Parasite genes drive up antimalarial resistance

"New drug-resistant strains of the parasite that causes malaria have been identified," is the worrying news being reported on the BBC News website. Covering the same piece of research, The Guardian outlines the ongoing "scientific detective hunt in Cambodia to find much-needed clues to the development of resistance in the malaria parasite to the life-saving artemisinin drugs".

While most of us are aware of the issue of antibiotic resistance, the growing problem of resistance to antimalarial drugs often goes unreported, at least in the developed world. But the potential impact of increasing antimalarial resistance could be devastating. Our armoury of malarial drugs is limited, so further resistance could lead to a world where malaria is practically incurable.

The "detective hunt" that has hit the headlines involved looking at the genetic make-up of more than 800 samples from Africa and southeast Asia of the malaria-causing parasite Plasmodium falciparum (P. falciparum).

Three genetically different subpopulations showed resistance to artemisinin drugs, the medication that is the basis of current treatments for P. falciparum malaria. This suggests that resistance can be caused by different genetic variations.

Researchers will now go on to look more closely at the genetic variations they identified to see which ones contribute towards artemisinin resistance. The researchers hope that these findings and subsequent research will help us better understand how resistance to antimalarial drugs develops, with the ultimate aim of being able to eliminate the resistant strains of the parasite.

Where did the story come from?

The study was carried out by researchers from several international research centres, including the University of Oxford. It was published in the peer-reviewed journal Nature Genetics and was funded by the Wellcome Trust, the UK Medical Research Council Division of Intramural Research, the US National Institutes of Health, and the Howard Hughes Medical Institute.

Scientists already knew that artemisinin-resistant strains of malaria existed in western Cambodia, but they did not know much about its genetic make-up.

The research was generally well reported by the BBC and The Guardian.

What kind of research was this?

This was a laboratory study looking at the genetic make-up of different strains of the malaria parasite Plasmodium falciparum collected from different parts of Asia and Africa. There are several different types of malaria parasite, but P. falciparum is the most common and causes the most severe malaria infections. Some strains of the P. falciparum parasite have evolved resistance to antimalarial drugs such as artemisinin, one of the main drugs used to treat this type of malaria.

Drug resistance occurs through genetic changes in the parasites, making them less susceptible to the drugs used to kill them. Essentially, "survival of the fittest" evolutionary pressure leads to the increased spread of resistance over time.

When the drug is used on mixed populations of the parasite, some of which have resistance, the resistant parasites are more likely to survive than the non-resistant parasites. This means their genes spread through the population, causing the resistance to spread.

The researchers report that successive waves of this drug resistance originated in western Cambodia. Resistance to artemisinin and related drugs is now reported to be well established in this area. They wanted to look at whether the genetic make-up of P. falciparum from western Cambodia could give clues about why this might be the case.

What did the research involve?

The researchers analysed the genetic make-up of 825 samples of P. falciparum collected from 10 areas in southeast Asia (including four areas in Cambodia) and west Africa. They focused on more than 86,000 single "letter" variations at sites throughout the DNA code of the parasite. Once they identified which letter each of the samples had at these sites, they used a computer programme to analyse how the different samples were likely to be related to each other.

For example, the programme estimates which strains are joined by a common "ancestor" strain and how closely the strains are related. These relationships are shown as a "family tree" which joins all of the samples together.

The researchers also looked at resistance of these parasite samples to the drug artemisinin. They analysed data on how quickly the parasites were cleared from patients' blood when treated with an artemisinin derivative drug called artesunate.

What were the basic results?

The researchers found that within a relatively small area of western Cambodia there were several distinct subpopulations of P. falciparum that had an unusually high level of genetic differences. This finding was surprising, as researchers would have expected the samples from a small area to be more genetically similar than they were.

Three of these subpopulations showed resistance to the antimalarial drug artesunate. Within each subpopulation there were high levels of genetic similarity, suggesting that they had high levels of recent inbreeding.

The researchers identified a number of single letter variations among the artemisinin-resistant strains. Some of these variations lay within genes and would have an effect on the proteins that the genes encoded (carried the instructions for making). These changes could be responsible for the resistance to artemisinin-derived drugs. For example, some of these changes were in genes responsible for repairing the DNA if it gets damaged. Researchers thought this might relate to how quickly these strains in western Cambodia developed DNA mutations and resistance to antimalarial drugs.

How did the researchers interpret the results?

The researchers conclude that their findings provide a framework for further investigations into how artemisinin resistance arises. They say that these discoveries suggest that there could be multiple forms of artemisinin resistance because multiple subpopulations of resistant parasites were discovered, each with different genetic characteristics.

Conclusion

This study provides researchers with more information about the genetic make-up of different subpopulations of a type of malaria parasite taken from Africa and southeast Asia called P. falciparum, which causes the most severe malarial infections. They were surprised by the high levels of genetic diversity in parasite samples from western Cambodia, an area where resistance to a number of antimalarial drugs has developed and then spread.

Some of these Cambodian subpopulations showed resistance to the antimalarial drug artesunate. Data about their genetic variations will now be investigated further to see exactly which of these variations could be contributing to this resistance, and how.

The researchers speculate that historical, as well as genetic, factors may also have been involved. Parts of Cambodia were historically very isolated in terms of human movement due to the civil war between government forces and the Khmer Rouge, as well as poor roads in forested mountain areas. This could have created pockets of isolation ideal for parasitical inbreeding.

In addition, in the 1950s and 1960s there was mass administration of the antimalarial drugs chloroquine and pyrimethamine in one area in western Cambodia, leading to a strong selection pressure for strains resistant to these drugs.

It is hoped that these findings and subsequent research will help us better understand how resistance to antimalarial drugs develops, with the ultimate aim of being able to eliminate these resistant strains so that we can continue to treat the disease.