There must be a way to topple a pathogen’s defenses. Hugo Luján, Miguel Navarro, and Isabel Roditi are finding ways to give the human immune system a chance against fast-changing infectious agents.

A handful of HHMI researchers are bringing determination and creativity to the fore. A bit like high-tech tailors examining and testing surface-protein garments, they are pushing a parasite to overload its coat and reveal all its defenses, investigating how the cloak is manufactured, and studying the role of the insect vectors that transfer the parasite to the human host. Their aim is to help develop treatments or vaccines for a wide range of masters-of-disguise microbes, including those that cause African sleeping sickness, diarrheal disease, and Lyme disease (see sidebar, “Another Shot at Lyme Disease”).

The challenge is not new. A century ago, researchers experimenting with Trypanosoma brucei-infected monkeys in the laboratory of Nobel Prize winning biochemist Paul Ehrlich first uncovered evidence of antigenic variation, reporting that the trypanosomes “have acquired other biological properties … that rendered them resistant to the defensive substances.” It took another seven decades before molecular parasitologist George A.M. Cross of the Rockefeller University in New York identified the molecular basis for antigenic variation in the African trypanosome. Since then, such variation has been studied in numerous parasites as well as bacterial and viral pathogens.

		Another Shot at Lyme Disease The first vaccine that Erol Fikrig helped develop against Lyme disease targeted a surface protein of the Borrelia burgdorferei bacterium. That approach was good, but it didn’t guarantee protection against the disease. Now he’s taking a different approach: targeting a protein in tick saliva that helps the pathogen infect the host. Read More

Many molecular details of antigenic variation remain inscrutable, says Cross, in part because of the complex cellular mechanisms involved. Even so, he is optimistic that scientists may find ways to slow down the rate of surface-protein switching and give the human immune response more leverage to control infections.

Giardia in Argentina

At his lab in Argentina, Luján has found a way to force the Giardia parasite to reveal nearly all its surface-protein defenses at once. In doing so, he has made progress in developing a vaccine to prevent the diarrheal infection caused by the parasite and created a model for attacking other pathogens with similar antigenic talents.

Giardia—which can evade the human immune response and survive as a cyst in adverse conditions—is a common cause of parasitic gastrointestinal disease, leading to as many as 2.5 million cases of giardiasis each year in the United States. It is estimated that nearly one-fifth of the world’s population is chronically infected.

Luján became interested in Giardia’s antigenic variation while he was a postdoc in the lab of Theodore E. Nash, head of the gastrointestinal parasites section of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. Nash, who first reported antigenic variation in Giardia, says the Argentinian was “a real star in my lab.” Later, Luján helped reveal that, from a repertoire of about 200 genes that encode surface proteins in the Giardia genome, only one is expressed at any one time on the surface of the parasite. By the time the human immune system identifies and tries to knock out one set of surface armor, the parasite—with a wardrobe of a couple of hundred different protein armor sets—has shifted to another set.

In a December 2008 Nature paper, Luján and colleagues showed that antigenic variation in Giardia is regulated by RNA interference, a mechanism that eliminates all but one of the surface proteins at any given time. Then, in a paper in Nature Medicine in May 2010, Luján’s group reported evidence that parasites engineered to express nearly all of their surface proteins at once could be used to rally an infected host’s immune system.

His group purified all the antigens expressed by those engineered parasites and used them to create a vaccine. They administered it orally to gerbils—first making sure the vaccine’s proteins could withstand the harsh environment of the gastrointestinal tract. It worked, successfully protecting the animals from future infections. “We were the first to demonstrate that, since the parasites continuously change their surface proteins, we must use all of the possible variants to confer full protection to subsequent infection.”

His lab has since shown that its vaccine approach works in dogs as well, and Luján is seeking a partner to try the approach on humans. In addition, he says, other researchers are now using the strategy, including a scientist at the Pasteur Institute in Paris who is investigating several candidate drugs that would promote the expression of all surface variants of the malaria parasite.

Photos: Luján and Navarro: David Rolls Roditi: Dirk Dobbelaere

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