Monkey malaria is just a few steps away from becoming a major human disease. The big question is whether or not it will take those steps.

New research shows that Plasmodium knowlesi, a form of malaria common in monkeys in South East Asia, is capable of flourishing in people even though so far it rarely does.

"We were really trying to understand whether what is normally thought to be a zoonotic disease — transmitted from animals to humans — is actually becoming something that is now transmitted between humans," says Manoj Duraisingh, a professor of immunology and infectious disease at the Chan School of Public Health at Harvard. Duraisingh is one of the authors of a new paper on P. knowlesi malaria published in Nature Communications.

Over the last decade human cases of knowlesi malaria have been on the rise in parts of Southeast Asia. So-called "monkey malaria" has become the most common form of malaria now detected in hospitals and clinics in Malaysian Borneo. Patients with knowlesi malaria suffer from intense bouts of fever. The symptoms are so similar to regular garden-variety malaria that it's often misdiagnosed as one of the five other human strains.

"There is growing concern that this simian parasite is adapting to infect humans more efficiently," Duraisingh and his co-authors write in this new paper.

Most of the time the Plasmodium knowlesi parasites reside in forest-dwelling macaques. The parasites are well adapted to the monkeys. The pests can reproduce easily in the macaques' blood. Mosquitoes that feed on the primates then spread the parasites to more and more monkeys.

Until the last decade or so, knowlesi parasites and macaques were pretty much a closed loop. But as deforestation and the expansion of palm oil plantations in Malaysia have cut into the monkeys' natural habitat, people and macaques have come in closer and more constant contact. That proximity has led to more people being bitten by mosquitoes laden with knowlesi parasites.

"In many parts of Malaysia now it's the predominant malaria parasite that [doctors] actually see," Duraisingh says. The knowlesi parasite however generally doesn't reproduce as efficiently in human blood as in monkey blood because of a gene mutation — a complicated fork in the evolutionary tree — that happened 3 million years ago. Macaques got one gene. We got another. Our gene makes it much harder for knowlesi parasites to invade our red blood cells compared to those of macaques.

This explains why most of the human cases of knowlesi malaria are fairly mild.

But Duraisingh says his team noticed a subset of malaria cases in Borneo that weren't mild at all. For these patients, as the parasites multiply there are cyclical spikes of intense fever. Knowlesi malaria can be fatal but it does respond to standard malaria treatment if identified early.

These intense cases of knowlesi malaria made Duraisingh and his colleagues think that there's something going on with the knowlesi parasite that might allow it to become more dangerous.

"We thought that some of these [knowlesi] parasites might have a way of invading red blood cells and growing faster than other [knowlesi] parasites," he says.

In their lab Duraisingh found that the knowlesi parasite was able to find new ways to invade human red blood cells. They write: "It has been shown that P. knowlesi can expand its preferred host cell niche by invading older red blood cells and this is an important factor influencing adaptation of P. knowlesi to the human population."

The number of human cases of monkey malaria in Malaysian Borneo is still only a few thousand a year. (A mere pittance compared to the 200-plus million cases each year of falciparum malaria.) But this new research shows that the knowlesi parasite is capable of adapting to a life in new host. At least in the laboratory it can learn how to invade human blood cells quite quickly.

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