AnthraxPage 1 of 1
ABOUT THE MICROBE
Anthrax is an acute infectious disease caused by the spore-forming, rod-shaped
bacterium Bacillus anthracis. Predominantly a cause of livestock
disease, B. anthracis forms durable spores that can lie dormant
in the soil for years. Once eaten by a grazing animal, the spores are
activated and the bacteria reproduce. After the bacteria spread, they
typically kill the infected animal and return to the soil or water once
again as spores.
The bacterium's destructive properties are due largely to toxins, which
consist of three proteins: protective antigen, edema factor, and lethal
factor.
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Protective antigen (PA) binds to select cells of an infected person
or animal and forms a channel that permits edema factor and lethal
factor to enter those cells.
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Edema factor (EF), once inside the cell, causes fluid to accumulate
at the site of infection. EF can contribute to a fatal buildup of
fluid in the cavity surrounding the lungs. It also can inhibit some
of the body's immune functions.
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Lethal factor (LF), once inside the cell, disrupts a key molecular
switch that regulates the cell's functions. LF can kill infected
cells or prevent them from working properly.
ABOUT THE DISEASE
People rarely contract anthrax from healthy animals. Contact with infected
livestock or their products such as leather and wool does, however, cause
a limited number of anthrax cases throughout the world. In the United
States, only 236 anthrax cases were reported between 1955 and 1999, an
average of about five per year. Most of those cases were occupational
exposures in people who work with animal carcasses or products. The treatable
cutaneous (skin) form of the disease is most common. Worldwide incidence
is unknown, but anthrax occurs more frequently in developing countries,
especially those without strong veterinary public health programs. Anthrax
is not transmitted from person to person.
Human anthrax occurs primarily in three forms: cutaneous, gastrointestinal,
and inhalation.
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Cutaneous anthrax occurs when the bacteria, usually from infected
animal products, enter a break in the skin. The skin reddens and
swells, much like an insect bite, then develops a painless blackened
lesion or ulcer that may form a brown scab. If left untreated, the
infection can spread through the body. Cutaneous anthrax is the
most common form of the diseases and responds well to antibiotics.
It is rarely fatal if treated before it becomes invasive.
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Gastrointestinal anthrax may arise when a person eats contaminated
food. The infection often causes fever accompanied by gastrointestinal
problems such as vomiting, abdominal pain, diarrhea, or loss of
appetite. In some cases, lesions may form in the nose and throat
instead of the lower digestive tract. In both cases, gastrointestinal
anthrax can spread through the body and is often fatal if not treated
immediately. This form of anthrax, however, is not known to have
occurred in the United States.
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Inhalation anthrax, sometimes called respiratory or pulmonary anthrax,
occurs when the bacterial spores are inhaled. The early symptoms
resemble those of a common cold or sore throat. The spores travel
from the lungs to immune cells called macrophages in the nearby
lymph nodes. There they begin to reproduce and secrete their toxins,
causing severe breathing problems and shock. Treatment is difficult
once the bacteria have reached that stage, and death often ensues.
Naturally occurring inhalation anthrax is rare. Prior to the bioterrorist
attack of 2001, the last known case of inhalation anthrax in the
United States occurred in 1976 in a California craftsman who apparently
contracted the infection from contaminated, imported yarn.
TREATMENT AND PREVENTION
Antibiotics
Several different antibiotics kill B. anthracis as it reproduces
within people and animals. If diagnosed early, anthrax can be treated.
Unfortunately, infected people often confuse early symptoms with more
common infections and do not seek medical help until severe symptoms appear.
At that point the destructive anthrax toxins, which are not affected by
antibiotics, have risen to high levels, making treatment difficult. Although
cutaneous anthrax has telltale signs and symptoms making diagnosis easy,
early stage gastrointestinal and inhalation anthrax are more likely to
be mistaken for common maladies.
Vaccine
An anthrax vaccine is licensed for limited use. The vaccine is currently
used to protect members of the military and individuals most at risk for
occupational exposure to the bacteria, such as abattoir workers, veterinarians,
laboratory workers, and livestock handlers. The vaccine consists of filtered
proteins and other components of a weakened B. anthracis strain
adsorbed to aluminum hydroxide. PA is the major component of the vaccine
that provides protection against infection. The vaccine contains no whole
bacteria.
Health experts currently do not recommend the vaccine for general use
by the public due to the rarity of anthrax and the potential for adverse
side effects. Researchers have not determined the safety and efficacy
of the vaccine in children, the elderly, and people with weakened immune
systems. In addition, the recommended vaccination schedule is 6 doses
given over an 18-month period, so the vaccine would likely offer little
protection in response to a bioterrorist attack. For these reasons,
a new anthrax vaccine is needed.
NIAID BASIC RESEARCH
Several biologic factors contribute to B. anthracis's ability
to cause disease. By uncovering the molecular pathways that enable the
bacterium to form spores, survive in people, and cause illness, NIAID
hopes to identify new ways to diagnose, prevent, and treat anthrax.
Toxin Biology
Scientists are studying the anthrax toxins to learn how to block their
production or action. Recently, NIAID grantees determined the three-dimensional
structure of the LF protein as it attaches to its target inside cells.
The research showed for the first time that LF uses a long groove on its
side to latch onto that target. At the same time, another group of researchers
identified a protein receptor on the surface of host cells to which PA
attaches. Using a specific fragment of that receptor protein, the researchers
were able to block the attachment of PA, thereby preventing formation
of the PA channel and inhibiting the toxic effects of LF and EF in test-tube
experiments. Other investigators have engineered mutant, inactive PAs
that prevent bacteria-produced PAs from forming the channel. The studies
of PA and LF should enable researchers to develop small molecules that
can be used as therapeutics to treat anthrax by inhibiting its toxins.
