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 September 28 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, Ph.D., of the MBL's Josephine Bay Paul Center 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 travelers. 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.
Giardia spends one phase of its lifecycle in the environment and the other in the gut of an infected human or wild animal. To maintain this dual existence, the parasite has two radically different microscopic forms.
In water, Giardia exists as a hardy, highly infectious cyst, which can survive for months, even in fresh water devoid of all nutrients. In the gut, Giardia exists in a swimming and feeding form known as a trophozoite.
The awakening of the dormant cyst happens quickly after someone swallows contaminated water or food. After the cysts encounter the warm acidic juices in the stomach, they change into trophozoites. Within about two hours, these trophozoites will be swimming in the intestines.
Unlike many other parasites, trophozoites do not invade tissues or cells. Instead they simply attach to cells, drink in nutrients and multiply. The parasite evades the immune system and persists in the intestine by shifting the proteins it displays on its surfaces.
Existing drugs can effectively treat people with Giardia infections, the disease known as giardiasis, but most infections resolve on their own. When trophozoites detach from the intestinal wall, they may swim and reattach to new intestinal cells, or they may pass down the digestive tract and into the bowels, transform back into cysts and be passed through the stools.
"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 centers," says Mitchell Sogin, Ph.D., director of the Josephine Bay Paul Center 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 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."
Eukaryotic organisms are so diverse that they include everything from amoebae to humans. But even within such a wide range, Giardia is unusual. In its trophozoite form, it has two nuclei instead of the more usual one. When it becomes a cyst, it multiplies its genetic material into four identical nuclei. But despite having these multiple copies of its nuclei, Giardia is really a genetic minimalist. It has fewer and simpler genetic components than most other eukaryotes.
Why? According to one theory, Giardia is simple because it has lost complexity: evolutionary pressure favors parasites that shed genes coding for functions they can borrow from their infected hosts. An alternative theory holds that the parasite may have always been simple because it diverged from other eukaryotic organisms more than a billion years ago, long before the complex modern eukaryotes emerged.
Hilary Morrison, Ph.D., and Mitchell Sogin, Ph.D., of MBL, who led the study, say their findings support this latter theory. Careful analysis of the genome reveals that Giardia’s molecular machinery -- even for the most basic processes usually shared by other eukaryotes -- is simple by comparison. This suggests that it has always been so. Its parasitic niche has allowed it to maintain its simple genetic makeup for billions of years -- long before it started showing up at daycare centers.
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 Zürich; 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).
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