Metacytofilin is a potent therapeutic drug candidate for toxoplasmosis.
Metacytofilin is a potent therapeutic drug candidate for toxoplasmosis.
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DOI：
10.1093/infdis/jiz501
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发表时间：
2019-10
期刊：
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通讯作者：
A. Leesombun;M. Iijima;Kousuke Umeda;D. Kondoh;Baldorj Pagmadulam;A. M. Abdou;Yutaka Suzuki;Shun‐ichi Ohba;K. Isshiki;Tomoyuki Kimura;Y. Kubota;R. Sawa;Coh-ichi Nihei;Y. Nishikawa
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文献类型：
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作者：
A. Leesombun;M. Iijima;Kousuke Umeda;D. Kondoh;Baldorj Pagmadulam;A. M. Abdou;Yutaka Suzuki;Shun‐ichi Ohba;K. Isshiki;Tomoyuki Kimura;Y. Kubota;R. Sawa;Coh-ichi Nihei;Y. Nishikawa
弓形虫病是由刚地弓形虫引起的一种寄生虫病，是导致流产或胎儿不良反应的重要原因，包括人类神经系统和眼部表现。目前的抗弓形虫药物对弓形虫病的疗效有限，而且有严重的副作用。因此，迫切需要新的有效药物。在这里，我们从一种真菌绿僵菌中鉴定出metacytofilin （MCF）作为一种潜在的抗弓形虫化合物。方法对MCF及其衍生物进行体外和体内抗弓形虫活性测定。然后，为了了解MCF的作用方式，我们利用RNAseq对宿主和寄生虫基因的RNA表达进行了研究。结果体外实验中，MCF可抑制细胞内和细胞外弓形虫的活力。与未治疗的小鼠相比，感染弓形虫速殖子的小鼠腹腔或口服MCF可提高小鼠存活率。值得注意的是，给怀孕小鼠口服MCF可以防止寄生虫的垂直传播。有趣的是，用MCF处理的弓形虫感染细胞的RNA测序显示，MCF抑制了寄生虫的DNA复制并增强了RNA降解。结论：其抗t细胞感染作用强。MCF是未来抗弓形虫病药物开发的有力候选。
BACKGROUND Toxoplasmosis, a parasitic disease caused by Toxoplasma gondii, is an important cause of miscarriage or adverse fetal effects, including neurological and ocular manifestations in humans. Current anti-Toxoplasma drugs have limited efficacy against toxoplasmosis and also have severe side effects. Therefore, novel efficacious drugs are urgently needed. Here, we identified metacytofilin (MCF) from a fungal Metarhizium species as a potential anti-toxoplasma compound. METHODS Anti-Toxoplasma activities of MCF and its derivatives were evaluated in an in vitro and in vivo using nonpregnant and pregnant mice. Then, to understand the mode of action of MCF, the RNA expression of host and parasite genes was investigated by RNAseq. RESULTS In vitro, MCF inhibited the viability of intracellular and extracellular T. gondii. Administering MCF intraperitoneally or orally to mice after infection with T. gondii tachyzoites increased mouse survival compared with the untreated animals. Remarkably, oral administration of MCF to pregnant mice prevented vertical transmission of the parasite. Interestingly, RNA sequencing of T. gondii-infected cells treated with MCF showed that MCF inhibited DNA replication and enhanced RNA degradation in the parasites. CONCLUSIONS With its potent anti-T. gondii activity, MCF is a strong candidate for future drug development against toxoplasmosis.