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New Discovery May Help Lead to Treatments

For the first time a team of researchers led by the University of Minnesota and Weill Cornell Medical College has determined the complete genome sequence of Cryptosporidium, a common diarrhea-causing parasite that can lurk in drinking water. The finding has been published in the March 25 issue of the electronic journal Science Express, to be followed by publication in April in the print version of Science.

Cryptosporidiosis is a hard-to-treat condition, largely because we lac ka basic understanding of the genetic make-up of the organism, said Dr. Mitchell Abrahamsen, principal investigator, faculty of the University of Minnesota College of Veterinary Medicine and Biomedical Genomics Center, where the genome sequencing was carried out.

The completion of the genome sequence represents the greatest advancement in our understanding of the organism, said Dr. Thomas J. Templeton, a co-first author of the study and Assistant Professor of Microbiology and Immunology at Weill Cornell Medical College and Weill Cornell Graduate School of Medical Sciences in New York. Currently there are no drug treatments for Cryptosporidium,and through genome sequence annotation, we have identified many new drug targets that may lead to new pharmaceuticals to treat the illness.

Cryptosporidium parvum is a protozoan and its infectious agent, called an oocyst, cannot be killed by the chlorine typically used to kill germs in drinking water. If the oocysts are swallowed, either from contaminated drinking water or food, the parasite can wreak havoc on the intestines. While those with healthy immune systems may suffer from diarrhea, abdominal pain, and fever, the parasite can be deadly for those with weakened immune systems, particularly AIDS patients.

Although healthy individuals rapidly recover from cryptosporidiosis, no drug therapy exists for treating people, and the parasite can cause an unrelenting infection in AIDS patients, said Dr. Templeton. This is a particular problem in some parts of the world, such as Africa, where HIV drug regimens are often unavailable.

And an infection can be acquired as easily as taking a drink of water or eating the wrong food.

Cryptosporidium has caused huge outbreaks in the US and Canada, including a 1998 outbreak involving 400 people that was traced to a diaper-contaminated drinking fountain at a Minnesota zoo. In 1993, a breakdown in a water filtration plant resulted in 400,000 cryptosporidiosis cases and 100 deaths in Milwaukee.

The parasite has also been found in contaminated ponds, lakes, and swimming pools with inadequate filtration, as well as in oysters and uncooked food washed in tainted water. Although tap water is generally considered safe, officials in some cities have recommended that HIV-infected individuals, particularly those with weaker immune systems, boil tap water to eliminate the risk of cryptosporidiosis.

Despite the risk to humans, Cryptosporidium has proven difficult to study. The parasite lurks inside cells of the gastrointestinal system during one stage of development, an environment that is hard to replicate. Cryptosporidium cannot be propagated continuously in the laboratory, and therefore cannot be genetically manipulated, said Dr. Templeton.

In the Science study, Dr. Templeton and a team of University of Minnesota researchers, led by Dr. Abrahamsen, studied Cryptosporidium DNA collected from oocysts found in the feces of infected calves. Description of the genetic makeup of the parasite was also aided by the invaluable expertise of the research group of Dr. L. Aravind at the National Center for Biotechnology Information in Bethesda, Maryland.

Genetic sequencing revealed a relatively pared-down organism with only 9 million DNA base-pairs, the building blocks of DNA, and eight chromosomes, the tightly coiled packets of DNA. In comparison, the malaria-causing parasite Plasmodium falciparum has 23 million base-pairs and 14 chromosomes. In contrast, humans have 3.2 billion base-pairs and 46 chromosomes.

This streamlined metabolism means that the parasite is supremely dependent on its host, and the researchers found the germ lacks some essential structures found in bacteria and other parasites. For example, Cryptosporidium lacks functioning mitochondria, the energy-generating structures found in most cells. This leaves the germ completely dependent on its host for nutrition.

Cryptosporidium is an 'extreme parasite,' in that it has a highly streamlined metabolism and cellular structure that makes its survival dependent on the cells lining the intestines, said Dr. Templeton. We hope to take advantage of that fact and find drugs that can halt the parasite.

Already the researchers have identified several unique enzymes and novel cell-surface and secreted proteins that could be potential Achilles heels for Cryptosporidium, according to the report.

The genome sequence has identified the genes and biochemical pathways in the parasite, providing a starting point for defining the mechanisms by which the organism causes disease, and thereby helping devise new strategies to detect, prevent and treat infection in humans and animals, said Dr. Abrahamsen.

Besides the University of Minnesota and Weill Cornell Medical College, the study's co-authors are from Tufts University, Texas AM University, Virginia Commonwealth University, and the National Center for Biotechnology at the National Institutes of Health (NIH).

The study was funded by the National Institute of Allergy and Infectious Diseases at NIH.