Toxoplasma Effector GRA15-Dependent Suppression of IFN-γ-Induced Antiparasitic Response in Human Neurons
Toxoplasma Effector GRA15-Dependent Suppression of IFN-γ-Induced Antiparasitic Response in Human Neurons
复制标题
DOI：
10.3389/fcimb.2019.00140
复制
发表时间：
2019-05-01
影响因子：
5.7
通讯作者：
Yamamoto, Masahiro
中科院分区：
文献类型：
--
作者：
Bando, Hironori;Lee, Youngae;Yamamoto, Masahiro
弓形虫是一种重要的人畜弓形虫病病原体，可引起危及生命的弓形虫病。宿主免疫系统产生干扰素-γ（IFN-γ）以抑制T。弓形虫增殖IFN-γ诱导的吲哚-2，3-双加氧酶1（IDO 1）介导色氨酸降解，在抗T.弓形虫在人体细胞中的免疫反应T.弓形虫分泌许多毒力分子进入宿主细胞以抑制IFN-γ依赖性抗寄生虫免疫应答。用于抑制IDO 1依赖性免疫应答的GRA 15诱导的前寄生虫机制先前仅在人肝细胞和单核细胞共培养物中进行了测试。因此，除了肝细胞以外的人类细胞是否含有这种毒力机制仍不清楚。在这里，我们表明，GRA 15依赖的毒力机制，抑制IDO 1依赖的抗T。弓形虫反应在人神经元细胞系和原代人神经元中起作用。对各种人类细胞系的分析显示，IL-1 β诱导的iNOS依赖性IDO 1 mRNA表达减少发生在脑细胞系（A172;胶质母细胞瘤，IMR-32;神经母细胞瘤和T98 G;胶质母细胞瘤）和肝细胞系（Huh 7和HepG 2）中，但不发生在其他细胞系中。此外，共培养II型T.用脑细胞系感染的THP-1人单核细胞抑制IDO 1介导的抗T. GRA 15依赖性的弓形虫反应。这些数据表明，GRA 15依赖性免疫应答机制在人脑细胞中促进IDO 1依赖性宿主免疫应答。
Toxoplasma gondii is an important human and animal pathogen that causes life-threatening toxoplasmosis. The host immune system produces interferon-gamma (IFN-gamma) to inhibit T. gondii proliferation. IFN-gamma-inducible indole-2,3-dioxygenase 1 (IDO1), which mediates tryptophan degradation, has a major role in anti-T. gondii immune responses in various human cells. In response to the host's immune system, T. gondii secretes many virulence molecules into the host cells to suppress IFN-gamma-dependent antiparasitic immune responses. The GRA15-induced proparasitic mechanism for suppressing IDO1-dependent immune responses has previously been tested only in human hepatocyte and monocyte co-cultures. Thus, whether human cells other than hepatocytes contain this virulence mechanism remains unclear. Here, we show that the GRA15-dependent virulence mechanism for suppressing the IDO1-dependent anti-T. gondii response operates in human neuronal cell lines and primary human neurons. Analysis of various human cell lines revealed that IL-1 beta-induced iNOS-dependent reduction of IDO1 mRNA expression occurred in brain cell lines (A172; glioblastoma, IMR-32; neuroblastoma, and T98G; glioblastoma) and liver cell lines (Huh7 and HepG2), but not in other cell lines. Moreover, co-culturing type II T. gondii-infected THP-1 human monocytes with the brain cell lines inhibited the IDO1-mediated anti-T. gondii response in a GRA15-dependent manner. These data suggest that a GRA15-dependent virulencemechanismantagonizes the IDO1-dependent host immune response in human brain cells.