Cloaking device helps pathogens
evade immune system
CAMBRIDGE, Mass. (May 12, 2006) — How does our
immune system recognize friend from foe? Why does it
easily identify many bacterial and viral infections
yet sometimes miss other invaders, such as pathogenic
fungi? This question has troubled biologists for decades.
Now, researchers in the lab of Whitehead Founding Member
Gerald
Fink have discovered a biological “cloaking
device,” a network of genes that may help pathogenic
fungi hide from the immune system. When this network
is disabled, these virulent fungal invaders are suddenly
rendered vulnerable to the body’s defenses.
“This network may very well be one more tactic
in the ongoing hide-and-seek game between our immune
systems and pathogenic fungi,” says Fink, lead
author of the paper that appeared in the April issue
of the journal PLoS Pathogens.
Pathogenic fungi are the fastest-growing cause of hospital-acquired
infections, preying mostly on patients with a compromised
immune system. Chemotherapy, organ transplantation and
HIV/AIDS are a few of the conditions that increase a
patient’s vulnerability.
“Interactions between the immune system
and pathogens are highly complex,” says
Whitehead Member Gerald Fink. “On the surface,
it looks like a ‘point, counter-point’
competition. One side evolves a particular defense,
and then, through natural selection, the other
side develops a way to counter that defense.” |
Researchers have known for many years that the membranes
of these fungal cells appear to be surrounded by an
outer shell, almost like an M&M. The inside of the
shell is marked by deposits of sugar called beta-glucan,
molecules that are easily spotted by the immune system.
The outer surface of the shell is composed primarily
of a protein called mannan, which the immune system
can’t see. While this sort of outer shell is unique
to fungal cells, no scientist had yet demonstrated what
sort of biological role it might play.
Robert Wheeler, a postdoctoral scientist in the Fink
lab, conducted experiments in which he placed fungal
cells in a dish and introduced an antibody designed
to detect the beta-glucan on the underside of the shell.
However, in these experiments, the antibody often seemed
to have trouble recognizing the beta-glucan, and, as
a result, could not detect the fungal cell.
“We decided that we needed a way to test if the
outer layer, the one made of mannan, might somehow be
protecting beta-glucan from the immune system,”
says Wheeler.
Since many species of fungal pathogens, including baker’s
yeast, contain this mannan layer, Wheeler decided to
use this common household product as a model for determining
mannan’s function.
After screening thousands of mutant yeast strains, Wheeler
discovered a network of genes responsible for creating
the mannan layer, genes that all had counterparts in
pathogenic fungi. When Wheeler then knocked out key
genes in the mannan network in pathogenic fungi and
placed them in a dish containing beta-glucan antibodies,
the antibodies immediately “recognized”
the fungi.
Next, Wheeler placed these fungal cells in a dish with
certain immune system cells. With mannan disabled, the
immune cells recognized the fungi far more efficiently.
In an organism, that reaction would produce a full immune
response.
“This mannan layer seems to be masking beta glucan
from the immune system,” says Wheeler.
“Interactions between the immune system and pathogens
are highly complex,” says Fink, who is also a
professor of biology at MIT. “On the surface,
it looks like a ‘point, counter-point’ competition.
One side evolves a particular defense, and then, through
natural selection, the other side develops a way to
counter that defense. This outer layer of mannan is
one of many processes that pathogenic fungi have evolved
to survive in what would otherwise be a hostile environment.”
These findings may also help explain why a certain class
of drugs called echinocandins are so effective against
pathogenic fungi. When administered in high doses, these
drugs kill the pathogens all in one fell swoop. When
Wheeler administered non-lethal doses of these drugs
along with a beta-glucan antibody, the drugs appeared
to unmask the pathogen just enough so that the antibody
could recognize it.
“In other words, these are drug concentrations
that, when placed alone in a dish with a pathogen, wouldn’t
affect its viability,” says Wheeler. “But
when accompanied by an immune system product, the pathogen
is eliminated.”
“No doubt these findings are certainly of interest
to companies developing anti-fungal therapeutics,”
adds Fink. In particular, using a drug to disable the
mannan layer and then allowing the immune system to
naturally attack the fungi may prove a powerful new
approach.
This research was supported by the Bushrod H. Campbell
and Adah F. Hall Charity Fund, and by the National Institutes
of Health.
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