Impact of clinically acquired miltefosine resistance by Leishmania infantum on mouse and sand fly infection.,International Journal for Parasitology: Drugs and Drug Resistance

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Impact of clinically acquired miltefosine resistance by Leishmania infantum on mouse and sand fly infection.
International Journal for Parasitology: Drugs and Drug Resistance ( IF 4.1 ) Pub Date : 2020-05-01 , DOI: 10.1016/j.ijpddr.2020.04.004
Lieselotte Van Bockstal ₁ , Dimitri Bulté ₁ , Sarah Hendrickx ₁ , Jovana Sadlova ₂ , Petr Volf ₂ , Louis Maes ₁ , Guy Caljon ₁

Affiliation

Objectives

This study evaluated the implications of clinically acquired miltefosine resistance (MIL-R) by assessing virulence in mice and sand flies to reveal the potential of MIL-R strains to circulate.

Methods

Experimental infections with the MIL-R clinical Leishmania infantum isolate MHOM/FR/2005/LEM5159, having a defect in the LiROS3 subunit of the MIL-transporter, and its syngeneic experimentally reconstituted MIL-S counterpart (LEM5159^LiROS3) were performed in BALB/c mice and Lutzomyia longipalpis and Phlebotomus perniciosus sand flies. In mice, the amastigote burdens in liver and spleen were compared microscopically using Giemsa smears and by bioluminescent imaging. During the sand fly infections, the percentage of infected flies, parasite load, colonization of the stomodeal valve and metacyclogenesis were evaluated. The stability of the MIL-R phenotype after sand fly and mouse passage was determined as well.

Results

The fitness of the MIL-R strain differed between the mouse and sand fly infection model. In mice, a clear fitness loss was observed compared to the LiROS3-reconstituted susceptible strain. This defect could be rescued by episomal reconstitution with a wildtype LiROS3 copy. However, this fitness loss was not apparent in the sand fly vector, resulting in metacyclogenesis and efficient colonization of the stomodeal valve. Resistance was stable after passage in both sand fly and mouse.

Conclusion

The natural MIL-R strain is significantly hampered in its ability to multiply and cause a typical visceral infection pattern in BALB/c mice. However, this LiROS3-deficient strain efficiently produced mature infections and metacyclic promastigotes in the sand fly vector highlighting the transmission potential of this particular MIL-R clinical Leishmania strain.

中文翻译：

临床上获得的婴儿利什曼原虫对miltefosine的耐药性对小鼠和沙蝇感染的影响。

目标

这项研究通过评估小鼠和沙蝇中的毒力以揭示MIL-R菌株传播的潜力，评估了临床上获得的miltefosine抗性（MIL-R）的含义。

方法

使用MIL-R临床婴儿分离利什曼原虫分离株MHOM / FR / 2005 / LEM5159进行实验感染，该感染在MIL转运蛋白的LiROS3亚基中有缺陷，并且其同系实验重建的MIL-S对应物（LEM5159 ^LiROS3）在BALB / c小鼠和长白僵菌（Lutzomyia longipalpis）和百日草（Phlebotomus perniciosus）蝇。在小鼠中，使用吉姆萨（Giemsa）涂片和生物发光成像技术在显微镜下比较了肝脏和脾脏中的鞭毛体负担。在沙蝇感染过程中，评估了受感染的果蝇的百分比，寄生虫负荷，脚趾瓣的定植和成环发生。还确定了沙蝇和小鼠通过后MIL-R表型的稳定性。

结果

在小鼠和沙蝇感染模型之间，MIL-R菌株的适应性有所不同。与LiROS3重建的易感株相比，在小鼠中观察到明显的适应性丧失。可以通过野生型LiROS3拷贝的游离型重组来挽救该缺陷。但是，这种适应性损失在沙蝇媒介中并不明显，从而导致了成环发生和有效的定模瓣膜定植。在沙蝇和小鼠中，传代后的抗性是稳定的。