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In 1993, a water-borne
parasite in Milwaukee was responsible for an estimated 403,000
cases of acute gastrointestinal disease, and the outbreak
revealed that patients with AIDS are at an especially grave
risk. About half of Milwaukee’s residents with AIDS
were infected with the parasite, 68 percent of whom died within
six months. This parasite, Cryptosporidium parvum, is highly
resistant to standard water treatment, which has caused additional
concerns over its potential use in bioterrorism.
Now, a team of UGA biologists led by Boris Striepen has discovered
that the parasite, in order to survive, depends on so-called
“salvage enzymes” to steal away nutrients from
its host. The discovery provides new targets for drug design
to treat victims of this parasitic disease, for which there
is currently no effective cure.
The findings were published last month in the Proceedings
of the National Academy of Sciences. Co-authors of the paper
are Jessica Kissinger, Andrea Pruijssers, Jinling Huang, Marc-Jan
Gubbels, Catherine Li and Nwakaso Umejiego of UGA’s
Center for Tropical and Emerging Global Diseases and Lizbeth
Hedstrom of the department of biochemistry at Brandeis University.
Outbreaks of disease caused by the parasite are not uncommon
in the United States and other industrialized nations, and
Cryptosporidium has become the most important contaminant
found in drinking water. Striepen says that the resistance
of C. parvum to standard drinking water treatments and its
ability to cause massive outbreaks have led the Centers for
Disease Control and Prevention to list C. parvum as a category
B pathogen.
Striepen, in close collaboration with Jessica Kissinger’s
bioinformatics group, discovered something somewhat unexpected
when they studied the genome of the parasite: The parasite
has lost the ability to synthesize a group of compounds called
pyrimidines, which are crucial building blocks of DNA in any
living organism.
Instead of synthesizing pyrimidines, the parasite “salvages”
them from the cells of its host. While parasites usually salvage
nucleotides of another crucial genetic compound, purine, from
their hosts, this is the first evidence of a parasite using
pyrimidine only from the cells it infects. Further analysis
reveals that the parasite is not only salvaging the DNA building
blocks but has also salvaged some of the genes involved in
this process.
The fact that the parasite thrives in a different way from
others may also explain why no drugs have been found thus
far to treat the infections it causes. Information gleaned
from this study points the way to new drugs to treat cryptosporidiosis.
This could allow a completely new approach to screen for potential
drug candidates, one of the next goals of the team at UGA.
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Boris
Striepen and his colleagues in the Center for Tropical and Emerging
Global Diseases are combining bioinformatics with experimental testing
to understand parasitic diseases.
