ABOVE: Plasmodium parasites inside red blood cells © ISTOCK.COM, toeytoey2530

Malaria is one of the world's deadliest diseases, responsible for 627,000 deaths worldwide in 2020 alone. In severe cases, patients develop dangerously low blood sugar levels. This complication is especially perilous in children and can be fatal if left untreated, but why it develops in the first place has been a long-standing mystery.

Now, in a study published Friday (July 15) in Cell Metabolism, researchers describe the complicated tug-of-war between host and parasite that appears to explain malaria-associated hypoglycemia. According to the study, the host’s blood sugar drops to dangerously low levels as the malaria parasite destroys blood cells. This starves the parasite, which responds by becoming less likely to kill the already-fragile host—but more likely to spread to others.

The researchers explain that both the host and the parasite are demonstrating adaptive behaviors during this process. The host is ridding itself of the parasite by lowering its blood sugar, they say, and the parasite is becoming less virulent to try and keep both itself and the host alive long enough to seed the next generation.  “The idea that a pathogen is hard-wired to be bad is sort of fading away,” study coauthor Miguel Soares, an immunologist at the Instituto Gulbenkian de Ciência in Portugal, tells The Scientist, “pathogens are just microorganisms that are trying to adapt and survive.”

“It's a great paper. It's very nice work.” says immunopathologist Phillipe Van den Steen, a researcher at the Rega Institute who was not involved in the study. “This is something that’s really not well understood currently . . . [Why], in patients with severe malaria, metabolism is really disturbed.”

See “Malaria Mosquitoes Bite More During the Day Than Previously Thought

The parasites that cause malaria—Plasmodium species—have complex lifecycles. They are spread between hosts by mosquitoes, spend some time maturing in liver cells, and then eventually end up inside red blood cells. Once there, the parasites proliferate, feasting on hemoglobin. But they can take one of two paths: they can essentially clone themselves, creating more blood cell–infecting parasites, or they can generate gametes, which wait somewhat quiescently until a mosquito slurps them up so they can become the next generation of parasites and infect other hosts. The former path allows the parasites to eventually produce more gametes, but in the meantime, the infected red blood cells burst, releasing the oxygen-transport molecule heme into the blood. Heme, in turn, is responsible for several severe symptoms of malaria.

Illustration of Plasmodium parasite lifecycle in red blood cells
Once inside a red blood cell, a malaria parasite can either reproduce asexually (1) to make blood cell–infecting parasites that stay within the host, or produce gametes (2) to ultimately spread to new hosts.

The study began when Susana Ramos and Temitope Ademolue, both from the Instituto Gulbenkian de Ciência in Portugal, became interested heme’s role in malaria. They observed that mice infected with Plasmodium (either P. chaubadi chaubadi or P. falciparum) exhibited the same symptoms as humans infected with the parasites: They stopped eating and their blood sugar levels dropped along with their red blood cell counts. And as those red blood cells disappeared, the mice also stopped producing the genetic instructions for a key glucose-producing enzyme called G6PC1 in their liver cells.  

The team speculated that heme might be responsible for decreasing glucose production in the liver. They found that injecting heme into normal mice recreated symptoms of Plasmodium infection, including low blood sugar levels. These mice stopped eating as well, cutting off their external source of glucose. When the scientists examined the genes expressed in liver cells during Plasmodium infection and after heme injection, they found similar changes to expression profiles, particularly for genes related to metabolism. “Heme groups . . . go to the liver, and they stop the liver from producing glucose,” Soares tells The Scientist. 

“They nicely showed that heme, which is a product of the parasite, might be responsible for this down-regulation of hepatic glucose production,” says Van den Steen. Heme “appears to be a really important molecule and have a big effect on glucose production in the liver.”

Next, the researchers wanted to understand what effect the host’s low blood sugar had on the parasite. The researchers bred transgenic mice that don’t express the G6PC1 gene in the liver, meaning that they can’t produce glucose via this organ at all. In these mice, the number of infected red blood cells was lower than in control mice, indicating that low liver glucose production leads to conditions that are less favorable for P. falciparum.

To probe further, the researchers performed single cell mRNA sequencing on P. falciparum from the transgenic and control mice. The researchers found that in the absence of liver glucose production, Plasmodium starts producing gametes instead of blood cell–infecting copies of itself. It also stops actively transcribing so-called virulence genes, which are genes linked to disease. 

Plasmodium depends so much on glucose,” says Soares. Once the host’s glucose levels come down, the parasite “starts dying and needs to get out of this host. . . . What we found is that [it] activates a genetic program that allows it to go out,” he concludes.

Immunologist Dyann Wirth at the Harvard T.H. Chan School of Public Health, who didn’t work on the paper, says that it’s “quite interesting” and “a good addition to the literature,” but says that she’s unsure how applicable the mouse models are to humans. She’s concerned that the number of infected red blood cells in the mouse models is “very high compared to what occurs in most clinically relevant human infections.”

The researchers concede that their work needs to be confirmed in humans, but they say the findings might help improve treatment outcomes in the distant future. Soares speculates that the results indicate that it may “be difficult to treat people just by giving them glucose or not,” because delivering life-saving glucose might worsen the infection. And while he stresses that the work is basic research, he hopes that scientists can “adapt this knowledge and translate it” into future therapies.