A conserved coccidian gene is involved in Toxoplasma sensitivity to the anti-apicomplexan compound, tartrolon E
A conserved coccidian gene is involved in Toxoplasma sensitivity to the anti-apicomplexan compound, tartrolon E
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DOI：
10.1016/j.ijpddr.2020.07.003
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发表时间：
2020-12-01
影响因子：
4
通讯作者：
O'Connor, Roberta M.
中科院分区：
文献类型：
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作者：
Bowden, Gregory D.;Reis, Patricia M.;O'Connor, Roberta M.
需要新的治疗方法来治疗由顶复门引起的疾病。最近，我们确定，酒石酮E（trtE），一个次级代谢产物来自一个船蛆共生细菌，具有广谱抗顶复门寄生虫活性。TrtE在体外以nM浓度抑制顶复虫，包括隐孢子虫、刚地弓形虫、神经肉孢子虫、恶性疟原虫、巴氏疟原虫属。和马泰勒虫。为了研究trtE对顶复门寄生虫的作用机制，我们检测了trtE处理的T。弓形虫RNA-Seq数据显示，在球虫中广泛保守的基因TGGT1_272370在处理4小时内显著上调。使用ToxoDB上的生物信息学和pmteome数据，我们确定了该酒石酸乙烯酯E响应基因（trg）的蛋白产物具有多个跨膜结构域、磷酸化位点，并定位于质膜。在表达胰蛋白酶的T.通过CRISPR/Cas9感染弓形虫菌株导致寄生虫对trtE处理的抗性增加68%，支持了trg蛋白产物在弓形虫应答中的作用。trtE治疗。Trg在球虫中是保守的，但在亲缘关系较远的顶复门中不是，这表明对trtE的这种反应可能是球虫所特有的，并且其他机制可能在其他trtE敏感的顶复门中起作用。揭示trtE抑制顶复门寄生虫的机制可能会发现对顶复门寄生虫生存至关重要的共同途径，并推动新治疗方法的研究。
New treatments for the diseases caused by apicomplexans are needed. Recently, we determined that tartrolon E (trtE), a secondary metabolite derived from a shipworm symbiotic bacterium, has broad-spectrum anti-apicomplexan parasite activity. TrtE inhibits apicomplexans at nM concentrations in vitro, including Cryptosporidium parvum, Toxoplasma gondii, Sarcocystis neurona, Plasmodium falciparum, Babesia spp. and Theileria equi. To investigate the mechanism of action of trtE against apicomplexan parasites, we examined changes in the transcriptome of trtE-treated T. gondii parasites. RNA-Seq data revealed that the gene, TGGT1_272370, which is broadly conserved in the coccidia, is significantly upregulated within 4 h of treatment. Using bioinformatics and pmteome data available on ToxoDB, we determined that the protein product of this tartrolon E responsive gene (trg) has multiple transmembrane domains, a phosphorylation site, and localizes to the plasma membrane. Deletion of trg in a luciferase-expressing T. gondii strain by CRISPR/Cas9 resulted in a 68% increase in parasite resistance to trtE treatment, supporting a role for the trg protein product in the response of T. gondii to trtE treatment. Trg is conserved in the coccidia, but not in more distantly related apicomplexans, indicating that this response to trtE may be unique to the coccidians, and other mechanisms may be operating in other trtE-sensitive apicomplexans. Uncovering the mechanisms by which trtE inhibits apicomplexans may identify shared pathways critical to apicomplexan parasite survival and advance the search for new treatments.