New Genetic Protection from Malaria Found in Mice

By Davide Castelvecchi

A number of genetic factors are known that give immunity — or at least a higher chance of survival — from malaria. A new one has been identified in mice, and may yield new insights in the fight against a disease that kills more people every day than have died in the entire SARS epidemic.

A team at McGill University in Montreal looked at two inbred strains of mice that are unusually resistant to Plasmodium chabaudi, the closest analogue to the human single-cell parasite. Part of the team had contributed to the discovery of this resistance in 2001. When inoculated with Plasmodium, the rodents get sick but have a high chance of surviving; however, they appear to have a mutation that causes the premature death of red cells in their blood. As a consequence, they suffer from anaemia and reticulocytosis, the presence of abnormally high numbers of red cell precursors.

By breeding the mutant mice with normal ones, the McGill team, led by Philippe Gros, tracked down the cause of reticulocytosis to one candidate gene. Indeed, DNA sequencing revealed a mutation in the gene that encodes an enzyme called Pyruvate kinase (PK), essential for the metabolism of red cells. The mutant mice had no PK at all.

“That raises the question that if you don’t have the enzyme, then the mutant cell is protected from malaria,” Gros says. PK deficiency could protect the mice indirectly, by killing the adult cells which are the parasite’s host. The Plasmodium might find it harder to reproduce inside red cell precursors, or it might have a harder time getting in them to begin with. If that is the case, the discovery wouldn’t help in developing a therapy, says Gros, because inducing anemia in a patient could do more harm than good.

But there is another possible explanation. The parasite is known to need PK to live and reproduce inside red cells. “It needs so much of it,” says Gros, “that it actually makes its own that is secreted inside the red cells. One possibility is that early during infection — and before it turns on its own — the parasite needs the host’s PK.”

It might then be possible, Gros says, to induce PK deficiency, and hence protection from malaria, in developed red cells — as long as one can find a way to do that without killing the red cells (Nature Genetics doi:10.1038/ng1260).

It’s too early to tell if the research will go anywhere, says Sarah Tishkoff of the University of Maryland, but it’s worth trying. “It’s exciting that it’s giving a candidate for a gene to look at,” she says.

The next step will be to find out if the same deficiency protects humans, by infecting red cells in vitro. “Right now, we’re looking for patients who have Pyruvate kinase deficiency to take small samples of their blood,” says Gros.

Note: This was a science reporting assignment in one of my classes in the Science Communication program at UCSC. The assignment was to generate a story idea, interview scientists, and write a short news story, following the style of New Scientist magazine.


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