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Stopping malaria by starving the parasite may lead to new drugs

The face of malaria - diagnosed with a severe case of malaria. Flickr/Gates Foundation, CC BY-ND

Stopping malaria by starving the parasite may lead to new drugs

A new drug for malaria could be developed after a way has been found to kill the parasite that causes the disease.

Malaria remains one of the world’s top three single-cause infectious diseases and is caused by large-scale infection of the body’s red blood cells with Plasmodium parasites.

The World Health Organisation’s 2013 Malaria Report estimates that 3.4 billion people are at risk of malaria – almost half the world’s population.

In 2012 there were 207 million clinical cases that tragically resulted in an estimated 627,000 deaths, mostly of children under the age of five.

Malaria parasites (green and blue) infecting human red blood cells (red) Paul Gilson

Yet there is no vaccine for malaria and the only effective treatments are anti-malarial drugs.

The good news is that recently the world has been winning the war against malaria, with new programs to introduce insecticide-treated nets over beds to protect against mosquito transmission, and widespread drug treatment programs, producing dramatic disease declines in some areas.

These gains though are now being threatened with the emergence of parasites that are becoming resistant to the latest drugs that are considered to be our last line of defence. For this reason new drugs need to be constantly under development and ready to roll out when existing treatments begin to fail.

Starving the parasite

In our paper published in Nature this week my colleagues and I have discovered a protein gateway that if blocked could starve the parasites, leaving them to wither away inside their host red blood cells.

The parasite’s choice to infect red blood cells seems sensible – there are plenty of these in the body and, as female mosquitoes require blood for development of their eggs, this provides a route for mosquito transmission from one person to another.

But red blood cells are small and prone to bursting, they are not nutritious (for the parasite!) and when infected they can be intercepted and destroyed in the spleen.

Malaria parasites invading new human red blood cells (white arrows).

To overcome these limitations the malaria parasite cleverly renovates its red blood cell to provide a safe home that allows it to thrive and survive. The renovations are carried out by hundreds of proteins that the parasite exports into the red blood cell.

These proteins strengthen the host cell, make it sticky so it stays hidden in the peripheral organs rather than being cleared through the spleen and, really importantly, they make the red blood cells porous so essential vitamins and amino acids can enter and be consumed by the parasite to fuel its rapid growth.

For a long time a major question has been how do the exported parasite proteins gain access to the red blood cell?

Finding the gateway into the cells

A few years ago, in a paper also published in Nature, we partially answered this question by discovering a parasite gateway that we envisaged might act as a portal from the parasite into the red blood cell.

In our latest paper we go one step further and show that exported proteins really do go through these gateways we call PTEX (Plasmodium Translocon of Exported Proteins). We also demonstrate that PTEX is the only gateway by which hundreds of diverse parasite proteins enter the host cell.

The complex part of our work was to insert genetic switches into a couple of the PTEX genes so that we could turn them on and off at will.

When we switched off the PTEX genes the PTEX gateways stopped being made and this caused exported proteins to build up beneath the parasite surface, unable to get out into the red blood cells. The parasites soon started to look sick and rapidly died.

A model of how the malaria parasite is thought to export proteins into its red blood cell via the PTEX complex. Paul Gilson

So why is it that when PTEX is turned off that parasites die? In an accompanying paper in the same issue of Nature, researchers from Washington University in St. Louis, US, replicate our main findings using a different approach. They show that the parasites may no longer be able to make their red blood cells porous.

This would deprive the parasites of nutrients, effectively starving them.

Red blood cell porosity is also believed to help parasites evacuate waste products and so in addition to starvation, the parasites might be choking in their own filth.

Whatever the case, the fact that parasites need PTEX to survive creates the opportunity to drug the complex with a molecular plug to prevent protein export.

Such a drug could be highly effective since in one blow it would prevent hundreds of parasite proteins from functioning properly in the red blood cell leading to rapid death of the parasite.

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