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Trypanosomes in Spain
Unfortunately, the full protein exposure model is not likely to work with every pathogen. The trypanosome parasite that causes African sleeping sickness, for example, devotes a tenth of its genome—as many as 1,500 genes—to antigenic variation. NIAID’s Nash also points out that the relatively streamlined Giardia has “an extremely different mechanism” for shifting its surface proteins than the more complex trypanosome.
In the crossroads city of Granada, Spain, HHMI international research scholar Miguel Navarro is well down the path to explaining the molecular mechanisms and intricate nuclear architecture of Trypanosoma brucei, including how the parasite’s bloodstream stage expresses only one surface-protein gene at a time, the variant surface glycoprotein (VSG).
The key appears to be the dynamic association of chromosomes with structures in the parasite’s nucleus. Navarro’s laboratory at the Spanish National Research Council’s Institute of Parasitology and Biomedicine investigates “which molecules are involved in the [surface-protein] transcription switching that allows the parasite to elude the host immune response,” he says.
“These pathogens keep changing their coats, fooling whatever the immune system sends after them.”
Hugo D. Luján
Adopting techniques of both molecular and cell biology, Navarro uses three-dimensional microscopy and green fluorescent protein tagging to visualize the position of chromosomes in the nucleus and to investigate the position and dynamics of the telomeres—chromosome ends—that are active in antigenic variation.
The team has discovered that the African trypanosome mechanism for achieving its astounding surface variation is complex. Navarro’s recent research has focused on a protein complex—called the cohesion complex—that is essential for gluing together replicated chromosomes, or chromatids, when a cell divides. When Navarro’s group knocked out the protein complex in the trypanosome, it led to premature separation of the chromatids that contain genes for variable surface proteins. That interruption, in turn, caused a change in the antigenic switching of those proteins. These and previous findings have deepened the understanding of the trypanosome’s nuclear architecture and are helping researchers find ways to target the parasites.
Navarro first worked on antigenic variation in Cross’s laboratory from 1994 to 1998 and then moved to the University of Manchester in the U.K., where he published an influential 2001 paper in Nature. The paper reported that transcription of surface-protein genes is located in a specific area in the nucleus—called the expression site body—in such a way that only one surface gene is expressed at a time.
After returning to Spain, Navarro continued to explore the role of nuclear chromatin dynamics in antigenic variation. Cross says that Navarro’s research and related investigations are “starting to identify several genetic factors and structural attributes” of variant surface proteins that affect their switching.
“We don’t have the right tools yet to track and monitor artemisinin resistance, which is why I’ve shifted my attention on the drug-resistance side to Southeast Asia,” says Plowe. “We’re trying, in a much more accelerated fashion, what it took Tom Wellems 15 years to do in pinpointing chloroquine resistance.”
In a project that involves scientists at Oxford University, Mahido University in Thailand, and the U.S. Armed Forces Institute of Medical Sciences in Bangkok, Plowe’s lab is doing genomic studies to pinpoint gene loci that could be used as markers for that resistance. The goal is to give scientists around the world access to comprehensive data to help determine which antimalarial drugs should be used in which regions.
“The whole discussion of malaria eradication and elimination will come to a screeching halt if artemisinin resistance spreads throughout Asia and gets to Africa,” he says. “We’re trying to develop the tools to detect that resistance and head it off.”