Parasite motility is critical for virulence of African trypanosomes.
Parasite motility is critical for virulence of African trypanosomes.
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寄生虫的运动性对于非洲锥虫的毒力至关重要。
DOI：
10.1038/s41598-018-27228-0
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发表时间：
2018
影响因子：
4.6
通讯作者：
Hill,KentL
中科院分区：
文献类型：
--
作者：
Shimogawa,MichelleM;Ray,SunayanS;Kisalu,Neville;Zhang,Yibo;Geng,Quanjie;Ozcan,Aydogan;Hill,KentL
非洲锥虫（Trypanosoma bruceispp.）是致命的病原体，会给人类带来巨大痛苦，并限制世界上一些最贫困地区的经济发展。锥虫（“螺旋细胞”）这个名字来源于寄生虫独特的运动能力，它由一根鞭毛驱动。然而，尽管经过数十年的研究，哺乳动物宿主感染中锥虫运动的要求尚未确定。 LC1 是鞭毛运动所需的保守动力蛋白亚基。之前对基于 RNAi 的条件性 LC1 突变体 RNAi-K/R 的研究表明，运动能力缺陷的寄生虫可能会感染小鼠。然而，RNAi-K/R 保留了野生型 LC1 的残余表达和残余运动性，从而排除了明确的解释。为了克服这些限制，我们在这里生成了组成型突变体，其中两个 LC1 等位基因都被突变体版本取代。与 RNAi-K/R 相比，这些双敲入突变体显示出运动性降低，并且在培养物中具有活力，但无法维持小鼠的血流感染。毒力缺陷与感染途径无关，但取决于完整的宿主免疫系统。通过比较不同的突变体，我们还揭示了 LC1 N 末端的运动性和毒力的关键依赖性。我们的研究结果表明，锥虫运动对于血流感染的建立和维持至关重要，这表明动力蛋白依赖性鞭毛运动是潜在的药物靶点。
African trypanosomes,Trypanosoma bruceispp., are lethal pathogens that cause substantial human suffering and limit economic development in some of the world’s most impoverished regions. The nameTrypanosoma(“auger cell”) derives from the parasite’s distinctive motility, which is driven by a single flagellum. However, despite decades of study, a requirement for trypanosome motility in mammalian host infection has not been established. LC1 is a conserved dynein subunit required for flagellar motility. Prior studies with a conditional RNAi-based LC1 mutant, RNAi-K/R, revealed that parasites with defective motility could infect mice. However, RNAi-K/R retained residual expression of wild-type LC1 and residual motility, thus precluding definitive interpretation. To overcome these limitations, here we generate constitutive mutants in which both LC1 alleles are replaced with mutant versions. These double knock-in mutants show reduced motility compared to RNAi-K/R and are viable in culture, but are unable to maintain bloodstream infection in mice. The virulence defect is independent of infection route but dependent on an intact host immune system. By comparing different mutants, we also reveal a critical dependence on the LC1 N-terminus for motility and virulence. Our findings demonstrate that trypanosome motility is critical for establishment and maintenance of bloodstream infection, implicating dynein-dependent flagellar motility as a potential drug target.