PDF(Pubmed)
Abstract：
As Toxoplasma gondii disseminates through its host, the parasite must sense and adapt to its environment and scavenge nutrients. Oxygen (O2) is one such environmental factor and cytoplasmic prolyl 4-hydroxylases (PHDs) are evolutionarily conserved O2 cellular sensing proteins that regulate responses to changes in O2 availability. Toxoplasma expresses 2 PHDs. One of them, TgPHYa hydroxylates SKP1, a subunit of the SCF-E3 ubiquitin ligase complex. In vitro, TgPHYa is important for growth at low O2 levels. However, studies have yet to examine the role that TgPHYa or any other pathogen-encoded PHD plays in virulence and disease. Using a type II ME49 Toxoplasma TgPHYa knockout, we report that TgPHYa is important for Toxoplasma virulence and brain cyst formation in mice. We further find that while TgPHYa mutant parasites can establish an infection in the gut, they are unable to efficiently disseminate to peripheral tissues because the mutant parasites are unable to survive within recruited immune cells. Since this phenotype was abrogated in IFNγ knockout mice, we studied how TgPHYa mediates survival in IFNγ-treated cells. We find that TgPHYa is not required for release of parasite-encoded effectors into host cells that neutralize anti-parasitic processes induced by IFNγ. In contrast, we find that TgPHYa is required for the parasite to scavenge tryptophan, which is an amino acid whose levels are decreased after IFNγ up-regulates the tryptophan-catabolizing enzyme, indoleamine dioxygenase (IDO). We further find, relative to wild-type mice, that IDO knockout mice display increased morbidity when infected with TgPHYa knockout parasites. Together, these data identify the first parasite mechanism for evading IFNγ-induced nutritional immunity and highlight a novel role that oxygen-sensing proteins play in pathogen growth and virulence.
摘要：
当弓形虫通过其宿主传播时，寄生虫必须感知并适应其环境并清除营养。氧气（O2）是这样的环境因素之一，胞质脯氨酸4-羟化酶（PHD）是进化上保守的O2细胞传感蛋白，可调节对O2可用性变化的反应。弓形虫表达2个PHDs。其中一个,TgPHYa羟基化SCF-E3泛素连接酶复合物的亚基SKP1。体外，TgPHYa对于在低O2水平下的生长是重要的。然而,研究尚未检查TgPHYa或任何其他病原体编码的PHD在毒力和疾病中的作用。使用II型ME49弓形虫TgPHYa基因敲除，我们报道TgPHYa对小鼠弓形虫毒力和脑囊肿形成有重要作用。我们进一步发现，虽然TgPHYa突变寄生虫可以在肠道中建立感染，它们不能有效地传播到外周组织，因为突变的寄生虫不能在募集的免疫细胞中存活。由于这种表型在IFNγ敲除小鼠中被废除，我们研究了TgPHYa如何在IFNγ处理的细胞中介导存活。我们发现，将寄生虫编码的效应子释放到中和IFNγ诱导的抗寄生虫过程的宿主细胞中不需要TgPHYa。相比之下,我们发现TgPHYa是寄生虫清除色氨酸所必需的，这是一种氨基酸，其水平在IFNγ上调色氨酸分解代谢酶后降低，吲哚胺双加氧酶(IDO)。我们进一步发现,相对于野生型小鼠，当感染TgPHYa基因敲除寄生虫时，IDO基因敲除小鼠的发病率增加。一起,这些数据确定了逃避IFNγ诱导的营养免疫的第一个寄生虫机制，并强调了氧敏感蛋白在病原体生长和毒力中发挥的新作用。
