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Thursday, September 27, 2007
Scientists Sequence Genome of Intestinal Parasite that Afflicts Hikers and Kids in Daycare
Giardia lamblia is a strange-looking parasite that swims in the gut, spreads through stool, persists in contaminated water, and is responsible for more than 20,000 reported infections a year in the United States. Now it has finally spilled its genetic secrets.
In the September 28, 2007, issue of the journal Science, an international team of researchers led by scientists at the Marine Biological Laboratory (MBL) in Woods Hole, MA, and funded by the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health (NIH), describes the complete genetic sequence of the parasite.
The bane of hikers drinking from mountain streams and of small children in daycare, G. lamblia is the most common intestinal parasite identified by public health laboratories in the United States, according to a 2005 report by the Centers for Disease Control and Prevention. Analysis of its genome has already shed light on the organism's evolution and revealed opportunities for future research.
"Existing drugs can effectively treat people with Giardia infections, but as with many pathogens, the concern is that the parasite will develop resistance to these medications," says NIAID Director Anthony S. Fauci, M.D. "The Giardia lamblia genome shows us that the parasite has a large complement of unusual proteins that are potential targets for new drugs or vaccines."
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.
Giardia performs this molecular chicanery so well that half of all people who are infected are unaware that they even harbor the parasite. Symptoms for the unfortunate other half include nausea, diarrhea, bloating and abdominal cramping. Because trophozoites cling to intestinal cells that absorb fats and nutrients, such infections can lead to severe complications such as poor nutrient absorption and weight loss.
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.
The completed genome is a publicly available resource that should help advance research on new ways to treat or prevent Giardia infections because it provides scientists with a comprehensive dossier of the parasite's genes — often an important first step in designing potential new drugs and vaccines. These "targets" include genes the parasite uses to make proteins involved in crucial stages of infection, evading the immune system, shifting between its two forms and feeding.
Besides providing new drug and vaccine targets, the parasite's genome also has provided clues to its evolution. An evolutionary curiosity, Giardia is a member of the protist kingdom, which with the animal, plant and fungi kingdoms make up the domain of eukaryotes. All eukaryotic organisms share certain key characteristics — chief among them, a defined nucleus containing genetic material.
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.
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 Karolinska Institute in Sweden; the Salk Institute for Biological Studies; and the University of Pennsylvania.
Since 1998, NIAID has supported the sequencing of many genomes of pathogenic microorganisms, including those considered emerging and re-emerging, as well as potential agents of bioterrorism. For more information about NIAID's large-scale sequencing efforts, see: http://www.niaid.nih.gov/dmid/genomes/mscs/.
Giardia lamblia sequence data is freely available to the scientific community and the public through GenBank, an Internet-accessible database of genetic sequences maintained by the National Center for Biotechnology Information (NCBI) at NIH's National Library of Medicine. To access GenBank, see http://www.ncbi.nlm.nih.gov/Genbank/GenbankSearch.html. To view a graphic illustrating the life cycle of Giardia lamblia, see http://www3.niaid.nih.gov/news/newsreleases/2007/giardiaImage.htm.
NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.
News releases, fact sheets and other NIAID-related materials are available on the NIAID website at http://www.niaid.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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H Morrison et al. Genomic minimalism in the early diverging, intestinal parasite, Giardia lamblia. Science 10.1126/science.1143837 (2007).