Discovery of critical iron-transport protein in malaria parasites could lead to faster-acting medications

Malaria kills over 600,000 people a year, and as the climate warms, the potential range of the disease is growing. While some drugs can effectively prevent and treat malaria, resistance to those drugs is also on the rise.
 
New research from University of Utah Health has identified a promising target for new antimalarial drugs: a protein called DMT1, which allows single-celled malaria parasites to use iron, which is critical for parasites to survive and reproduce.
 
The results suggest that medications that block DMT1 might be very effective against malaria.
 
The new results are published in PNAS.

An ironic mystery

Paul Sigala, PhD, associate professor of biochemistry in the Spencer Fox Eccles School of Medicine (SFESOM) at the University of Utah, knew that iron is essential for parasite survival. Without iron, parasites rapidly die. And getting that iron from the human red blood cells in which the parasites live and divide is no simple task.
 
“We still don't really understand how parasites acquire iron in the red blood cell, which is rather ironic given that it's the most iron rich cell in the human body,” says Sigala, who is the senior author on the paper. 

Researchers knew that the malaria parasites had to harvest iron-rich hemoglobin from human blood cells, crack it open to get at the iron inside, and move the iron to the parts of the parasite that need it.

But the proteins involved were “a bit of a black hole,” says Kade Loveridge, a graduate researcher in biochemistry in SFESOM and the first author on the paper. Malaria parasites are so distinct from better-studied organisms that the scientists had little prior knowledge to go on. “They don't have a lot of the normal proteins that you would need to get iron and transport it.”

A key player

The researchers suspected that DMT1 might help malaria parasites use iron because it looks somewhat similar to genes involved in metal transport in other organisms.
 
Importantly, they found that DMT1 is absolutely critical for parasite survival. The researchers edited the malaria parasites’ genome so that they could turn off DMT1 protein production at will. When they turned DMT1 off, the parasites died before being able to infect more blood cells—an unusually rapid demise, even for the loss of an essential protein.
 
The parasites’ rapid death could be a consequence of the importance of iron transport in many processes, Sigala says. “Blocking [this protein] is expected to impair not just one or two key processes but nearly all aspects of parasite viability during blood-stage infection,” he says.
 
Sure enough, DMT1 is necessary specifically because it’s involved in iron transport, the team confirmed. When they turned DMT1 activity down but not totally off—like a light on a dimmer switch—the parasites could still survive, but their growth slowed down. Intriguingly, giving them lots of extra iron brought them back up to speed. The researchers believe that, when iron is abundant in the environment, the handful of remaining DMT1 proteins can transport it quickly enough for parasites to grow normally. When there’s no DMT1 whatsoever, it doesn’t matter how much iron is around—malaria parasites can’t use it and rapidly die.

A crack in the door

The researchers are hopeful that DMT1 could be an effective target for new antimalarial drugs, thanks to its moderate similarity to human iron transporters, Loveridge says. “It’s similar enough that we could identify it,” he says, “but different enough that it’s possible that you could design a parasite-specific inhibitor of this transporter that has minimal impacts on the human protein.”
 
The fact that the parasites die so quickly when DMT1 is turned off is promising; if a drug can be developed or identified that prevents DMT1 activity, it could be faster-acting than current options. The lab is currently testing existing iron transport inhibitors to see if they could work as antimalarial drugs.
 
Loveridge adds that whether or not their discovery leads to new drug development, it’ll make it easier for future scientists to uncover more information about how the parasite grows and how to stop it. “We’re kind of cracking the door,” he says. “I hope that other people can throw it wide open.”

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These results were published as "Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites" in PNAS on October 28, 2024.

This research was supported by NIH grants R35GM133764 and T32TR004392, the Utah Center for Iron and Heme Disorders, and the American Heart Association.