| 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.
“There are a number of reasons why it’s urgent to find
some way to treat those infected with C. parvum,”
says Striepen, who is also affiliated with the CTEGD. “Chronic
severe diarrhea caused by the parasite is a frequent and life-threatening
complication in AIDS patients, and the disease also causes significant
morbidity in children in many areas of the world, especially when
combined with malnourishment.”
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.
In 2000 and 2001, there were three drinking-water-associated outbreaks
in Northern Ireland, for instance, and several hundred cases of
illness discovered. Striepen says that the resistance of C.
parvum to standard drinking water treatments and its ability
to cause massive outbreaks have also caused concern among those
fighting bioterrorism and have led the Centers for Disease Control
and Prevention to list C. parvum as a category B pathogen.
Fortunately, the effort to sequence the genome of C. parvum
is nearly complete, giving researchers a powerful tool to study
how the organism works.
“One of the strengths of this research is that it combines
bioinformatics and experimental testing in the laboratory,”
says Striepen. “Using both approaches, we got to solid conclusions
fast.”
Striepen, in close collaboration with Jessica Kissinger’s
bioinformatics group, discovered something somewhat unexpected in
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. The loss of the entire
pathway for synthesis of pyrimidine was surprising, since recent
genetic analysis of Toxoplasma gondii, a related parasite
which causes encephalitis, showed that functional pyrimidine de
novo synthesis is “essential for the development, and hence
virulence, of this parasite in the host.”
What the UGA team has demonstrated in this paper is that the parasite
escapes this pinch by “salvaging” pyrimidines 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.
“Both the pyrimidine and purine synthesis pathways are unlike
those in related parasites that have been studied in the past,”
says Striepen. The ability to pick up genes from other organisms
by “gene transfer” is well known in bacteria (and the
reason why resistance to antibiotics is spreading so fast among
them) but a new concept in parasites.
As a result of gene transfers, the enzymes used by C. parvum
represent an “evolutionary patchwork, stitched together from
protozoan, bacterial, and potentially algal sources,” according
to the study.
“The finding that these parasites collect useful genes from
other organisms can help us to understand how they could adapt so
well to a parasitic lifestyle,” says Striepen. “From
an applied point of view, the discovery of a series of bacterial
[and therefore very different from human] genes gives us an exciting
list of new and highly ‘drugable’ targets.”
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. (A class of drugs called antifolates have
been widely and successfully used against the phylum of which C.
parvum is a part—the Apicomplexa.)
For now, C. parvum remains hard to kill. But information gleaned
from this study points the way to new drugs to treat cryptosporidiosis.
One intriguing possibility may be genetically engineered model parasites
created to express C. parvum genes.
This could allow a completely new approach to screen efficiently
for potential drug candidates, one of the next goals of the team
at UGA. |
