Babesia duncani multi-omics identifies virulence factors and drug targets.
Babesia duncani multi-omics identifies virulence factors and drug targets.
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DOI：
10.1038/s41564-023-01360-8
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发表时间：
2023-05
影响因子：
28.3
通讯作者：
Ben Mamoun, Choukri
中科院分区：
文献类型：
--
作者：
Singh, Pallavi;Lonardi, Stefano;Liang, Qihua;Vydyam, Pratap;Khabirova, Eleonora;Fang, Tiffany;Gihaz, Shalev;Thekkiniath, Jose;Munshi, Muhammad;Abel, Steven;Ciampossin, Loic;Batugedara, Gayani;Gupta, Mohit;Lu, Xueqing Maggie;Lenz, Todd;Chakravarty, Sakshar;Cornillot, Emmanuel;Hu, Yangyang;Ma, Wenxiu;Gonzalez, Luis Miguel;Sanchez, Sergio;Estrada, Karel;Sanchez-Flores, Alejandro;Montero, Estrella;Harb, Omar S.;Le Roch, Karine G.;Ben Mamoun, Choukri
巴贝斯虫病是人类和动物中一种疟疾样疾病，由巴贝斯虫引起，巴贝斯虫是蜱传播的顶复合体病原体。邓肯巴贝斯虫在人类中引起严重到致命的感染，但是尽管这种寄生虫作为一种新出现的病原体具有风险，但对其生物学、代谢需求或发病机制知之甚少。与其他感染红细胞的顶复合体寄生虫不同，邓肯贝氏杆菌可在体外持续培养于人红细胞中，并可感染小鼠导致暴发性巴贝斯虫病和死亡。我们报告全面，详细的分子，基因组学，转录组学和表观遗传学分析，以获得对邓肯双歧杆菌生物学的见解。我们完成了其核基因组的组装、三维结构和注释，并分析了其在人类红细胞无性生命周期阶段的转录组学和表观遗传学特征。我们使用RNA-seq数据制作了寄生虫红细胞内生命周期代谢图谱。duncani的基因组、表观基因组和转录组鉴定了候选毒力因子、诊断活动性感染的抗原和几个有吸引力的药物靶点。此外，基因组标注的代谢重构和体外功效研究发现，抗叶酸、乙胺嘧啶和WR-99210是有效的邓肯氏杆菌抑制剂，从而建立了一个小分子管道，可以开发为治疗人类巴贝斯虫病的有效疗法。邓肯巴贝斯虫的多组学研究揭示了巴贝斯虫的进化、药物敏感性和毒力。
Babesiosis is a malaria-like disease in humans and animals that is caused by Babesia species, which are tick-transmitted apicomplexan pathogens. Babesia duncani causes severe to lethal infection in humans, but despite the risk that this parasite poses as an emerging pathogen, little is known about its biology, metabolic requirements or pathogenesis. Unlike other apicomplexan parasites that infect red blood cells, B. duncani can be continuously cultured in vitro in human erythrocytes and can infect mice resulting in fulminant babesiosis and death. We report comprehensive, detailed molecular, genomic, transcriptomic and epigenetic analyses to gain insights into the biology of B. duncani. We completed the assembly, 3D structure and annotation of its nuclear genome, and analysed its transcriptomic and epigenetics profiles during its asexual life cycle stages in human erythrocytes. We used RNA-seq data to produce an atlas of parasite metabolism during its intraerythrocytic life cycle. Characterization of the B. duncani genome, epigenome and transcriptome identified classes of candidate virulence factors, antigens for diagnosis of active infection and several attractive drug targets. Furthermore, metabolic reconstitutions from genome annotation and in vitro efficacy studies identified antifolates, pyrimethamine and WR-99210 as potent inhibitors of B. duncani to establish a pipeline of small molecules that could be developed as effective therapies for the treatment of human babesiosis. Comprehensive multi-omics of Babesia duncani reveals evolution, drug sensitivity and virulence.
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影响因子：
3.4
作者：
Guizetti J;Scherf A
通讯作者：
Scherf A
影响因子：
48
作者：
Cheng H;Concepcion GT;Feng X;Zhang H;Li H
通讯作者：
Li H
影响因子：
2.9
作者：
Kjemtrup, AM;Lee, B;Conrad, PA
通讯作者：
Conrad, PA
影响因子：
3.2
作者：
Baneth, Gad;Nachum-Biala, Yaarit;Aroch, Itamar
通讯作者：
Aroch, Itamar
影响因子：
10.7
作者：
Katoh K;Standley DM
通讯作者：
Standley DM