July 15, 2005
Trypanosome Genomes May Reveal New Drug, Vaccine Targets
Cells from mammals infected with T. cruzi. The green color results from labeling with antibodies directed to a protein on the surface of the trypanosome.
A team of international scientists has sequenced the genomes of
three species of parasites responsible for causing diseases that kill
or cripple millions, primarily in tropical and sub-tropical countries.
Howard Hughes Medical Institute (HHMI) scientists who participated in
the project say the sequencing of the genomes of the parasitic protozoa
that cause Chagas disease, African sleeping sickness, and
leishmaniasis, could significantly impact world health. Some of the
genes discovered may prove to be good drug and vaccine targets.
The research is published in a special issue of the journal
Science focusing on the genome sequences of Trypanosoma
brucei, Trypanosoma cruzi, and Leishmania
major and the public health threat that these parasites represent.
One of the studies' key findings is the identification of gene
sequences that are involved in the host-parasite relationship and in
the regulation of the parasite metabolism.
“This study will advance tropical medicine by helping us develop new drugs against these diseases.”
Shulamit Michaeli
Another important finding, according to Mariano Levin, a co-author
of the T. cruzi paper, is that scientists now know what the
three trypanosomes have in common. “We know that they share 6,000
genes, and 2,000 of those genes are found only in these three
parasites,” said Levin, a HHMI international research scholar at
the Institute for Research on Genetic Engineering and Molecular Biology
in Buenos Aires, Argentina. “This is extremely important because
among those 2,000 genes, you may be able to find targets for drugs that
will only affect the parasite and not the host.”
Shulamit Michaeli, a HHMI international research scholar at Bar-Ilan
University in Israel and co-author on the L. major
paper, also is optimistic about the impact of the work on drug
development. “By providing information on virulence factors,
critical enzymes in key metabolic pathways, and potential vaccine
candidates, this study will advance tropical medicine by helping us
develop new drugs against these diseases,” she said.
Alberto Frasch, a HHMI international scholar from Argentina, agrees.
“Having a sequenced genome should aid us immeasurably in finding
new drugs,” said Frasch, who is director of the Institute for
Research in Biotechnology of the National University of General San
Martin in Buenos Aires and an author on the T. cruzi and
L. major papers. Frasch explained that the drugs
currently available to treat diseases caused by trypansomes
“either have toxic side effects or lack efficiency in some stages
of infection, as in chronic Chagas disease.” “Also,”
he said, “drug resistance in diseases caused by trypanosomatids
complicates their treatment. The information obtained from genome
analysis might help us understand the resistance mechanisms to drugs
now used.”
Trypanosomes are a type of single-celled microorganism that has
developed elaborate schemes to evade the immune systems of their hosts.
They are spread to humans through contact with infected animals.
Trypanosoma cruzi causes Chagas disease, a devastating public
health problem in Cental and South America and Mexico, while
Trypanosoma brucei causes African sleeping sickness, and
Leishmania major causes leishmaniasis.
African sleeping sickness, which affects people living in
sub-Saharan Africa, is characterized by early fever and progresses to
heart and kidney dysfunction, neurological destruction, and eventual
death. Fever and heart impairment are also hallmarks of Chagas disease,
which infects 16 to 18 million people, causing severe chronic illness
and tens of thousands of deaths per year. Heart failure is responsible
for most deaths from Chagas disease, which also causes liver problems
and neurological impairments that can affect swallowing. Fever and
liver disorders characterize leishmaniasis.
The sequencing of the trypanosome genomes presented significant
challenges, according to Michaeli. Certain characteristics of the
trypanosomes' genome made thistask particularly tricky, she said.
“The basic tools of cloning and sequencing were normal, but
because there are lots of repetitive sequences, reassembling the genome
in the right order was more complex,” she explained.
“The outcome of the genome project has major impact not only
from the medical point of view,” Michaeli added. “The
genome project confirmed that trypanosomes lack the ability to control
the expression of protein-encoding genes at the level of transcription.
It is the first eukaryote we have seen whose gene regulation occurs
mainly post-transcription and mainly through exotic mechanisms such as
trans-splicing and editing.”
Another HHMI international research scholar, Santuza Teixeira of
Brazil, was a co-author of the T. cruzi paper. HHMI's
international research scholars serve as role models for scientists in
developing countries, who increasingly are joining a global battle
against the infectious and parasitic diseases that decimate their
people.
HHMI supports the research of outstanding scientists in 38
countries, many of them developing nations.
Image: Vanina Campo
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Jennifer Michalowski
