Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis.
Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis.
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DOI：
10.15252/emmm.201607370
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发表时间：
2017-03
影响因子：
11.1
通讯作者：
Hakimi MA
中科院分区：
文献类型：
--
作者：
Palencia A;Bougdour A;Brenier-Pinchart MP;Touquet B;Bertini RL;Sensi C;Gay G;Vollaire J;Josserand V;Easom E;Freund YR;Pelloux H;Rosenthal PJ;Cusack S;Hakimi MA
弓形虫是一种重要的食物和水传播病原体，可引起弓形虫病，这是一种免疫功能低下或先天性感染的潜在严重疾病。现有的治疗药物受到疗效不佳和可能导致停止治疗的频繁副作用的限制。在此，我们报道了苯并恶硼化合物AN3661具有较强的体外抗弓形虫活性。筛选出对AN3661有抗性的寄生虫存在TgCPSF3突变，TgCPSF3编码真核细胞中参与mRNA加工的内切酶CPSF-73或CPSF3的裂解和多聚腺苷酸化特异性因子亚单位3(CPSF-73或CPSF3)的同源物。利用CRISPR/Cas9系统将TgCPSF3的点突变导入野生型寄生虫，重现了抗性表型。重要的是，感染了弓形虫并经AN3661口服治疗的小鼠没有出现任何明显的疾病，而未经治疗的对照组有致命的感染。因此，Tg CPSF3是弓形虫一个很有前景的新靶点，为抗寄生虫药物的开发提供了机会。
Toxoplasma gondii is an important food and waterborne pathogen causing toxoplasmosis, a potentially severe disease in immunocompromised or congenitally infected humans. Available therapeutic agents are limited by suboptimal efficacy and frequent side effects that can lead to treatment discontinuation. Here we report that the benzoxaborole AN3661 had potent in vitro activity against T. gondii. Parasites selected to be resistant to AN3661 had mutations in TgCPSF3, which encodes a homologue of cleavage and polyadenylation specificity factor subunit 3 (CPSF‐73 or CPSF3), an endonuclease involved in mRNA processing in eukaryotes. Point mutations in TgCPSF3 introduced into wild‐type parasites using the CRISPR/Cas9 system recapitulated the resistance phenotype. Importantly, mice infected with T. gondii and treated orally with AN3661 did not develop any apparent illness, while untreated controls had lethal infections. Therefore, Tg CPSF3 is a promising novel target of T. gondii that provides an opportunity for the development of anti‐parasitic drugs.