$11.4 Million CDC Grant Goes to TSRI to Study Immune Response
to Anthrax Toxins
By Jason Socrates Bardi
The U.S. Centers for Disease Control and Prevention (CDC)
has awarded a group of researchers at The Scripps Research
Institute (TSRI) a multi-year, $11.4 million grant to study
the interaction of the human immune system with toxins of
the bacterium Bacillus anthracis, the causative agent
of the disease anthrax.
The goal of the grant is to understand how B. anthracis
toxins suppress immune responses in humans, circumventing
the usual mechanisms by which the body would destroy the bacterium.
Normally, when humans are infected with a bacterium, innate
immune cells and other components of the immune system mount
a vigorous defense and clear the body of infection. However,
B. anthracis is able to defend itself from being killed
through the protection of its highly inert outer capsule and
through the production of special toxins, which shut off parts
of the immune system.
The importance of these toxins is well established, since
strains of the bacterium that do not express these toxins
are much less virulent. While the identity and structure of
the toxins is known by now, how they modulate cell function
and allow the bacteria to evade immune surveillance is not
really understood at the molecular and biochemical levels.
"It's clear that when someone is infected with Bacillus
anthracis, [the bacterium] is able to suppress the immune
system of that person," says TSRI Professor Gary Bokoch, who
is one of the lead investigators on the grant. But how?
Bokoch and several other TSRI scientists will define genetic
and cellular elements that determine susceptibility to anthrax
infection and progression, which should facilitate the translation
of basic research into clinical applications.
The program project grant is one of several recently announced
by CDC Director Dr. Julie Gerberding to fund research grants
in biodefense and emerging infectious diseases. These awards
are part of the United States Department of Health & Human
Service's efforts to build and sustain a robust and long-term
program for biodefense research. The duration of funding for
the grant is five years, subject to congressional appropriations.
Anthrax and the Immune System
Anthrax is a deadly disease that is caused by infection
with the bacterium Bacillus anthracis. It is an ancient
disease—both Homer and Virgil wrote about a disease that
was probably anthrax.
The Greeks named the disease anthrax, which means coal,
because of the characteristic black ulcers that form on the
skin of people and animals infected with the bacterium. This
cutaneous form of the disease was responsible for widespread
outbreaks among livestock through the centuries, and Louis
Pasteur famously demonstrated the first anthrax vaccine in
1881, which helped confirm the germ theory of disease.
However, despite the centuries of human and B. anthracis
coexistence, little is known about the pathogenic basis
of anthrax.
"It's amazing to me that for as long as this disease has
been around, there's not a lot understood about the basic
mechanisms of how it affects the cells of the immune system,"
says Bokoch.
Understanding how B. anthracis causes disease is
a major public health priority today, particularly since aerosolized
anthrax spores cause inhalation anthrax, the most deadly form
of the disease, and have the potential to be used as a bioterror
weapon.
The TSRI team is not studying these deadly aerosolized spores
directly, but is focusing on the interaction of B. anthracis
toxins with the immune system that occurs during inhalation
anthrax.
In inhalation anthrax, B. anthracis is inhaled as
a spore. B. anthracis naturally forms spores when conditions
are not right for the bacterium to replicate. When it converts
into a spore, it can lie dormant inside its protective, almost
indestructible protein coat. When spores of anthrax are breathed
in, they are taken up through the lungs by cells called macrophages.
The macrophages transport ingested spores to other parts of
the body, where they germinate into bacteria and begin reproducing
and making toxins.
Two toxins in particular are known to interact with the
host immune system. These are the "lethal toxin," which is
a metalloprotease (an enzyme that chops up other proteins),
and the "edema toxin", which is an adenylate cyclase (a protein
that makes cAMP, an important "second messenger" molecule
in the body that has a variety of systemic effects).
The lethal toxin, in particular, seems to have the ability
to inhibit the immune system. "It shuts off these [immune]
responses that would normally be used by the body to kill
the bacteria," says Bokoch.
It is not known how the toxins do this. Most of their targets
in human cells and their mechanisms of action have not been
identified.
The Program Project Grant
The program project grant is designed to be an interactive
collaboration among various TSRI investigators. The overall
goal of the grant is to elucidate the molecular targets and
mechanisms by which B. anthracis suppresses the innate
immune responses in humans and to determine susceptibility
to anthrax infection and progression.
The grant seeks to define these mechanisms at several different
levels—genetic, biochemical, and physiological—and
is composed of several different projects that approach the
question from different angles. A core laboratory, directed
by TSRI Associate Professors Ulla Knaus and Marta Perego,
will be established to produce necessary reagents.
One thing that is not clearly understood is why some people
are more susceptible to infection than others, and some of
the projects in the grant will address this question. TSRI
Professor Bruce Beutler, for instance, will investigate which
host genes are required for susceptibility and/or resistance
to the anthrax lethal toxin.
"The anthrax lethal toxin has been identified," says Beutler.
"But the mechanism of toxicity is very poorly understood.
We hope to find proteins in the pathway that leads to killing
of macrophages."
Similarly, another project on the grant will look for polymorphisms—DNA
variations that differ from person to person—that might
make some people more susceptible to anthrax than others.
TSRI Associate Professor Bruce Zuraw, will look at the interaction
of B. anthracis toxins with human alveolar macrophages—a
type of innate immune cell that normally clears the lungs
of bacteria and other particles by engulfing and destroying
them. During inhalation anthrax, most B. anthracis spores
are destroyed by these macrophages, but a few may survive
and use the macrophages as a vehicle to spread within the
body. The macrophages shuttle the ingested B. anthracis
to the regional lymph nodes, where the spores germinate
and multiply.
Knaus will look at the interplay between anthrax toxins
and lung epithelial cells—specialized cells that form
a layer lining the lung. She is asking what happens to these
cells when they are exposed to anthrax in the tiny airways
of the lungs and how they are damaged by the toxins.
"It's really not clear at all what happens," says Knaus.
Bokoch will look at the effect of B. anthracis toxins
on another type of innate immune cell, the neutrophil. Neutrophils,
the most common white blood cell in circulation, are our first
line of defense against invading pathogens. They search out
bacteria and fungi and kill them with highly reactive oxidizing
agents and toxic proteins. Bokoch and his colleagues have
been studying these sorts of cells for many years.
"Because of the work that has been going on here in the
Immunology Department at Scripps," says Bokoch, "we are really
in a good position to identify these biochemical and genetic
mechanisms."
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