The Anthrax Bacterium Genome
The instructions that dictate how a microbe works are encoded within its
genes. Bacteria often contain genes at two locations. The bacterial chromosome
is a long stretch of DNA that houses most of those genes, but smaller
loops of DNA called plasmids also carry genes that can be exchanged between
different bacteria. Because plasmids often contain genes for toxins and
antibiotic resistance, knowing their DNA sequence is important.
In B. anthracis, the genes for PA, LF, and EF are found on
plasmids that have already been sequenced. In addition, researchers
recently reported the complete chromosomal DNA sequence of two B.
anthracis isolates, including the bacterium that infected a Florida
victim of the recent anthrax attack. Genome sequencing of more than
a dozen other B. anthracis strains and related bacteria has
already begun.
By comparing the DNA blueprints of different B. anthracis
strains, researchers hope to learn why some strains are more virulent
than others. Small variations among the genomes of different strains
may also help investigators pinpoint the origin of an anthrax outbreak.
Knowing the genetic fingerprint of B. anthracis might lead
to gene-based detection mechanisms that can alert scientists to the
bacteria in the environment or allow rapid diagnosis of anthrax in infected
people. Variations between strains might also point to differences in
antibiotic susceptibility, permitting doctors to immediately determine
the appropriate treatment.
DNA sequencing also opens the door to functional genomics, in which
the B. anthracis genome will be analyzed to determine the function
of each of its genes and how they interact with each other or with host-cell
components to cause disease. Genes are the instructions for making proteins,
which in turn build components of the cell or carry out its biochemical
processes. Knowing the sequence of B. anthracis genes therefore
helps scientists discover key bacterial proteins that can then be targeted
by new drugs or vaccines.
Spore Biology
B. anthracis spores are essentially dormant and therefore must
wake up, or germinate, to become reproductive, disease-causing bacteria.
Researchers are therefore studying the germination process to learn more
about the signals that cause spores to become active once inside an animal.
Efforts are underway to develop models of spore germination in laboratory
animals; scientists hope those models will enable discoveries leading
to drugs that block the germination process.
Host Immunity
People who contract anthrax produce antibodies to PA, and similar antibodies
appear to protect animals from infection. Recent studies also suggest
that some animals can produce antibodies to components of B. anthracis
spores. Those antibodies, when studied in a test tube, prevent spores
from germinating and increase their uptake by the immune system's microbe-eating
cells. It therefore might be possible to develop a vaccine that can be
given after exposure to fight both the reproductive form of B. anthracis
and any spores that may linger in the lungs following antibiotic treatment.
As part of NIAID's strategic plan, researchers will study how both
the innate and adaptive immune responses are triggered by a B. anthracis
infection. The adaptive immune response consists of B cells and T cells
which specifically recognize components of the anthrax bacterium. The
innate immune system, however, responds more generally to a wide range
of microbial invaders and likely plays a key role in the body's front-line
defenses. Scientists will conduct studies of how those two arms of the
immune system act to counter infection, including how B. anthracis
spore germination affects individual immune responses.
NIAID THERAPEUTICS RESEARCH
Following the recent discoveries of how PA and LF interact with their
cellular targets, researchers are screening thousands of small molecules
in hopes of finding a compound that is practical for use as an anti-anthrax
drug. In addition, NIAID is working with the Food and Drug Administration
(FDA), Centers for Disease Control and Prevention (CDC), and Department
of Defense (DoD) to accelerate testing of collections of compounds for
their effectiveness against inhalation anthrax. Many of those compounds
have already been approved by FDA for other indications and therefore
could quickly be approved for use in treating anthrax should they prove
effective.
NIAID is seeking new drugs that attack B. anthracis at many
levels. These include agents that prevent the bacterium from attaching
to cells, compounds that inhibit spore germination, and inhibitors that
block the activity of key enzymes such as anthrax lethal factor. The
Institute will also develop the capacity to synthesize promising anti-anthrax
compounds in sufficient purity and quantity for preclinical testing.
NIAID VACCINE RESEARCH
Researchers are working on new, improved anthrax vaccines that may be
more easily given to a diverse population. NIAID is collaborating with
DoD to develop a next-generation vaccine based on a laboratory-produced,
or recombinant, PA variant. Antibodies to PA also appear to recognize
some components of the bacterial spore, making PA-based vaccines promising
candidates for broad protection against anthrax. The Institute will supervise
phase I and phase II trials of the recombinant PA vaccine in different
formulations.
To help move potential vaccines into clinical testing, NIAID will develop
the infrastructure to produce pilot lots of promising candidates and
expand the Institute's testing capacity. To assist in its vaccine research
efforts, NIAID will establish a centralized immunology laboratory to
assess the efficacy of different vaccine candidates.
NIAID DIAGNOSTICS RESEARCH
Research is underway to develop improved techniques for spotting B.
anthracis in the environment and diagnosing it in infected individuals.
A key part of that research is the functional genomic analysis of the
bacterium, which should lead to new genetic markers for sensitive and
rapid identification. Genomic analysis will also reveal differences in
individual B. anthracis strains that may affect how those bacteria
cause disease or respond to treatment.
ANTHRAX AND BIOTERRORISM
CDC has classified B. anthracis as a Category A agent. Those
agents are considered the highest threat to national security due to their
ease of transmission, high rate of death or serious illness, and potential
for causing public panic.
In October 2001, anthrax spores were sent through the U.S. mail and
caused 18 confirmed cases of anthrax (11 inhalation, 7 cutaneous). Five
individuals with inhalation anthrax died; none of the cutaneous cases
was fatal.
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