The antifilarial activity of ivermectin and diethylcarbamizine

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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.