A cluster of interferon-γ-inducible p65 GTPases plays a critical role in host defense against Toxoplasma gondii.
A cluster of interferon-γ-inducible p65 GTPases plays a critical role in host defense against Toxoplasma gondii.
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DOI：
10.1016/j.immuni.2012.06.009
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发表时间：
2012-08
期刊：
影响因子：
32.4
通讯作者：
Masahiro Yamamoto;M. Okuyama;Ji Su Ma;Taishi Kimura;Naganori Kamiyama;H. Saiga;J. Ohshima;Miwa Sasai;H. Kayama;T. Okamoto;D. Huang;Dominique Soldati-Favre;K. Horie;J. Takeda;K. Takeda
中科院分区：
文献类型：
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作者：
Masahiro Yamamoto;M. Okuyama;Ji Su Ma;Taishi Kimura;Naganori Kamiyama;H. Saiga;J. Ohshima;Miwa Sasai;H. Kayama;T. Okamoto;D. Huang;Dominique Soldati-Favre;K. Horie;J. Takeda;K. Takeda
干扰素-γ（IFN-γ）是宿主防御胞内病原体的必需因子。IFN-γ对先天免疫细胞的刺激上调了约2,000个效应基因，例如免疫相关的GTP酶，包括p65鸟苷酸结合蛋白（Gbp）家族基因。我们发现，一个Gbp基因簇是宿主细胞免疫细胞内寄生虫弓形虫所必需的。我们通过靶向染色体工程产生了位于3号染色体（Gbpchr 3）上的所有六个Gbp基因缺陷的小鼠。缺乏Gbpchr 3的小鼠对弓形虫感染高度易感，导致免疫器官中寄生虫负荷增加。此外，Gbpchr 3缺失的巨噬细胞在IFN-γ介导的对弓形虫细胞内生长的抑制和IFN-γ诱导的p47 GT3 Irgb 6向寄生虫空泡的募集方面存在缺陷。此外，Gbpchr 3的一些成员恢复了对Gbpchr 3缺失的细胞中的弓形虫的保护性反应。我们的研究结果表明Gbpchr 3通过控制IFN-γ介导的Irgb 6依赖的细胞天然免疫在抗弓形虫宿主防御中发挥关键作用。
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 ofGbpgenes was required for host cellular immunity against the intracellular parasiteToxoplasma gondii. We generated mice deficient for all sixGbpgenes located on chromosome 3 (Gbpchr3) by targeted chromosome engineering. Mice lackingGbpchr3were highly susceptible toT. gondiiinfection, resulting in increased parasite burden in immune organs. Furthermore,Gbpchr3-deleted macrophages were defective in IFN-γ-mediated suppression ofT. gondiiintracellular growth and recruitment of IFN-γ-inducible p47 GTPase Irgb6 to the parasitophorous vacuole. In addition, some members of Gbpchr3restored the protective response againstT. gondiiinGbpchr3-deleted cells. Our results suggest that Gbpchr3play a pivotal role in anti-T. gondiihost defense by controlling IFN-γ-mediated Irgb6-dependent cellular innate immunity.