The deadly parasite Leishmania causes a staggering 40 000 deaths every year. By analysing the pathogen's biology, the EU-funded project KALADRUG-R found out how it has managed to become a super parasite. This knowledge opens the door for scientists to find new ways to undermine the parasite's newly evolved strengths.
According to official statistics, some 310 million people are at risk of carrying the parasite that causes leishmaniasis. Spread mainly by the bite of infected sand flies, the visceral form of the disease is fatal if not treated. Ironically, the single-cell pathogen lives and multiplies in blood cells called macrophages that usually get rid of the body’s foreign invaders.
A super parasite emerges
The chemical element antimony has been used in the treatment of leishmaniasis for more than 60 years, but the drug has lost its effectiveness. "At the end of the 1990s in the Bihar State in India, up to 70% of patients were not responding to treatment with antimony," says Jean-Claude Dujardin, scientific coordinator of the KALADRUG-R project and Head of the Molecular Parasitology Unit at Belgium’s Institute of Tropical Medicine.
The KALADRUG-R team discovered an unexpected feature of this tricky parasite: some Leishmania strains had merely developed into more virulent parasites and had actually become better at living in the macrophages than their predecessors by manipulating the blood cells for their own survival. So even after treatment with antimony stopped, the super strains continued to thrive, and in fact became more successful than their less well adapted counterparts.
"This is a warning for the scientific community and the pharma world, that when we introduce a new drug, there is a danger of creating a super parasite. This is not a reason not to use that drug, but we must do this with extreme care. Moreover, as so-called antimony-resistant strains are more virulent, this might make the job of new drugs more difficult," says Dujardin.
In a bid to eliminate the parasite, health authorities introduced the drug miltefosine; lab tests have however shown that resistance to this can develop very quickly in experimental conditions. Taken orally, miltefosine is easy to administer but patients may stop treatment before the end, rapidly leading to resistance.
KALADRUG-R scientists monitored two groups of patients treated with miltefosine. "We found that the worst situation was in Nepal, where up to 20% of patients on miltefosine relapsed within 12 months of follow-up," Dujardin explains. Interestingly, lab tests showed this is not due to resistance as yet. "Many other factors such as under-dosage, immunological factors or parasite virulence can be responsible," Dujardin continues, "but this needs to be followed closely because the moment one resistant strain emerges, it will spread rapidly."
Continuing the fight
Recent data suggest that the number of new leishmaniasis cases has decreased in the Indian sub-continent as a consequence of a regional elimination programme. "The main danger now is to relax and decrease the attention on the disease," warns Dujardin. Monitoring how effective treatment is for patients will be an indication of the emergence of possible drug resistance.
New, robust drugs are needed, and the project recommends combination treatments as the parasite finds it more difficult to develop resistance to two drugs. Moreover, the researchers have discovered two drugs normally used to tackle depression that reverse the parasite's ability to be successful in the macrophages. These could be used in combination therapy.
However, the KALADRUG-R scientists have tracked future scenarios of Leishmania infection rates in the population using mathematical modelling. Using these simulations, the scientists predict that taking medication alone will not control the disease.
As such, KALADRUG-R recommendations also go beyond the parasite, the drug and patient behaviour. Leishmaniasis is a disease associated with poverty. Introducing ‘integrated vector management’, including measures such as spraying insecticides, implementing nets and making sure the environment is clean (as the fly needs moisture and organic matter for the larva to survive) would help keep the parasite at bay.
Summing up what is needed to continue the successful elimination campaign, Dujardin stresses how the project generated the theoretical knowledge and several tools that can be used for surveillance. “Now energy and means must be deployed to implement them in the field."
Project acronym: KALADRUG-R
Participants: Belgium (Coordinator), Germany, India, UK