Malaria Parasites Use "Cloaking Devices" to Trick Body

Amitabh Avasthi
for National Geographic News
October 8, 2008
Malaria parasites use elaborate forms of deception, such as molecular mimicry, to fool the human immune system, new gene studies say.

The discovery could lead to new vaccines for the disease, which kills millions and is rapidly becoming resistant to treatment.

Gene sequencing of two parasites, Plasmodium vivax and Plasmodium knowlesi, comes six years after researchers unraveled the genome of Plasmodium falciparum, the malaria parasite that causes the most fatal infections worldwide. Gene sequencing determines the order of chemical building blocks in a species's DNA.

While P. vivax is rarely fatal and causes less severe infections, it accounts for more than a third of about 500 million infections, most of them in Asia.

"The P. vivax parasite can lie dormant in the liver, and patients can get infected months, even years, after the first infection," said Jane Carlton, a parasitologist at the New York University Medical Center, whose team sequenced P. vivax.

"You cannot eradicate malaria unless you eradicate P. vivax," said Carlton, who co-authored one of a pair of related studies to be published tomorrow in the journal Nature.

A Stealthy Species

Malaria infections begin when parasites are injected into humans via mosquito bites. Once inside the body, the parasites enter the bloodstream and are quickly carried to the liver.

There, the parasites grow into a form that lets them infect red blood cells and proliferate. Subsequent mosquito bites ferry the parasites to others—and the infectious cycle continues.

Carlton and her team have discovered sets of genes and proteins that help the parasite successfully invade red blood cells and evade the immune system.

"Once the parasite is inside a red blood cell, it produces certain proteins to coat the surface of those cells," Carlton explained.

Continuous changes on the surfaces of the red blood cells prevent the body's defense mechanisms from detecting the parasites.

Among the 5,433 genes in the P. vivax genome, the researchers found 346 that help the parasites trick the immune system.

Carlton and her colleagues have yet to identify the mechanism that helps P. vivax lie dormant, but they believe that discovery is in sight.

"We found genes in the P. vivax genome that seem to be related to genes found in dormant stages in other organisms such as yeast," Carlton explained. "This is like a first foot on the ladder."

Cloaking Device

In the related study, researchers announced the gene sequencing of P. knowlesi, a monkey parasite that is now recognized as a significant cause of human malaria.

In certain parts of Southeast Asia, where people live near monkeys and mosquitoes, P. knowlesi appears to cause human infections in fairly large numbers.

Arnab Pain is lead author of the study and a researcher at the Wellcome Trust Sanger Institute in Cambridge, England.

Like researchers in the P. vivax study, Pain and his colleagues found a family of genes that coats the surface of infected red blood cells with proteins to dodge the immune system—but with a twist.

"We found a small subgroup of genes [with] segments of amino acids that are exactly identical to a key protein—CD99—found on host cells," Pain said. "The match is exact in monkeys, and a close one in humans."

Molecules of CD99 play a critical role in regulating the immune system. Researchers believe the parasite may be masking itself to interfere with recognition by the body.

"This is a unique case of molecular mimicry and the first of its kind in a malaria parasite," Pain said. While the precise molecular mechanism behind the mimicry is unclear, he believes it is probably part of the parasite's evolutionary strategy.

Relapse Prevention

Donald Krogstad is a molecular geneticist at Tulane University in New Orleans. He has just concluded human safety tests of new antimalarial drugs and is about to begin human clinical trials in the African country of Mali.

The P. knowlesi and P. vivax genomes share similarities with those of other malaria parasites, so drugs effective against other malaria strains could attack P. vivax as well.

P. vivax is the primary target, because it tends to relapse, and has become largely drug-resistant in Asia.

But the full picture of what makes one malaria strain more virulent than the other remains unclear.

"Relapse occurs in a number of strains with predictable time intervals. Some strains relapse in a month, and others in six months," Krogstad noted.

"It is not clear what is driving the parasite clock for turning on those relapses. That is an unknown and unanswered biological question."

The two studies could unravel the kinds of genetic changes that give the parasites their varying virulence. And they might help explain why P. falciparum infections cause death while P. vivax causes less severe, relapsing infections, said Nirbhay Kumar of the Johns Hopkins Malaria Research Institute in Baltimore, Maryland.

Finding the "meaning" of a genome sequence is far from simple, however.

"Having a genome sequence is like having a dictionary," he said. "It doesn't mean you know the spelling of each and every word, unless you know which word you are looking for."

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