The antifilarial activity of ivermectin and diethylcarbamizine

描述（由申请人提供）：淋巴丝虫病是一种严重的人类热带疾病，有时被称为象皮病，由几种寄生蛔虫引起。72个国家的13亿多人受到这种疾病的威胁，其中1.2亿人感染了寄生虫，4 000万人因此毁容。全球正在努力减少和消除淋巴丝虫病，这取决于每年给药；通常给予两种药物，阿苯达唑加乙基卡马嗪（DEC），或者，如果存在相关的河盲症，阿苯达唑加伊维菌素。这些药物具有快速和持久的效果，可以将幼虫从循环中清除，从而防止它们感染蚊子，从而传播给新的受害者。这些药物已经分发了数十亿剂，但我们不知道DEC是如何起作用的，而且以前关于伊维菌素如何治疗LF的想法可能是不正确的。这个项目的目的是试图找出DEC和伊维菌素是如何从淋巴丝虫病感染者的血液中清除幼虫的。这些药物将被给予感染寄生虫的沙鼠，并将通过下一代测序方法研究这对寄生虫基因表达的影响。分析结果将使我们能够识别受药物影响的生理过程，并可能揭示新的药物靶点。DEC的抗寄生虫作用依赖于宿主免疫系统，伊维菌素可能也是如此。我们将研究两种免疫细胞的能力，称为中性粒细胞和单核细胞，从健康的未感染的志愿者中纯化，以识别并可能杀死培养的寄生虫幼虫。我们还将研究药物对这一过程的影响，因为我们有证据表明它们增强了免疫细胞对寄生虫的识别。研究人员将再次使用下一代测序技术，研究这些药物对健康、未受感染人群的先天免疫系统细胞基因表达的影响，以找出这些药物，尤其是DEC对它们的影响。这些实验将共同确定DEC和伊维菌素的抗丝虫作用模式，揭示寄生虫和免疫系统中潜在的新药物靶点。

DESCRIPTION (provided by applicant): Lymphatic filariasis is a serious human tropical disease, sometimes called elephantiasis, that is caused by several species of parasitic roundworm. More than 1.3 billion people in 72 countries are threatened by this disease, with 120 million infected with the parasites and 40 million disfigured as a result. There is a global effort to reduce and eliminate lymphatic filariasis, which depends on annual administration of drugs; two drugs are usually given, either albendazole plus diethylcarbamazine (DEC) or, if the related disease river blindness is present, albendazole plus ivermectin. These drugs have the rapid and long-lasting effect of removing larval worms from the circulation, which prevents them from infecting mosquitoes and hence being transmitted to new victims. Billions of doses of these drugs have been distributed, yet we do not know how DEC works, and it is likely that previous ideas about how ivermectin worked against LF may be incorrect. The aim of this project is to try and find out how DEC and ivermectin remove the larvae from the bloodstream of people infected with lymphatic filariasis. The drugs will be given to parasite-infected gerbils and the effect of this on gene expression in the parasite will be examined using next-generation sequencing methods. Analysis of the results should enable us to identify the physiological processes affected by the drugs and may reveal new drug targets. The anti-parasitic effects of DEC are dependent on the host immune system, and the same may be true for ivermectin. We will study the ability of two kinds of immune cells, called neutrophils and monocytes, purified from healthy uninfected volunteers to recognize and possibly kill parasite larvae in culture. We will also study the effects of the drugs on this process, since we have evidence that they enhance the recognition of the parasite by the immune cells. The effects of the drugs on gene expression in cells of the innate immune system of healthy, uninfected people will be studied, again using next-generation sequencing, to find out what effect the drugs, especially DEC, have on them. Together these experiments should determine the anti-filarial mode of action of DEC and ivermectin, revealing potential novel drugs targets in both the parasites and the immune system.