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A Cluster of Interferon-gamma-Inducible p65 GTPases Plays a Critical Role in Host Defense against Toxoplasma gondii


Yamamoto, M; Okuyama, M; Ma, JS; Kimura, T; Kamiyama, N; Saiga, H; Ohshima, J; Sasai, M; Kayama, H; Okamoto, T; Huang, DCS; Soldati-Favre, D; Horie, K; Takeda, J; Takeda, K
2012-08-24
IMMUNITY
Journal Article
37
2
302-313
Interferon-gamma (IFN-gamma) is essential for host defense against intracellular pathogens. Stimulation of innate immune cells by IFN-gamma upregulates similar to 2,000 effector genes such as immunity-related GTPases including p65 guanylate-binding protein (Gbp) family genes. We show that a cluster of Gbp genes was required for host cellular immunity against the intracellular parasite Toxoplasma gondii. We generated mice deficient for all six Gbp genes located on chromosome 3 (Gbp(chr3)) by targeted chromosome engineering. Mice lacking Gbp(chr3) were highly susceptible to T. gondii infection, resulting in increased parasite burden in immune organs. Furthermore, Gbp(chr3)-deleted macrophages were defective in IFN-gamma-mediated suppression of T. gondii intracellular growth and recruitment of IFN-gamma-inducible p47 GTPase Irgb6 to the parasitophorous vacuole. In addition, some members of Gbp(chr3) restored the protective response against T. gondii in Gbp(chr3)-deleted cells. Our results suggest that Gbp(chr3) play a pivotal role in anti-T. gondii host defense by controlling IFN-gamma-mediated Irgb6-dependent cellular innate immunity.
CELL PRESS
IMMUNITY-RELATED GTPASES; NECROSIS-FACTOR-ALPHA; INTRACELLULAR PATHOGENS; INNATE RESISTANCE; NITRIC-OXIDE; P47 GTPASES; L-ARGININE; TNF-ALPHA; VIRULENCE; MACROPHAGES
Chemical Biology
10.1016/j.immuni.2012.06.009
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Creation Date 2012-08-24 12:00:00