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An end to malaria? Mission definitely not impossible

Researches have uncovered a vital piece of the anti-malaria puzzle. Larah McElroy

More than 200 million people are infected annually with the malaria parasite Plasmodium falciparum, and around 800,000 people die every year of the mosquito-borne disease, most of them children.

As reported earlier today on The Conversation, Australian researchers have uncovered new detail on how the malaria parasite reacts to anti-malarial drugs and adapts to neutralise their effects. The hope is that the discovery will set the stage for better-designed drugs in future.

Lead researcher, Professor Leann Tilley from the Department of Biochemistry at La Trobe University, explains more.

How is malaria transmitted?

Malaria is caused by several species of parasite but the most important one is called Plasmodium falciparum. It’s a protozoan parasite that is transmitted by mosquitoes.

The parasite is transmitted to a human when the mosquito bites and enters the victim’s liver cells, then eventually their red blood cells – and that’s where it really wreaks havoc.

Once it’s inside the red blood cells the parasite starts devouring the red cell haemoglobin and changing the red blood cells so that the infected red blood cells stick to blood vessel walls.

It’s the adhesion of the infected red cells in sites such as the brain which induces an inappropriate immune reaction from the victim: you get a release of the parasites and an “immune cascade” in the brain and that sends the patient into a coma.

Very often, if people get to that point they don’t recover.

What methods are currently used to treat malaria?

The main defence we have against malaria is a series of anti-malarial drugs, the most important of which is artemisinin or members of the artemisinin family.

We also have some anti-malarial drugs that can help to prevent you from catching malaria, and the other major defence is bed-nets – trying to keep the mosquitoes away from people and particularly from young kids.

Artemisinin saves millions of lives every year. It was discovered by the Chinese and used in a herbal remedy to treat fevers hundreds of years ago.

In the 1960s, some researchers went back and looked through the various herbal remedies to find a new anti-malarial – and they came up with artemisinin.

Over the last ten years it’s become the most important anti-malarial as the parasite has developed resistance to all of the other drugs that were available.

Currently, it’s mainly artemisinin derivatives, second-generation artemisinins, that are being used. In some ways it’s the best drug we’ve ever had, particularly for the fact that it acts very rapidly.

Artemisinin can start killing the parasites almost immediately and can drastically reduce the parasite burden in only a few hours.

That’s good because malaria can kill you very quickly – there’s no point taking a drug that’s going to work in 48 hours if you’re going to be dead in 12 hours.

There are some problems though, the major one being that it’s very short-lived in the body.

When you get an artemisinin treatment, the drug only lasts in your bloodstream for a couple of hours. This means it can’t really completely cure you of the disease – it can’t kill 100% of the parasites by itself – so it’s always given in combination with another long-lived drug, something like Mefloquine.

Artemisinin greatly reduces the parasite burden and then the longer-lived drug cleans up the last few parasites.

The other major problem with artemisinin is that there are recent reports of decreased clinical efficacy. This is obviously very concerning because artemisinin is often what stands between the victim and death. It’s very important we understand what’s happening with artemisinin and artemisinin resistance.

This will enable us to develop better drugs to get around the resistance mechanism or use artemisinin in such a way that it avoids that resistance mechanism.

And your research taps directly into this?

Yes, it does. There have been a number of hypotheses floating around for a number of years as to how artemisinin kills malaria parasites.

Different scientists have different ideas about how the drug works but the study we’ve just published in the Proceedings of the National Academy of Science shows very clearly that artemisinin kills malaria parasites by being activated by a breakdown product of haemoglobin digestion.

A parasite developing inside a red blood cell has to eat haemoglobin because it needs amino acids and it needs space, but in doing so in the presence of artemisinin it effectively causes its own death.

This is because at the centre of every haemoglobin molecule there’s a molecule of haem and upon release, that haem iron reacts with artemisinin and converts the artemisinin into a toxic, activated, free-radical species.

What are the implications of your discovery?

To design better anti-malarial drugs, we need to know exactly what it is we’re aiming for. From a synthetic chemist’s point of view, if you understand how drugs work then you can design better ones.

If you have the wrong idea about how they work you’ll go down a wrong path.

Our work also helps to understand how the parasite becomes resistant to artemisinin. We now realise that when you treat the parasite with low concentrations of artemisinin you slow down its growth and stop it from taking up haemoglobin.

Our work shows the parasite has a natural mechanism by which it can defend itself against the drug. What it does is take a little rest – it shuts down its metabolism for a little while and doesn’t eat – and if it doesn’t consume the haemoglobin then the artemisinin is not active.

So this suggests the mechanism by which parasites, in the field, could become resistant to artemisinin. What is likely happening is that by using artemisinin in sub-optimal treatment regimens, we’re “selecting” a population of parasites that have an enhanced ability to enter a dormant state upon exposure to artemisinin.

Because the drug lives for such a short time in the blood stream, the parasite only has to avoid its toxic effect for a few hours. As long as it can survive that period it can awaken from the dormant state after the drug has been removed and then go on to multiply and cause disease.

Will your discovery assist with the development of longer-lasting artemisinin derivatives?

As it happens there’s another group in Australia – including Susan Charman from the Pharmacy College in Melbourne – who’s been working with colleagues in the US, such as Jonathan Vennerstrom from the University of Nebraska, and they have recently been testing a fully synthetic artemisinin relative which has longer life in the blood stream.

It’s very exciting that our two pieces of work have come together very nicely and it’s likely the new drug – which is currently going into clinical trials – will be a much better drug against resistant parasites.

How will your discovery, and the drugs that are being developed as result, work with other treatment methods for malaria? Will this replace existing methods or work in tandem?

We’re entering a new era of malaria research. The Gates Foundation has provided a lot of funding and has had the audacity to talk about the idea of malaria eradication.

It’s been unpopular to mention the word “eradication” for many years because so many people have tried and failed, but currently there is the political will and some funding to make things happen.

If you’re going to think about eradicating malaria then obviously you need to hit it on several fronts. You need better insecticide-treated bed-nets for children; you need effective ways of decreasing mosquito populations (if you can reduce mosquitoes then you reduce transmission); and we’d really like to have a vaccine against malaria.

That’s still a little way off but there are promising early developments in terms of at least partially-effective malaria vaccines. And, as already discussed, we need several drugs.

The endoperoxides – which is what artemisinin is – are a fantastic set of drugs but, as I said, they need to be used in combination, so we need better partner drugs for artemisinin as well.

When might we see the eradication of malaria?

The timeframe people are looking at to make a significant dent in malaria is over the next ten years.

I suspect we’ll be facing the scourge of malaria for somewhat longer than that but if we can develop good anti-malarial treatments and keep one step ahead of the development of drug resistance, we should be in a position to drastically reduce the number of people dying from malaria, and we should eventually be able to wipe out the disease altogether.

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