Emerging drug resistance in young malaria parasites

Immature malaria parasites are more resistant to treatment with key antimalarial drugs than older parasites, a finding by researchers from the University of Melbourne has revealed.

The study, conducted by a team led by Professor Leann Tilley and Dr Nectarios (Nick) Klonis, has shown that malaria parasites in the early stages of development are much less sensitive to the artemisinin-based drugs that currently represent a last line of defence against malaria.

“We were surprised to find that juvenile parasites were up to 100 times less sensitive to the drug than mature parasites, and that in some strains the juvenile parasites showed a particularly high degree of resistance. This would result in a large number of juvenile parasites surviving against clinical treatment and helps explain how resistance to drugs develops,” Tilley said.

The malaria parasite, Plasmodium falciparum, is transmitted to humans via the bites of infected mosquitoes. Once inside the human body, the parasites travel to the liver to mature, multiply and then infect red blood cells. The disease is widespread in tropical and subtropical regions.

If not treated, malaria can quickly become life threatening by disrupting the blood supply to vital organs. The disease kills one person every minute and the parasites have already developed resistance to a number of drugs.

Although artemisinin is effective in saving millions of lives each year, it is still not clear exactly how it works. Tilley’s team has developed a novel approach to examine how the parasite responds to drugs under the conditions it encounters in the body. This is important because the malaria parasite takes two days to reach maturity in each cycle but the drug only remains in the bloodstream for a few hours.

To survive in the human body, the parasite must inhabit red blood cells for part of its life cycle. To do this it first digests the cell contents, including the oxygen-carrying haemoglobin protein.

The researchers found that the parasite was most susceptible to drug treatment when it was digesting haemoglobin. This led to them suggesting that a breakdown product, possibly the haemoglobin pigment, was activating artemisinin to kill the parasites. Immature parasites do not have an active digestive system, which explains how they can avoid the effects of the drug.

“We hope that our findings will provide a guide for changing the timing of the drug treatment regime and developing longer lasting drugs, thereby killing more of the parasites and reducing the development of drug resistance,” said Tilley.

The next steps for the team are to try and establish why certain strains are more resistant to artemisinin drug attack than others.

This work was recently published in the journal PNAS.