A cluster of interferon-γ-inducible p65 GTPases plays a critical role in host defense against Toxoplasma gondii.
Interferon-γ (IFN-γ) is essential for host defense against intracellular pathogens. Stimulation of innate immune cells by IFN-γ upregulates ∼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-γ-mediated suppression of T. gondii intracellular growth and recruitment of IFN-γ-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-γ-mediated Irgb6-dependent cellular innate immunity.
Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan. myamamoto@biken.osaka-u.ac.jp
Masahiro
M
Yamamoto
Megumi
M
Okuyama
Ji Su
JS
Ma
Taishi
T
Kimura
Naganori
N
Kamiyama
Hiroyuki
H
Saiga
Jun
J
Ohshima
Miwa
M
Sasai
Hisako
H
Kayama
Toru
T
Okamoto
David C S
DC
Huang
Dominique
D
Soldati-Favre
Kyoji
K
Horie
Junji
J
Takeda
Kiyoshi
K
Takeda
D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology; D008163:Luminescent Measurements; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009569:Nitric Oxide / Q000378:metabolism; D014122:Toxoplasma / Q000276:immunology* / Q000378:metabolism; D014123:Toxoplasmosis / Q000276:immunology*
D009569:Nitric Oxide; D007371:Interferon-gamma; D019204:GTP-Binding Proteins