OBJECTIVES To gain insight into the propagation of miltefosine (MIL) resistance in visceral leishmaniasis, this laboratory study explored development of resistant parasites with a defective miltefosine transporter (MT) in sand flies. METHODS Infectivity, colonization of stomodeal valve and metacyclogenesis of a MIL-resistant (MIL-R) Leishmania infantum LEM3323 line with a defective MT were assessed in the natural sand fly vectors Phlebotomus perniciosus and Lutzomyia longipalpis. Given our recent description of partial drug dependency of the MT-deficient line, the impact of MIL pre-exposure on sand fly infectivity was explored as well. RESULTS A significant reduction in sand fly infection, stomodeal valve colonization and differentiation into metacyclics (determined by a lower flagellum/cell body length ratio) was observed in both vectors for MIL-R as compared to the isogenic parent MIL-susceptible line. Re-introduction of the wildtype MT gene into MIL-R tended to partially rescue the capacity to infect sand flies. Pre-exposure to MIL did not alter infectivity of the MIL-R line. CONCLUSION The MIL resistant L. infantum LEM3323 line is significantly hampered in its development and transmissibility potential in two sand fly vector species. Additional studies are warranted to evaluate whether this applies to other visceral Leishmania parasites with acquired MIL-resistance.

中文翻译：

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在沙蝇载体Plebotomus perniciosus和Lutzomyia longipalpis中，耐耐米替膦碱的婴儿利什曼原虫婴儿菌株的发育受到损害。

目的为了深入了解内脏利什曼病中的miltefosine（MIL）耐药性传播，本实验室研究探索了有缺陷的miltefosine转运蛋白（MT）在沙蝇中产生抗药性寄生虫的方法。方法在天然沙蝇媒介Plebotomus perniciosus和Lutzomyia longipalpis中评估了具有缺陷性MT的MIL抗性（MIL-R）婴儿利什曼原虫LEM3323株的感染力，足部瓣膜定植和突变发生。鉴于我们最近对MT缺陷品系的部分药物依赖性的描述，还探讨了MIL预暴露对沙蝇感染性的影响。结果显着减少了沙蝇感染，与同基因的亲本MIL易感株系相比，在两种载体中均观察到了MIL-R的两种模式均出现了模式性瓣膜定居并分化为亚环（由较低的鞭毛/细胞体长度比决定）。将野生型MT基因重新引入MIL-R倾向于部分恢复感染沙蝇的能力。预先暴露于MIL不会改变MIL-R系的感染性。结论在两种沙蝇媒介物种中，抗MIL的婴儿乳杆菌LEM3323品系的发育和传播潜力受到很大的阻碍。有必要进行额外的研究来评估这是否适用于其他获得性MIL耐药的内脏利什曼原虫。将野生型MT基因重新引入MIL-R倾向于部分恢复感染沙蝇的能力。预先暴露于MIL不会改变MIL-R系的感染性。结论在两种沙蝇媒介物种中，抗MIL的婴儿乳杆菌LEM3323品系的发育和传播潜力受到很大的阻碍。有必要进行额外的研究来评估这是否适用于其他获得性MIL耐药的内脏利什曼原虫。将野生型MT基因重新引入MIL-R倾向于部分恢复感染沙蝇的能力。预先暴露于MIL不会改变MIL-R系的感染性。结论在两种沙蝇媒介物种中，抗MIL的婴儿乳杆菌LEM3323品系的发育和传播潜力受到很大的阻碍。有必要进行额外的研究来评估这是否适用于其他获得性MIL耐药的内脏利什曼原虫。