Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka, Japan.
Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
mBio. 2018 Oct 9;9(5):e01738-18. doi: 10.1128/mBio.01738-18.
Although virulence mechanisms targeting gamma interferon (IFN-γ)-induced cell-autonomous antiparasitic immunity have been extensively characterized in mice, the virulence mechanisms in humans remain uncertain, partly because cell-autonomous immune responses against differ markedly between mice and humans. Despite the identification of inducible nitric oxide synthase (iNOS) as an anti- host factor in mice, here we show that iNOS in humans is a pro- host factor that promotes the growth of the parasite. The GRA15 effector-dependent disarmament of IFN-γ-induced parasite growth inhibition was evident when parasite-infected monocytes were cocultured with hepatocytes. Interleukin-1β (IL-1β), produced from monocytes in a manner dependent on GRA15 and the host's NLRP3 inflammasome, combined with IFN-γ to strongly stimulate iNOS expression in hepatocytes; this dramatically reduced the levels of indole 2,3-dioxygenase 1 (IDO1), a critically important IFN-γ-inducible anti- protein in humans, thus allowing parasite growth. Taking the data together, utilizes human iNOS to antagonize IFN-γ-induced IDO1-mediated cell-autonomous immunity via its GRA15 virulence factor. an important intracellular parasite of humans and animals, causes life-threatening toxoplasmosis in immunocompromised individuals. Gamma interferon (IFN-γ) is produced in the host to inhibit the proliferation of this parasite and eventually cause its death. Unlike mouse disease models, which involve well-characterized virulence strategies that are used by to suppress IFN-γ-dependent immunity, the strategies used by in humans remain unclear. Here, we show that GRA15, a effector protein, suppresses the IFN-γ-induced indole-2,3-dioxygenase 1-dependent antiparasite immune response in human cells. Because NLRP3-dependent production of IL-1β and nitric oxide (NO) in -infected human cells is involved in the GRA15-dependent virulence mechanism, blocking NO or IL-1β production in the host could represent a novel therapeutic approach for treating human toxoplasmosis.
虽然针对γ干扰素 (IFN-γ) 诱导的细胞自主抗寄生虫免疫的毒力机制在小鼠中已得到广泛研究，但人类的毒力机制仍不确定，部分原因是小鼠和人类之间的细胞自主免疫反应有很大的不同。尽管已经确定诱导型一氧化氮合酶 (iNOS) 是小鼠中的一种抗宿主因子，但在这里我们表明，人类中的 iNOS 是一种促宿主因子，可促进寄生虫的生长。当寄生虫感染的单核细胞与肝细胞共培养时，寄生虫生长抑制的 IFN-γ 诱导被 GRA15 效应物依赖性消除。单核细胞以依赖 GRA15 和宿主 NLRP3 炎性小体的方式产生的白细胞介素-1β (IL-1β) 与 IFN-γ 结合，强烈刺激肝细胞中 iNOS 的表达；这极大地降低了吲哚 2,3-二加氧酶 1 (IDO1) 的水平，IDO1 是人类中 IFN-γ 诱导的一种重要的抗寄生虫蛋白，从而允许寄生虫生长。综合这些数据，表明利用人类 iNOS 通过其 GRA15 毒力因子拮抗 IFN-γ 诱导的 IDO1 介导的细胞自主免疫。刚地弓形虫是一种重要的人类和动物内寄生虫，会导致免疫功能低下个体的威胁生命的弓形体病。宿主产生γ干扰素 (IFN-γ) 以抑制寄生虫的增殖并最终导致其死亡。与涉及 抑制 IFN-γ 依赖性免疫的特征明确的毒力策略的小鼠疾病模型不同， 在人类中使用的策略仍不清楚。在这里，我们表明，效应蛋白 GRA15 抑制人细胞中 IFN-γ 诱导的吲哚-2,3-二加氧酶 1 依赖性抗寄生虫免疫反应。由于 GRA15 依赖性的宿主中 NLRP3 依赖性白细胞介素-1β和一氧化氮 (NO) 的产生参与了 GRA15 依赖性毒力机制，阻断宿主中的 NO 或白细胞介素-1β的产生可能代表治疗人类弓形体病的一种新的治疗方法。
