported by the Intramural Research Program of the NIAID, NIH. We are grateful to our colleague Gregory Taylor for his pioneering work on the IRG system.

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  1. Institute for Genetics, University of Cologne, Zuelpicher Str. 47a, 50674, Cologne, Germany

    Julia P. Hunn & Jonathan C. Howard

  2. Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Carl G. Feng & Alan Sher

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  1. Julia P. Hunn
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  2. Carl G. Feng
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Correspondence to Jonathan C. Howard.

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Hunn, J.P., Feng, C.G., Sher, A. et al. The immunity-related GTPases in mammals: a fast-evolving cell-autonomous resistance system against intracellular pathogens. Mamm Genome 22, 43–54 (2011). https://doi.org/10.1007/s00335-010-9293-3

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