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13 May 2014

Jean-Claude Dujardin – Overcoming Leishmania’s drug-resistant Trojan horse effect

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Leishmania parasites hijack macrophages turning them against their human hosts. New insights reveal how novel therapies can reverse this effect despite the parasite’s complex resistance.

Visceral leishmaniasis, or Kala-Azar, is a tropical disease caused by several types of Leishmania parasites transmitted by sandflies. The parasite hijacks white blood cells called macrophages, turning them into Trojan horses that harm the human body, but favour the parasite. It has also built up considerable resistance to drugs. Now, the EU funded project KALADRUG-R, which ended in 2013, may have increased understanding about the parasite'sdefense mechanisms against drugs. And how novel therapies can reclaim turned macrophages. Project coordinator Jean-Claude Dujardin, a medical researcher at the Institute of Tropical Medicine in Antwerpen, Belgium, talks to about such insights.

Why is it that no vaccine has been developed for leishmaniasis in humans?
There are already some commercial vaccines for dogs. But for humans it is still in the phase of development. The main problem is a biological one. The Leishmania parasite is an expert in the manipulation of the immune system. And a vaccine will really need to counter this manipulation. There is a family of white blood cells, macrophages, whose function is to swallow any pathogen, kill it, and mount an immune response. Leichsmania just invades these cells, changing them into Trojan horses. The parasite forces the macrophages to do things that are not good for the human body, but good for the parasite.

By what mechanisms have the parasites’ built up complex drug resistance?
It is true that there is an amazing complexity in the responses that the parasites have developed using several mechanisms, which are linked to the high virulence. There are, among others, two fascinating mechanisms. First, the parasite can play with the number of copies of its chromosomes. In humans, an extra copy of chromosome 21 (trisomy 21), for instance, causes Down Syndrome. In the Leishmania parasite the situation is totally opposite. When the parasite needs to respond to a stress, for example, the attack of a drug, it will increase the number of some chromosomes. It will become trisomic, or tetrasomic, resulting in three or four copies of some chromosomes. This amplifies all the genes of the respective chromosomes—among them those needed by the parasite to survive the stress. 

Second, the parasite can amplify specific groups of genes and create plasmids, which are small DNA molecules, just like bacteria. These plasmids are subsets of genes, usually two or three genes. And the parasite starts to amplify them extensively as small circular molecules in response to a stress. We found, for instance, some pumps, which are important to throw away a drug from the parasite cells. And which are present in this type of circular molecules. Probably the parasite is using them to throw out a drug from its body.

How can we improve the currently used antimonial drugs that fight the parasite?
Some of our Indian colleagues, led by Syamal Roy senior principal scientist at the CSIR-Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, in Kolkata, found that imipramine, a drug used for depression, could counter the manipulation skills of the parasite. They treated hamsters infected with a resistant parasite with imipramine in combination with an antimonial drug. And they found that the imipramine could restore the functionality of the macrophages that are invaded by the parasite. Before we can use this drug, however, a new clinical trial should be done so that it can be registered for this specific application.

What recommendations has the research been able to make?
At several meetings, we have recommended setting up a deep surveillance of the parasite and its response to drugs. Similar to the use of sentinel sites for malaria that cover the whole world, we provide the tools obtained by our investigation of the Leishmania genome and with our susceptibility testing, allowing us to do this surveillance.It is really important that such a monitoring programme is launched now. On the Indian subcontinent there is an elimination programme using vector control and chemotherapy. And the objective is to eliminate leishmaniasis by 2015. provides its content to all media free of charge. We would appreciate if you could acknowledge as the source of the content.