Mar. 3, 2005 Rockville, MD – The genome sequence of the parasitic amoeba Entamoeba histolytica, a leading cause of severe diarrheal disease in developing countries, includes an unexpectedly complex repertoire of sensory genes as well as a variety of bacterial-like genes that contribute to the organism's unique biology.
The report, which appears in the February 24 issue of Nature, presents the first genome-wide study of an amoeba. It is also the first genome sequence to be published from this class of amitochondrial human pathogens.
The analysis reveals the degradation of the E. histolytica genome in its transition from a free-living organism into a parasite of the human gut. At the same time, scientists also cataloged the retention and expansion of some gene families characteristic of more complex organisms.
Detailing the first systematic study of relatively recent horizontal gene transfer into a protist, scientists report evidence in the DNA sequence that E. histolytica likely picked up a significant number of its metabolic genes from bacterial co-inhabitants of the human gut. Identification of these genes sheds new light on the unusual shared biology between the parasitic amoeba and anaerobic gut bacteria.
The E. histolytica genome sequence is expected to help in the development of new vaccines as well as diagnostic tests that can distinguish the amoeba's most deadly strains. The parasite infects an estimated 50 million people and causes as many as 100,000 deaths a year -- second only to malaria as a cause of morbidity and mortality from a protist. The disease caused by E. histolytica is called amebiasis.
The sequencing of E. histolytica was a collaborative effort led by The Institute for Genomic Research (TIGR) in Rockville, MD, and by the Wellcome Trust Sanger Institute in the U.K. The project was supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the National Institutes of Health, and from the Wellcome Trust.
The study's first author, TIGR scientist Brendan Loftus, says the contents of the amoeba's genome surprised many scientists. "The parts list we identified implies that E. histolytica may have re-engineered aspects of its metabolism," says Loftus, citing the protist's loss of some genes and its apparent gain of other bacterial-like genes through lateral transfer. "This study will provoke interest in what secrets may lie undiscovered in the sequences of other supposedly 'simple' amoeba genomes."
Named for its effectiveness in killing other cells, E. histolytica was long considered to be a 'primitive' organism – originating from the time that bacterial lineages diverged from eukaryotic lineages – because the amoeba lacked many of the visible traits of eukaryotic cells (such as endoplasmic reticulum, golgi apparatus and mitochondria) and also shared some bacteria-like traits.
While the Nature study catalogs a reduced genome (sometimes characteristic of an organism's transition to a parasitic lifestyle), Loftus says scientists found ample evidence of a variety of gene families characteristic of more complex organisms. For example, a family of membrane receptors appears to be one of the mechanisms by which the parasite senses the presence of its human host and translates environmental cues into signaling events, which are processed by the parasite.
Another unusual feature of the genome is the presence of an unprecedented number of tRNA (transfer RNA) genes, which constitute nearly 10 percent of the sequence data collected for the project. These genes appear to be present within the genome in long arrays whose structural or functional significance is not yet known.
"Clearly, this amoeba has genes that allow it to sense certain facets of its environment and respond to those cues," says Neil Hall, a TIGR scientist who is the senior author of the Nature study. He did most of his work on the E. histolytica genome while in his previous position at Sanger.
Matthew Berriman of Sanger said, "The results give a fascinating glimpse of how this ancient parasite evolved and highlight unusual metabolic processes that may be exploitable as drug targets."
The project also identified some large families of surface proteins that may help mediate the amoeba's ability to evade the human immune system. This could explain why the parasite can stay hidden in the body for years at a time. Such information may help researchers find better means to harness the immune system to eradicate infection through vaccine development.
A number of the metabolic adaptations and stratagems identified from the E. histolytica genome also have commonalities with those reported in two other amitochondrial human pathogens of global importance: Trichomonas vaginalis and Giardia lamblia.
"The enzymes that form the basis of these shared metabolic strategies are substantially different from human enzymes, making them potential targets of inhibitors that could form the basis of new drug therapies," says TIGR President Claire M. Fraser, who supervised the Institute's role in the project.
E. histolytica is a voracious predator of bacteria and shares a close relationship in the human gut with its bacterial neighbors. Because the parasite uses the same methods to kill bacteria as it uses to damage human cells and cause disease, the level of certain bacteria in the colon can be an important determinant of the amoeba's virulence.
Biomedical scientists say the E. histolytica sequence will help researchers develop new tools to predict which of the millions of people who ingest amoeba cysts in contaminated fluids will actually develop the disease.
"Every aspect of research is changed by having the genome sequenced," says Dr. William A. Petri, Jr., a collaborator who is chief of the University of Virginia Health System's Division of Infectious Diseases. He says the DNA typing from the genome sequenced is allowing the development of "new diagnostic tests that help distinguish the most deadly substrains of the parasite."
Dr. Alok Bhattacharya, a collaborator at the School of Life Sciences at India's Jawaharlal Nehru University, says having the genome sequence "will help to identify new drug and vaccine targets" and also may help researchers understand why the disease hits only a small fraction of those who are hosts to the parasite. "Intestinal infections are one of the major health problems in developing countries and the number of people who are infected with amoeba cysts is enormous," he says.
Typically, those cysts are transmitted when people ingest contaminated food or water. The disease can cause liver damage but more often causes dysentery, a severe diarrhea that is often associated with blood in the feces. Unchecked, the diarrhea associated with the disease can be fatal, especially in children. One field study in Bangladesh found that E. histolytica infection occurred at least once in 80 percent of 300 children. Over a period of four years, about a third of the children suffered from amebic colitis, an ulceration of the stomach lining.
Petri says the genome data will help researchers find more about what makes some people innately resistant to infection by E. histolytica, and what acquired immune responses can protect people from re-infection. Says Petri: "The genome project has spawned rapid discovery of the parasite's mechanisms for replication, gene expression, motility, metabolism, and the killing of host cells."
The Institute for Genomic Research (TIGR) is a not-for-profit research institute based in Rockville, Maryland. TIGR, which sequenced the first complete genome of a free-living organism, has been at the forefront of the genomic revolution since the institute was founded in 1992. The Institute's scientists conduct research involving the structural, functional, and comparative analysis of genomes and gene products in viruses, bacteria, archaea, and eukaryotes.
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