Parasites sneak into the brain – and give science good ideas

A research team from the University of Copenhagen is the first to prove that malaria parasites use a sneaky trick to cross the human blood-brain barrier. And this finding could potentially play a role in the design of new therapies for brain disorders.

If you want to enter a heavily guarded place – to which you would usually not have access – a fake ID might get you through the door.

This is a method commonly used by thieves, con-men and other fraudsters.

However, it can also be used for perfectly respectable purposes; for instance, when scientists are seeking to wrest secrets from biology in order to develop novel treatments for serious diseases, or to improve existing therapies.

This is demonstrated in an article recently published in the scientific Journal of Experimental Medicine by a group of researchers at the Department of Immunology and Microbiology, University of Copenhagen (UCPH).

The UCPH researchers applied a special investigative technique to reveal the strategy malaria parasites use to attack the human brain.

This is news in itself, since this has never been shown before, and it is a major breakthrough in our understanding of cerebral malaria.

However, there is an added dimension: learning from the strategy of the malaria parasite – and using this knowledge to produce a type of fake ID – may help us design new forms of medical treatment for brain disorders.

For example, therapies targeting certain types of brain cancer.

 

A MYSTERY

For many years, science has grappled with the question of how malaria parasites attack the human brain – where they can cause extensive neurological damage and, in some cases, are a cause of death.

The strange thing is that the parasites should not be able to get into the brain at all.

When someone is bitten by a mosquito and infected with malaria, the parasites live in their bloodstream and take up residence in the red blood cells. And red blood cells cannot cross the brain’s guarding barrier, the blood-brain barrier.

This barrier consists of a dense network of cells, efficiently guarding the access route to the brain and meticulously checking which biochemical substances pass through.

It keeps harmful substances and pathogenic microorganisms out of the brain and brain tissue. On the other hand, it allows white blood cells, which are an important part of our immune system, to penetrate.

‘Since red blood cells cannot cross the blood-brain barrier, it has so far been our understanding that malaria parasites could not enter into brain tissue. Now we can show that the parasite is able to mimic the mechanism that the immune system’s white blood cells use to cross the barrier. And we now know that this helps to explain the disease mechanism behind cerebral malaria,’ says Professor Anja Ramsted Jensen.

Together with her colleague, Assistant Professor Yvonne Adams, Professor Jensen headed the scientific study, which received funding from the Lundbeck Foundation.

 

To reveal the malaria parasite’s sneaky trick, the UCPH researchers used a 3D model based on brain cells they had grown in the laboratory.

Other researchers have previously used this model – which, in reality, is a “ball” of cells in a solution – to study whether certain drugs can cross the blood-brain barrier.

However, the UCPH researchers are the first to use this pinhead-sized 3D model to mimic and test the steadfastness of the barrier when it comes to keeping an infection at bay.

 

A TINY MEDICINE TRANSPORTER?

After Ramsted Jensen, Adams and their colleagues had performed a range of tests with the 3D model, they could see that some – but not all – of the malaria parasites were able to create special proteins.

The parasites then use these proteins to mimic the white blood cells and, thus, to penetrate the blood-brain barrier.

The question is whether, by mimicking the function of these proteins, we could create a kind of tiny “transporter” to penetrate the blood-brain barrier and, for instance, carry drugs into the brain.

‘We certainly can’t rule that out,’ says Andreas Kjær, professor at the University of Copenhagen and chief physician at Copenhagen University Hospital. Professor Kjær specialises in nuclear medicine and molecular imaging,

and he heads a research group at the University of Copenhagen and Copenhagen University Hospital which has received a Lundbeck Foundation grant with DKK 40 million to develop new forms of treatment for glioblastoma.

Glioblastoma is a malignant form of brain cancer untreatable by the therapies available to the medical profession today because it is impossible to remove all the cancer cells by surgery.

Professor Kjær and his colleagues are therefore seeking to design fluorescent tracers which bind to the cancer cells, so that neurosurgeons can see whether they have succeeded in removing all the malignant cells during surgery.

Another way of using these tracers is to attach a radioactive substance to them.

By doing this, the researchers who are currently developing the technique will create a kind of radioactive precision missile to target and destroy the glioblastoma’s cells.

‘We can learn a lot from malaria parasites, both when it comes to testing the ability of tracers to cross the blood-brain barrier and, in the future, when we want to pass other drugs for brain disorders through the barrier. And our group has now begun working with Anja Ramsted Jensen and Yvonne Adams to test substances with the 3D model they use,’ says Andreas Kjær.