The obligate intracellular parasite Toxoplasma gondii reprograms host gene expression through multiple mechanisms that promote infection, including the up-regulation of mTOR-dependent host mRNA translation. In addition to the mTOR-4E-BP1/2 axis, MAPK-interacting kinases 1 and 2 (MNK1/2) control the activity of the mRNA cap-binding protein eIF4E. Herein, we show that T. gondii inhibits the phosphorylation of MNK1/2 and their downstream target eIF4E in murine and human macrophages. Exposure to soluble T. gondii antigens (STAg) failed to fully recapitulate this phenotype indicating the requirement of live infection. Treatment with okadaic acid, a potent phosphatase inhibitor, restored phosphorylation of MNK1/2 and eIF4E regardless of infection. T. gondii replication was higher in macrophages isolated from mice mutated at the residue where eIF4E is phosphorylated (eIF4E S209A knock-in) than in wild-type (WT) control cells despite no differences in infection rates. Similarly, parasitemia in the mesenteric lymph nodes and spleen, as well as brain cyst burden were significantly augmented in infected eIF4E S209A knock-in mice compared to their WT counterparts. Of note, mutant mice were more susceptible to acute toxoplasmosis and displayed exacerbated levels of IFNγ. In all, these data suggest that the MNK1/2-eIF4E axis is required to control T. gondii infection and that its inactivation represents a strategy exploited by the parasite to promote its survival.

专性细胞内寄生虫 弓形虫通过促进感染的多种机制（包括上调mTOR依赖性宿主mRNA翻译）重新编程宿主基因表达。除mTOR-4E-BP1 / 2轴外，MAPK相互作用激酶1和2（MNK1 / 2）还控制mRNA帽结合蛋白eIF4E的活性。在这里，我们表明弓形虫抑制鼠和人类巨噬细胞中MNK1 / 2及其下游靶标eIF4E的磷酸化。接触可溶物弓形虫抗原（STAg）无法完全概括此表型，表明需要活感染。冈田酸（一种有效的磷酸酶抑制剂）治疗可恢复MNK1 / 2和eIF4E的磷酸化，而与感染无关。弓形虫尽管在感染率上没有差异，但从野生型（WT）对照细胞中分离出的小鼠的巨噬细胞的复制比在野生型（WT）对照细胞中的eIF4E被磷酸化的残基突变的小鼠（eIF4E S209A敲入）高。同样，与野生型WT小鼠相比，感染eIF4E S209A敲入小鼠的肠系膜淋巴结和脾中的寄生虫血症以及脑囊肿负担明显增加。值得注意的是，突变小鼠更易患急性弓形虫病并表现出加剧的IFNγ水平。总之，这些数据表明需要使用MNK1 / 2-eIF4E轴来控制弓形虫 感染及其灭活是寄生虫利用其促进生存的策略。