Malaria infection linked to iron in red blood cells

Malaria kills about a million people each year; most are children and most live in Africa. But while Africa is afflicted with the deadly Plasmodium falciparum, the rest of the world is plagued by the less-lethal but still debilitating Plasmodium vivax.

 Now an Australian-led international team has identified the key portal used by P. vivax to enter human red blood cells. 

Because all the clinical symptoms of malaria occur doing the blood-borne stage, the findings, published in the journal Science, deliver a new target against which to design antibodies that might not only prevent illness, but could also help finally eradicate the parasite. 

It’s a key new strategy at a time when the malaria parasite is developing resistance to first line drugs such as artemisinin and chloroquine.

“This is a substantial step forward for the field – a key missing link in our understanding of this ‘second’ malaria,” says Brendan Crabb, director of Melbourne’s Burnet institute, who was not involved in the study.  

P. vivax accounts for more than 16 million cases of malaria each year. Papua New Guinea boasts the highest rates of infection, with the microbe exacting a high toll in debilitating illness, especially amongst children and pregnant mothers.

Often this occurs when the parasite comes out of hibernation in the liver – where it causes no symptoms – and starts infecting newly minted and rare red blood cells known as reticulocytes.

So a key goal has been to find a way to stop the parasite from entering them. To land a passing reticulocyte, P. vivax needs to latch on to one of the cell’s receptors. One such receptor is well known – the so called Duffy antigen. Most Africans resist infection by P. vivax because their red cells have lost the Duffy antigen (though it doesn’t help them resist P. falciparum).

For many years now, researchers have tried to copy nature and interfere with the ability of P.vivax to latch to the Duffy protein by developing vaccines that target the parasite’s grappling hook, known as Duffy Binding Protein or DBP. 

But they also knew the parasite must have another way of entering young red blood cells. That’s because older red blood cells, known as erythrocytes, also have the Duffy antigen but are not targeted by P. vivax.

 “How P. vivax chooses to invade reticulocytes over mature red blood cells when many of the receptors on these blood cells are the same, has been a mystery until now,” says Paul Gibson, a malaria researcher at the Burnet Institute, who was also not involved in the research.  

“That was the mystery we were trying to solve,” say Wai-Hong Tham, the senior author of the paper, based at Melbourne’s Walter and Eliza Hall Institute.  

The researchers discovered that the identify of this other receptor was a surprisingly mundane piece of the cell’s componentry: the transferrin receptor which ferries iron into red blood cells. That became clear when they generated red blood cells that carried a mutated form of the transferrin receptor. P. vivax was no longer able to enter.

But blocking the transferrin receptor is not a useful clinical approach. Iron is vital for the haemoglobin protein to do its job of carrying oxygen. 

So, the researchers focussed on the parasite’s grappling hook for grabbing the transferrin receptor. By studying its crystal structure, they were able to zero in on a part of the hook, known as PvRBP, that was essential for the docking function, and then targeted their antibodies specifically against it. The parasite is notoriously variable, explains Tham, but if it mutates away from this structure it won’t be able to infect cells.

For Tham, the take-home message is that “the best vaccine will be a combination of both one that targets PvRBP and one against the Duffy binding protein, as they potentially function in different molecular steps of parasite invasion.”

Such antibodies may also come with fringe benefits. Co-author Jonathan Abraham from Harvard University points out the transferrin receptor is also co-opted by five viruses that cause Ebola-like diseases in South America, known as New World haemorrhagic fevers.

“Our increasing understanding of how several pathogens are taking advantage of transferrin receptor, means we are getting closer to disrupting infection for a number of deadly diseases,”  Abraham said.