Dr Hugo D. Luján of Catholic University of Córdoba in Argentina and the Howard Hughes Medical Institute, has found that the Giardia lamblia parasite changes its shape when meeting the human immune system. The parasite causes about 200 million cases of diarrhea each year, and the research into its function is helping to develop a genetically modified strain that can serve as a possible vaccine for the disease.
The Giardia genome contains nearly 200 genes that code for surface antigens. Despite the large number of genes, each parasite displays only a single antigen—derived from a single gene—on its surface at any given time. Normally, the RNA instructions for each gene are copied from the parasite’s DNA then run through the cell’s internal machinery to create proteins, including surface antigens. As Luján and his group delved into this mystery, he discovered that the molecular machinery in the parasite actually reads and transcribes most of the 200 surface antigen genes, but only one antigenic protein makes it to the outer coat on the parasite’s surface.
That observation suggested to Luján that the RNA instructions—called messenger RNA—had been created and were inside the organism, but something was stopping the RNA from being translated into proteins and expressed on the cell’s surface. “That was a surprise,” Luján said. “Because it takes a lot of energy for the organism to transcribe all of those genes into messenger RNA.”So Luján sought to find out why most of the parasite’s RNA never gets translated into a working surface antigen. Something must be interfering with that process for Giardia’s surface antigens.
He suspected that a powerful cellular mechanism called RNA interference, or RNAi, might be the cause of the holdup. Discovered a decade ago, RNAi identifies short segments of RNA and then destroys all RNA that matches the segments. The result: None of the protein that would have been created by that RNA is released into the cell. Researchers originally found that RNAi is a protective mechanism that helps cells fight off invading viruses. But as the new work by Luján shows, the process can also control which genes are switched on and off in Giardia.
In a series of experiments, Luján found that the cellular machinery involved in RNAi squelches most of the RNA in Giardia that codes for surface antigens. At any given time, in fact, only the RNA for a single type of antigen is left untouched. The rest is destroyed. “At that point, we realized RNAi was strongly linked to antigenic variation,” Luján said.
Next, Luján inhibited the enzymes involved in RNAi in Giardia. Again, he made a surprising discovery: The cells with defective RNAi machinery displayed many surface antigens simultaneously—a kind of parasitic Technicolor dream coat. “That was the direct link between enzymes involved in the RNAi pathway and antigenic variation in Giardia that we had been looking for,” Luján said.
Full story at HHMI: New Research Reveals How Giardia Parasite Changes Its Appearance …