Pathogenic fungi reveal new mechanism
for evolution
CAMBRIDGE, Mass. (September 29, 2005) - As medical
procedures that compromise a person's immune system
become more common, opportunistic infections that exploit
these weaknesses are an increasing public health concern.
Pathogenic fungi are chief among these invaders that
prey upon organ-transplant recipients and chemotherapy
patients. Not only are these infectious agents a scourge
in hospitals, but they have also demonstrated an alarming
ability to quickly sidestep drug treatment.
Now, researchers in the laboratory of Whitehead Member
Susan Lindquist have identified a key mechanism that
enables pathogenic fungi to evolve drug-resistant capabilities
with such distressing rapidity.
"Ultimately, these results establish a new
role for Hsp90 in the evolution of adaptive traits,"
says Cowen. "Looking at this more broadly, this
research also helps us to understand more clearly
how evolution occurs at a molecular level." |
"We are extremely excited about the potential of Hsp90
inhibitors for treating infections in the clinic, but
the implications here are much broader," says Lindquist,
whose paper will be published in the September 30 issue
of the journal Science. "We now have a clearer
understanding of the forces that shape the evolution
of a new trait and the molecular mechanisms by which
it is accomplished. The potential to evolve is an inherent
biological property of the organism."
In a perspective piece that accompanies the paper,
Joseph Heitman of Duke University Medical Center states,
"The emergence of drug resistance in pathogenic microbes
provides a resounding validation of Darwinian evolution."
For many years, Lindquist and her colleagues have been
poring over a protein called Hsp90. Hsp is an acronym
for "heat shock protein," meaning that the protein responds
rapidly to certain environmental stresses, such as elevated
temperatures.
But Hsp90 is also what's called a "chaperone protein,"
a member of a family of proteins dedicated to helping
fellow proteins assume their proper shapes. Proteins
are often compared to origami figures: They fold into
a vast array of conformations whose precision is essential
to the cell's well being. One misfold can prove toxic
to the cell. Hsp90 directs this folding process in a
wide range of key proteins.
In a 2002 Nature paper, Lindquist and her
research team found that by lowering levels of Hsp90
in plants, they could cause sudden and unexpected changes
in a vast array of traits, including pigmentation and
leaf shape. (These results paralleled a 1998 Nature
paper in which Lindquist and colleague Suzanne Rutherford
discovered the same mechanism in fruit flies.) As a
result of these findings, the team deduced that these
plants must, over time, gradually accumulate genetic
variations that Hsp90 somehow manages to keep in check.
But if Hsp90 is compromised, perhaps due to an environmental
stress, this reserve of dormant mutations is suddenly
unleashed.
Leah Cowen, a postdoctoral scientist in the Lindquist
lab, was interested in using the model yeast Saccharomyces
cerevisiae to study how Hsp90 might contribute
to evolution. Further, she wanted to investigate whether
Hsp90 enabled pathogenic fungi such as Candida albicans
and Aspergillus species-prime sources of hospital
infections-to resist treatment.
To do this, Cowen designed experiments in which fungal
cells were exposed to two common classes of antifungal
drugs: azoles and echinocandins. Azoles, such as fluconazole,
are the most widely prescribed antifungals, while echinocandins
are the newest class of these drugs to reach the clinic.
Cowen genetically engineered fungal strains to have
either high levels of Hsp90, or low levels, and then
exposed them to these drugs. Results were striking.
"Strains with high levels of Hsp90 could rapidly evolve
drug resistance, while the ability of strains with low
levels of Hsp90 to evolve resistance was impaired,"
says Cowen. Further, Cowen also looked at strains that
had already evolved drug resistance through many different
mutations. Even in these cases, "when Hsp90 levels were
reduced these new resistance traits were lost."
Cowen also found that once fungal strains became drug
resistant, they could eventually evolve the ability
to retain this resistance independent of Hsp90.
"Ultimately, these results establish a new role for
Hsp90 in the evolution of adaptive traits," says Cowen.
"Looking at this more broadly, this research also helps
us to understand more clearly how evolution occurs at
a molecular level."
"This has broad therapeutic implications as well,"
says Lindquist, who also is a professor of biology at
MIT. "Drugs that inhibit Hsp90 might prove to be an
effective strategy for combating these infections."
Such drugs, theoretically at least, could both render
these pathogens more responsive to treatment and prevent
them from ever developing such resistance in the first
place.
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