Inhibitors of eIF2α Dephosphorylation Slow Replication and Stabilize Latency in Toxoplasma gondii
Inhibitors of eIF2α Dephosphorylation Slow Replication and Stabilize Latency in Toxoplasma gondii
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DOI：
10.1128/aac.01899-12
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发表时间：
2013-04-01
影响因子：
4.9
通讯作者：
Sullivan, William J., Jr.
中科院分区：
文献类型：
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作者：
Konrad, Christian;Queener, Sherry F.;Sullivan, William J., Jr.
刚地弓形虫是一种专性细胞内寄生虫，通过其转化为潜伏组织包囊形式的能力永久感染温血脊椎动物。如果宿主免疫力减弱，潜伏型（缓殖子）可重新引发危及生命的急性感染，最常见于艾滋病或器官移植患者。我们以前已经表明，缓殖子的发展是伴随着磷酸化的寄生虫真核起始因子2 α亚基（eIF2 α），抑制全球蛋白质合成和基因表达的重编程。在这项研究中，我们分析了两种eIF α去磷酸化的特异性抑制剂salubrinal（SAL）和guanabenz（GA）的活性。我们确定这些药物能够抑制弓形虫eIF2 α的去磷酸化。我们的研究结果表明，SAL和GA减少速殖子复制在体外和体内。此外，这两种药物在体外诱导缓殖子形成并抑制潜伏的缓殖子的再激活。为了解决SAL和GA的抗寄生虫活性是否涉及宿主eIF2 α磷酸化，我们感染了不能磷酸化eIF2 α的突变小鼠胚胎成纤维细胞（MEF），这对SAL和GA抗弓形虫感染的功效没有影响。本研究结果提示，SAL和GA有可能成为治疗急性和慢性弓形虫病的潜在新药。
Toxoplasma gondii is an obligate intracellular parasite that permanently infects warm-blooded vertebrates through its ability to convert into a latent tissue cyst form. The latent form (bradyzoite) can reinitiate a life-threatening acute infection if host immunity wanes, most commonly in AIDS or organ transplant patients. We have previously shown that bradyzoite development is accompanied by phosphorylation of the parasite eukaryotic initiation factor 2 alpha subunit (eIF2 alpha), which dampens global proteinsynthesis and reprograms gene expression. In this study, we analyzed the activities of two specific inhibitors of eIF alpha dephosphorylation, salubrinal (SAL) and guanabenz (GA). We establish that these drugs are able to inhibit the dephosphorylation of Toxoplasma eIF2 alpha. Our results show that SAL and GA reduce tachyzoite replication in vitro and in vivo. Furthermore, both drugs induce bradyzoite formation and inhibit the reactivation of latent bradyzoites in vitro. To address whether the antiparasitic activities of SAL and GA involve host eIF2 alpha phosphorylation, we infected mutant mouse embryonic fibroblast (MEF) cells incapable of phosphorylating eIF2 alpha, which had no impact on the efficacies of SAL and GA against Toxoplasma infection. Our findings suggest that SAL and GA may serve as potential new drugs for the treatment of acute and chronic toxoplasmosis.