Giardia genome unlocked

Giardia lamblia, one of the most common human parasites in the United States, causes more than 20,000 intestinal infections a year, often through contact with contaminated drinking or swimming water. In the current issue of Science, an international team led by researchers at the MBL (Marine Biological Laboratory) describe the complete genome (genetic sequence) of Giardia, which could lead to the development of new drugs to combat this persistent infection, called giardiasis.

'Even though there are treatments now available, a number of people get chronic giardiasis, which is difficult to eliminate. So there is interest in new treatments,' says Hilary Morrison, PhD, of the MBL's Josephine Bay Paul Centre for Comparative Molecular Biology and Evolution, the first author on the paper. The Giardia parasite lives in the human intestine in a swimming and feeding form called a trophozoite, which is eventually expelled through the stools. Outside the body, Giardia takes the form of a highly infectious cyst that can live for weeks in water, soil, food, or on other surfaces.

Giardiasis is most common among children, especially those who are exposed to diaper changing. Swimmers, hikers, campers and others who drink untreated water are also prone to the infection (hence the nickname 'backpacker's disease' or 'beaver fever'), as are international travellers. Common symptoms include diarrhea, nausea, stomach cramps and gas, and usually persist two to six weeks. Because the parasite clings to intestinal cells that absorb fats and nutrients, giardiasis can lead to severe complications such as poor nutrient absorption and weight loss.

'Although not life threatening, Giardia is a rather fastidious parasite and quite important from an economical viewpoint worldwide and in the United States, where it constitutes a major cause of diarrheal disease in children in daycare centres,' says Mitchell Sogin, PhD, director of the Josephine Bay Paul Centre and leader of the Giardia study.

Analysis of the Giardia genome revealed several unusual proteins that are promising drug targets, Morrison says. 'These proteins are different enough from human proteins that if you affect them with a drug, it's not going to affect the human counterparts,' she says. 'Drugs can be devised that will interfere with the parasite's ability to replicate, or to move or bind in the small intestine, or to exist at all.'

The MBL team also investigated the evolutionary history of this ancient parasite. Giardia is a single-celled eukaryote, meaning its cell has a nucleus, as do the cells of humans and most other multicellular organisms. But the Giardia genome is compact compared to other eukaryotes, with simplified machinery for several basic processes, such as DNA replication and RNA processing. If the Giardia genome had originally been complex and experienced gene loss over evolutionary time, Morrison says, one would expect to see parts of the machinery intact and parts missing. This, however, wasn't the case. 'It looks like the genome was just simpler to begin with,' she says. The authors hypothesize that Giardia diverged from other eukaryotes more than a billion years ago.

'We embarked upon this genome project because of its importance to human health and suggestions from earlier molecular analyses that Giardia represents a very early-diverging lineage in the evolutionary history of eukaryotes,' Sogin says. 'Giardia's genome content and architecture support these theories about the parasite's ancestral character.'

Another important finding, Sogin says, is that the genes that allow Giardia to evade the human immune response are organized differently than in other parasites. In the host intestine, Giardia eludes an immune system attack by shifting the proteins it displays on its surfaces. The genes for these surface proteins are scattered throughout the Giardia genome rather than found in clusters, as in other parasites.

Along with Drs Morrison, Sogin and their MBL colleagues, collaborators on the project included researchers from the University of California, San Diego; the University of Texas at El Paso, University of Arizona College of Medicine; University of Illinois at Urbana - Champaign; Uppsala University in Sweden, the University of Zuerich; Boston University Goldman School of Dental Medicine; the Swedish Institute for Infectious Disease Control; the Salk Institute for Biological Studies; and the University of Pennsylvania. The research was funded by the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health (NIH). Since 1998, NIAID has supported the sequencing of many genomes of pathogenic microorganisms, including those considered emerging and re-emerging.