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Malaria parasite takes refuge in human livers. Duke scientists seek way to fight back.

Malaria, once known as “swamp fever” by U.S. colonists, has been eliminated in this country. But it’s still a big problem worldwide.

The Centers for Disease Control says that almost half the world’s population is at risk of contracting malaria in South American, African and Asian countries.

But Duke University researchers are taking a different approach to treating the disease by hitting it where it grows inside the human body: the liver.

A human hijacker

Malaria needs to hijack an animal’s body to reproduce. The malaria parasite is a protozoan, a single-celled organism that infects red blood cells that carry oxygen to the rest of the body’s cells. Once inside a red blood cell, malaria replicates over and over again until the cell explodes, further spreading the disease.

But malaria first has to make itself at home in the liver. When mosquitoes bite, they use their six needlelike mouthparts to suck blood. Two of those needles saw into the flesh, and one can sense chemicals from blood vessels to find them.

One needle is particularly problematic for humans. It injects mosquito saliva into the bloodstream to thin the blood. Malaria parasites can travel from the saliva of an infected mosquito to the liver.

But what exactly is it doing in there? According to Maria Toro Moreno, a Duke doctoral student in the Department of Chemistry and coauthor of a new study, when malaria enters the liver, it can’t immediately infect red blood cells.

Instead, it hides, transforms itself, makes multiple copies of the infectious version, then heads into the bloodstream to inhabit red blood cells, potentially leading to anemia, seizure and organ failure.

Toro Moreno explained that she and the rest of the Duke research team wanted to know what would happen if they modified human liver cell genes. Would the parasites do as well?

How the test worked

To find out, they used Plasmodium berghei, a kind of rodent malaria extracted from mosquitoes. As Emily Derbyshire, a Duke assistant professor of chemistry, explained, this kind of malaria can infect human liver cells. But if the lab mosquitoes were to bite a human, they wouldn’t develop malaria in their blood cells.

Next, the team “silenced” almost 7,000 different genes in cancerous human liver cells, then exposed those cells to malaria parasites from the mosquitoes.

“Most researchers use cancer cells from a patient from 30 or 40 years ago because they can replicate fast,” explained Toro Moreno.

In some cases, dimming the liver cell genes caused the infectious form of malaria to grow to a smaller size. This finding could mean fewer parasites overall to infect red blood cells. Derbyshire noted that limiting malaria growth could also reduce the chance of drug resistance.

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A view of a feeding female Anopheles albimanus mosquito. James Gathany CDC

Xinxia Peng, an associate professor in the N.C. State University College of Veterinary Medicine, has worked with the liver stage of malaria parasites. He called the study interesting and important, but cautioned that there could be a difference between what happens in cultured liver cancer cells and human livers.

Overall, he told The News & Observer, “more studies are needed in order to be clinically relevant.”

Rene Raphemot, the study’s lead author and now blood drive coordinator at the American Red Cross at Aviano Airbase in Italy, said in an email message that he didn’t believe that using cancerous liver cells harmed the experiment. He is interested to see how trials with malaria parasites that can infect humans will go.

Raphemot notes that, while researchers are far away from developing drugs based on this study, they hope to use small molecules to target liver genes that are used to malaria’s advantage.

Importance of research

The CDC in Atlanta was founded in part to rid the south of malaria, which it did through insecticides and draining pools of stagnant water where Anopheles mosquitoes — the type that spread malaria — lay their eggs.

The World Health Organization estimated that 219 million people contracted malaria in 2017, and about 435,000 people died from it.

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Rene Raphemot, who was a postdoctoral researcher at Duke, works on malaria research at the Derbyshire Lab at Duke in 2016. Duke University

Moreno Toro pointed out that there are good reasons for North Americans to support malaria research.

“Malaria has been eradicated in the U.S. for a long time,” said Toro Moreno. “But climate change might change that just from having the vectors — the mosquitoes — come back to the U.S.”

Derbyshire has also seen the effects of malaria, which motivates her research.

“I know people who live in those countries where every year they had malaria, and that’s just something you live with growing up. It has a pretty large footprint.”

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