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Malaria claims a million lives a year, a majority of which are children, and threatens the lives of billions more within its tropical ranges. It is caused by Plasmodium, a parasite that uses mosquitoes as a way of getting in to and out of humans. Initial infection from the bite of a carrier mosquito is followed by the parasite’s massive proliferation and colonisation of the host’s blood, causing a suite of debilitating symptoms and providing a parasitized food source for the next mosquito. In the absence of a vaccine, prevention and treatment remain our only effective weapons against malaria. Today, the most effective treatment regime relies heavily on artemisinin, a compound from an Asian herb that effectively targets the parasite within red blood cells. But, as was the case for previous anti-malarial drugs, the spectre of artemisinin-resistant Plasmodium strains is rising. Worryingly, as there is currently no clear fall back to artemisinin, a global spread of resistance will seriously harm our ability to tackle the disease.
The research of Miotto, et al. was stimulated by the observation that resistance to artemisinin, and indeed some of its forebear drugs, appears to originate in the same part of the world: the remote mountains of western Cambodia. To tackle the question of why drug resistance originates here, the researchers sought clues within the parasite’s genome. They had previously developed a technique to isolate Plasmodium DNA directly from the blood of infected patients: a blood sample is taken, white blood cells removed (this removes a lot of the human DNA content which can complicate analysis), and DNA extracted and sequenced using modern sequencing technology. For this work they do not require the parasite genome sequenced in its entirety; rather, they seek sufficient coverage to allow reliable identification of variability between samples.
The researchers collected samples from infected patients in west Africa and southeast Asia, including four sites in Cambodia, one in the east and three in the west. A global survey of the genetic data revealed that the Asian and African populations have distinct patterns of genetic variation, consistent with their geographical isolation. Within the Asian sample, the story was a little more complex. Samples from western Cambodia were notably distinct from those in eastern Cambodia and Thailand. The western Cambodian populations were also ‘structured’, that is, the population was split into subpopulations, each with their own distinct genetic signatures. The subpopulations were also relatively inbred, lacking in genetic diversity, which is often a signature of a recent expansion from a small, homogenous population. Crucially, the researchers were able to show that the subpopulations that predominate in western Cambodia showed artemisinin resistance, as infected patients responded poorly to treatment. Thus, while the distinct subpopulations of Plasmodium in western Cambodia are genetically distinct, they present the same problem: artemisinin resistance.
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The beauty of these kinds of genomic studies is that as well as just looking at the variation between groups accross the genome, on a global scale, we can zoom in and focus on the individually varying regions to ask whether these parts do anything relevant. The researchers made the important observation that the western Cambodian subpopulations harbour a number of genetic changes associated with drug resistance, including alterations to genes which control the entrance of molecules into the cell. One of the subpopulations even harboured mutations in genes involved in preventing mutations, raising the intriguing possibility that a general increase in mutability of the genome may provide more drug resistance mutations.
Identifying the source of emerging drug resistance, both in terms of geography and underlying genetic causation, is a critical task if we are to control its spread. Hence the importance of this work for malaria control. The fact that there are multiple, independent artemisinin-resistant subpopulations shows that there are many routes for a parasite to become resistant. In practical terms the genetic signatures within the resistant strains can be used as biomarkers for artemisinin resistance in any sample of Plasmodium DNA, allowing health authorities to monitor its spread. Furthermore these genetic signatures will add to our biological understanding of how the parasites evolve to resist the drug.
We are still however left with our opening question: why Cambodia, specifically why Western Cambodia? The authors propose a number of potential contributory factors, including the potential higher mutation rate, heavy use of drugs and local isolation of the populations (favouring inbreeding) due to the remoteness of the region. General features of host-parasite interactions are thus married with particularities of the region to provide a potent reservoir of drug resistance. Whatever the underlying causes, the next imminent step will be containment of these variants to prevent their global spread.
This summary by Aidan Maartens was shortlisted for Access to Understanding 2014 and was awarded third prize. It describes research published in the following article, selected for inclusion in the competition by the Wellcome Trust:
O. Miotto, J. Almagro-Garcia, M. Manske, B. MacInnis, S. Campino, K. A. Rockett, ... D. P. Kwiatkowski.
Nature Genetics (2013) 45(6), 648-655.
Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2014 there were 10 articles to choose from, selected by the Europe PMC funders. The articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.
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