Genetics of parasite resistance to malaria drugs

20 January 2015

A new report outlines the genetic basis of resistance to the main anti-malarial drug, artemesinin.

Malaria is a tropical disease spread by mosquitoes that is endemic in almost 100 countries worldwide, notably in sub-Saharan Africa and South East Asia. It is a leading cause of illness, as well as being responsible for over half a million deaths each year. Babies and young children in these regions are particularly vulnerable, as are travellers from the rest of the world.

There is currently no form of vaccination possible against infection with the Plasmodium parasites that cause malaria . Besides measures to reduce exposure such as the use of mosquito repellent and bed nets, prevention and treatment for malaria relies on the use of anti-malarial drugs.

Artemisinin-based combination therapies (ACTs) are the current first-line drug of choice for the treatment of malaria caused by the most common P. falciparum parasite. However, there is increasing concern over the rapidly rising incidence of artemisinin resistance among the parasites, especially in South East Asia. Effective treatment of malaria has long been beset by the rapid emergence and spread of resistance to previously effective drugs (such as cholorquine) from South East Asia to the rest of the world.

Now, writing in Nature Genetics, researchers report identification of mutations in a key gene, kelch13, associated with artemisinin resistance. They also found that kelch13 mutations are particularly likely to arise when mutations in the fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) genes are present; these variants are particularly common in South East Asian parasites, which could explain why resistance tends to emerge from that part of the world. The authors observe that an effective strategy to combat drug resistance and contain it within Southeast Asia requires understanding of the genetic factors that determine how it emerges and spreads. 

Lead author Dr Olivo Miotto of the Mahidol-Oxford Tropical Research Unit in Thailand, said that artemisinin was “the best drug we have had for a very long time”, and that the findings could also help map and monitor resistance. Simply mapping the kelch13 mutations alone is not helpful, as there are many known mutations and more continue to emerge; mapping them in the context of fdarps10mdr2 and crt mutations is more specific.

Dr Miotto also explained that the role of these additional mutations in drug resistance was not yet known, but that it might be to counteract the impact of kelch13 mutations on the malaria parasites, saying: "Some may not affect drug resistance directly, but rather provide an environment where drug resistance mutations are tolerated. Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change c a n counteract this negative effect."

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