The Parasite Puzzle

New Ideas / by Joe Kloc /

How one of Africa’s deadliest pathogens uses on-the-fly, genetic costume changes to outsmart our immune system.

Illustration: Joe Kloc

Death takes many forms in sub-Saharan Africa. It sometimes comes without warning, brought by wild animals, droughts, or wars. But often it’s more subtle, floating from person to person as an almost unstoppable parasite. Recently, a team of researchers at Rockefeller University set out to understand more about how one of Africa’s deadliest pathogens is so good at outfoxing the human immune system.

The parasite Trypanosoma brucei, which causes African sleeping sickness, exists almost exclusively in Africa’s sub-Saharan region. It moves between humans by way of the tsetse fly’s bite, entering the host’s bloodstream, often causing confusion, tiredness, insomnia, and eventually death.

Our immune system hunts and kills invading parasites like T. brucei using B-lymphocytes, which detect pathogens and produce custom antibodies to attack them. B-cells determine what type of antibodies to fight an invader with based in part on the structure of the proteins on the surface of the invading cells. But the T. brucei parasite responsible for African sleeping sickness has evolved to hide from antibodies by constantly rearranging its surface proteins. The immune system then has to produce new antibodies to attack the parasitic cells. And by the time these new antibodies are produced, the parasite has again changed its disguise. It’s a back-and-forth battle of one-upsmanship that the immune system never wins.

“The problem is that even if 99.99 percent of parasites are eliminated, the fraction that remain have already switched their surface proteins. So to the antibodies in the blood, they now look like a totally different parasite,” says Nina Papavasiliou, who led the Rockefeller study of T. brucei.

A running theory among scientists who study T. brucei proposed that protein switching is initiated by breaks in the cell’s DNA; once these breaks occur, the resulting strands then shuffle their genetic information with one another by a process known as gene conversion. The result is that the cell develops a fresh protein coat that acts like camouflage, hiding it from its host’s immune system.

Papavasiliou’s team was able to test and confirm this hypothesis for the first time by using an enzyme found in yeast to deliberately sever the parasite’s DNA. They showed that the switching process only happens when the DNA is broken in specific locations.

“This is an unprecedented finding about the protein switching that has made a vaccine elusive despite 100 years of research,” says Enock Matovu, a parasitologist at Makerere University in Uganda. According to Matovu, who won the Royal Society Pfizer Award in 2008 for his work with T. brucei, the next step in combating the parasite is finding a way to prevent it from breaking its DNA and rearranging its surface proteins. Discovery of such an inhibitor would “provide a breakthrough in conquering African sleeping sickness,” Matovu says.

“It turns out that a lot of the principles behind T. brucei’s success are operating in the human immune system as well,” says Papavasiliou. Our antibodies rearrange their DNA in order to attack parasites. But what seems to give the parasite the advantage is that it knows exactly when to switch disguises to evade the immune system’s response. If the parasite switches its appearance too quickly, it will run out of disguises. And if it waits too long, antibodies will kill it off. But by switching at exactly the right moments, it continually strings the immune system along, exhausting its capacity to make more cells. How these parasites developed this rope-and-dope strategy remains a mystery.

“It’s a weird puzzle,” Papavasiliou says. And it gets weirder. T. brucei parasites all seem to follow the same strategy when switching their surface protein coats. Even when parasites are in two separate human hosts, the probability is very high that after the same number of protein switches they will be wearing very similar disguises. “There is some kind of hierarchy to their switching,” she says, which is controlled by something encoded into this parasite that presumably has evolved through millions of years of battling mammalian immune systems.

“It’s kind of cool,” Papavasiliou says, “I mean, nasty, but cool.”

Originally published April 27, 2009

Tags disease dna genetics medicine pandemics resilience

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