Is the ‘other’ malaria getting more dangerous?

Two new genetic studies of a parasite that causes malaria suggest that it may be evolving new ways to invade human blood cells. The development could make certain strains of the parasite more dangerous for populations who have some natural immunity. Now roughly 95 percent of people in sub-Saharan Africa — where the malaria burden is the highest — are thought to be resistant to the parasite in question, Plasmodium vivax. If the parasite were to overcome their genetic defense against the disease, it would potentially threaten hundreds of millions more people than it does today.

Vivax malaria is widespread in Asia and South America. Although less deadly than its cousin Plasmodium falciparum, which causes most malaria deaths, P. vivax is starting to be recognized as an important cause of serious disease across the globe. To enter human blood cells, the parasite usually uses the so-called Duffy blood group protein, a protein on the surface of red blood cells. But because up to 95 percent of the population across sub-Saharan Africa lacks the protein – a genetic trait called “Duffy negative” – they have long been thought to be protected from infection. Yet reports have emerged in recent years of Duffy-negative people who are nevertheless infected with vivax malaria. Peter Zimmerman, of Case Western Reserve University in Cleveland, and his colleagues have found, for example, that nearly 10 percent of Duffy-negative patients in Madagascar who had clinical malaria were infected with P. vivax.

Now, Zimmerman and his colleagues have found a genetic clue that might help to explain their clinical observations. They sequenced the genomes of several P. vivax strains from patients in Madagascar and found that they had two copies of the gene that codes for the Duffy-binding protein. The duplication occurred at higher rates in areas in which relatively more Duffy-negative patients have vivax malaria, the researchers reported last week at the American Society of Tropical Medicine and Hygiene annual meeting in Washington.

Because P. vivax can’t be grown in the lab, it is difficult to test how the extra copy of the gene might change the parasite’s behavior. But Zimmerman thinks that the duplication may be somehow helping the parasite to invade Duffy-negative blood cells. It’s still just an association, he says, but “two things are happening in Madagascar that are unusual in the rest of the world,” the Duffy-negative infections and the gene duplication. The genetic signature of the extra copy suggests it may be a relatively recent mutation, he says.

In a second study presented at the meeting last week, David Serre of the Cleveland Clinic’s Genomic Medicine Institute reported that he and his colleagues have found a previously unidentified gene in a P. vivax strain from Cambodia that seems to code for another protein that helps the parasite invade blood cells. The gene is present in strains from around the world – but is missing in the first strain of P. vivax to be sequenced – which provided the “reference strain” for the species. That was a strain that had adapted to infect lab monkeys, because the parasite can’t be grown in the lab. Serre says the lab-tamed parasite may have lost the gene, which is why it wasn’t found in the reference sequence. The gene may also be playing a role in Duffy-negative infections, he says.

That is “biologically plausible,” says Kevin Baird, of the Eijkman-Oxford Clinical Research Unit in Jakarta. But it’s not yet clear whether Duffy-negative infections are an emerging phenomenon or have been present, undetected, all along. “It is certainly worrying and deserves thorough investigation,” he says.