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Anthrax - Medical Details |
What is Anthrax?
Bacillus anthracis is a very large, Gram positive, sporeforming rod (1-1.5um x 4-10um). The organism is readily cultivated on ordinary nutrient medium and grows best aerobically, but will also multiply under anaerobic conditions. Genotypically and phenotypically, it is very similar to Bacillus cereus, which is isolated readily from soil habitats. However, the natural history of B. anthracis remains obscure.
Pathogenicity
Anthrax is primarily a disease of domesticated and wild animals, particularly herbivorous animals. Humans become infected incidentally when brought into contact with diseased animals, their hides or hair, or their excrement. Many species of animals and birds can acquire the disease naturally.
In humans, anthrax is fairly rare (in non-bioterrorism settings); the risk of infection is about 1/100,000. The most common form of the disease in humans is cutaneous anthrax, which is usually acquired via injured skin or mucous membranes. A minor scratch or abrasion, usually on an exposed area of the face or neck or arms, is inoculated by spores from the soil or a contaminated animal or carcass.
The spores germinate, vegetative cells multiply, and a characteristic gelatinous edema develops at the site. This develops into papule within 12-36 hrs after infection. The papule changes rapidly to a vesicle, then a pustule (malignant pustule), and finally into a necrotic ulcer from which infection may disseminate, giving rise to septicemia. Lymphatic swelling also occurs within seven days. In severe cases, where the blood stream is eventually invaded, the disease is frequently fatal.
Another form of the disease is inhalation anthrax (woolsorters' disease) which results most commonly from inhalation of dust where animal hair or hides are being handled. The disease begins abruptly with high fever and chest pain. It progresses rapidly to a systemic hemorrhagic pathology and is often fatal if treatment cannot stop the invasive aspect of the infection.
The toxigenic properties of Bacillus anthracis were
not recognized until 1954. Prior to that time, because of the tremendous
number of anthrax bacilli observed in the blood of animals dying of the
disease (>10^9 bacteria/ml), it was assumed that death was due to blockage
of the capillaries, popularly known as the "log-jam" theory.
But experimentally it was shown that only about 3 x 10^6 cells/ml are
necessary to cause death of the animal. Furthermore, the cell-free plasma of
animals dying of anthrax infection contained a toxin which causes symptoms
of anthrax when injected into normal guinea pigs. These observations left
little doubt that a diffusible exotoxin plays a major role in the
pathogenesis of anthrax.
One component of the anthrax toxin has a lethal mode of the action that is
not understood at this time. Death is apparently due to oxygen depletion,
secondary shock, increased vascular permeability, respiratory failure and
cardiac failure. Death from anthrax in humans or experimental animals
frequently occurs suddenly and unexpectedly. The level of the lethal toxin
in the circulation increases rapidly quite late in the disease, and it
closely parallels the concentration of organisms in the blood.
Determinants of Virulence
Bacillus anthracis possesses a unique a cell wall polysaccharide antigen, and forms a single antigenic type of capsule consisting of poly-D-glutamate polypeptide. All virulent B. anthracis form this capsule. Smooth (S) to Rough (R) colonial variants occur, which is correlated with ability to produce the capsule. R variants are relatively avirulent.
The poly-D-glutamate capsule is itself nontoxic, but functions to protect the organism against the bactericidal components of serum and phagocytes, and against phagocytic engulfment. The capsule plays its most important role during the establishment of the infection, and a less significant role in the terminal phases of the disease, which are mediated by the anthrax toxin.
In addition to the capsule, virulent strains of Bacillus anthracis produce three distinct antigenic components related to a complex exotoxin called the anthrax toxin. Each component of the toxin is a thermolabile protein with a mw of approximately 80kDa.
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Factor I is the edema factor (EF) which is necessary for the edema producing activity of the toxin. EF is known to be an inherent adenylate cyclase, similar to the Bordetella pertussis adenylate cyclase toxin.
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Factor II is the protective antigen (PA), because it induces protective antitoxic antibodies in guinea pigs. PA is the binding (B) domain of the anthrax toxin which has two active (A) domains, EF (above) and LF (below).
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Factor III is known as the lethal factor (LF) because it is essential for the lethal effects of the anthrax toxin.
Apart from their antigenicity, each of the three factors exhibits no significant biological activity in an animal. However, combinations of two or three of the toxin components yield the following results in experimental animals.
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PA+LF combine to produce lethal activity
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EF+PA produce edema
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EF+LF is inactive
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PA+LF+EF produces edema and necrosis and is lethal
These experiments suggest that the anthrax toxin has the familiar A-B enzymatic-binding structure of bacterial exotoxins with PA acting as the B fragment and either EF or LF acting as the active A fragment.
EF+PA has been shown to elevate cyclic AMP to
extraordinary levels in susceptible cells. Changes in intracellular cAMP are
known to affect changes in membrane permeability and may account for edema.
In macrophages and neutrophils an additional effect is the depletion of ATP
reserves which are needed for the engulfment process. Hence, one effect of
the toxin may be to impair the activity of regional phagocytes during the
infectious process.
The effects of EF and LF on neutrophils have been studied in some detail.
Phagocytosis by opsonized or heat-killed Bacillus anthracis cells is not
inhibited by either EF or LF, but a combination of EF + LF inhibits
engulfment of the bacteria and the oxidative burst in the pmns. The two
toxin components also increased levels of camp in the neutrophils. These
studies suggest that the two active components of the toxin, EF + LF,
together increase host susceptibility to infection by suppressing neutrophil
function and impairing host resistance.
LF+PA have combined lethal activity as stated above. The lethal factor is a
Zn++ dependent protease that induces cytokine production in macrophages and
lymphocytes, but its mechanism of cytotoxicity is unknown.
In summary, the virulence of Bacillus anthracis is attributable to three
bacterial components:
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1. Capsular material composed of poly-D-glutamate
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2. EF component of exotoxin
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3. LF component of exotoxin
Both the capsule and the anthrax toxin may play a
role in the early stages of infection, through their direct effects on
phagocytes. Virulent anthrax bacilli multiply at the site of the lesion.
Phagocytes migrate to the area but the encapsulated organisms can resist
phagocytic engulfment, or if engulfed, can resist killing and digestion.
A short range effect of the toxin is its further impairment of phagocytic
activity and its lethal effect on leukocytes, including phagocytes, at the
site. After the organisms and their toxin enter the circulation, the
systemic pathology, which may be lethal, will result.
Bacillus anthracis coordinates the expression of its virulence factors in
response to a specific environmental signal. Anthrax toxin proteins and the
antiphagocytic capsule are produced in response to growth in increased
atmospheric CO2. This CO2 signal is thought to be of physiological
significance for a pathogen which invades mammalian host tissues.
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