The largest genome wide study of the malarial parasite Plasmodium falciparum has uncovered the genetic changes that underlie its resistance to the first line antimalarial treatment: artemisinin. Researchers have found genetic markers they hope can be used in to allow early detection of artemisinin resistance in endemic areas. Early detection of resistance will allow targeted interventions – such as elimination programmes – that could help to control and prevent the spread of resistance and secure the efficacy of this important drug.
Malaria is a life-threatening disease that is found across the tropics and affects hundreds of millions each year. In 2013 there were 198 million cases of malaria worldwide and 584,000 deaths – the large majority of these occurring in African children. Malaria is caused by four species of the parasite – with P. falciparum being the most deadly. Falciparum malaria is associated with greater complications (including cerebral malaria and permanent brain damage in children) and a higher mortality rate.
Progress has been made in the treatment and control of malaria. Malaria deaths in children have been halved since 2000 – and much of this is due to better detection and medical treatment of the disease. However this progress is threatened by the emergence of drug resistant strains. Since the 1950s P. falciparum has rendered nearly all available antimalarial drugs ineffective. Most recently P. falciparum is developing resistance to artemisinin – the first line treatment for malaria worldwide. Though currently confined to South East Asia, there is fear that artemisinin resistance could spread globally, causing treatment and cure to become near impossible.
Considering the potential impact of artemisinin resistance, protecting its efficacy has become a priority. This recent genomic work has found a genetic marker for the emergence of resistance and a way to identify at-risk regions.
The study, undertaken by the Wellcome Trust Sanger Institute, found two factors that must co-exist in order for resistance to develop. The first is a mutation in the Kelch13 gene. And the second is a set of background mutations in four other genes, which together support artemisinin resistance. Both factors must be present before the parasite becomes resistant. For example mutations in Kelch13 were present, but rare, in African parasites – however these did not have the background mutations and were still artemisinin sensitive.
Mutations in Kelch13 are incredibly variable, with new abnormalities constantly emerging. By comparing Plasmodium genomes across South East Asia scientists found that the distribution of different Kelch13 mutations were well localised within geographical areas. Migration across borders appeared relatively limited and it is likely that the mutations arose independently in several areas. Taken together this information suggests a key role for the dysfunction of Kelch13 in artemisinin resistance. However using it as a marker for genetic surveillance is not feasible due to the large variety in mutations.
However all Kelch13 mutations occurred alongside a fixed set of mutations in the Fd, Arps10, Mdr2, and Crt genes. These were reproducible across strains and by evaluating their presence, researchers could assess areas at risk of developing artemisinin resistance, even before the parasites become prevalent.
There are still questions to be answered. The function of these genes is unknown, as is their relation to artemisinin resistance. The current theory is that the background mutations arise independently and create an environment that is permissive to Kelch13 mutations. However Kelch13 must mutate for artemisinin resistance to be triggered.
Artemisinin resistance is a very real threat to current malaria control. Multi-drug resistant strains could undo all progress made over the last decade and increase the morbidity and mortality associated with this infection. This new data provides a real tool for monitoring parasite populations and could be vital in the understanding and possible prevention of artemisinin resistance.