Anthrax pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

The genetic material of Bacillus anthracis is coded within 1 chromosome and 2 plasmids that are fundamental for its toxicity. The spores of B. anthracis are the infectious form and can remain dormant in the environment for decades. The bacterium causes disease through 2 mechanisms: toxemia and bacterial infection. B. anthracis begins to produce toxins within hours of germination. Protective antigen (PA) and edema factor (EF) combine to form edema toxin (ET), and PA and lethal factor (LF) combine to form lethal toxin (LT). Bacterial toxins have a direct cytotoxic effect by interfering with cellular pathways and they are also responsible for weakening the immune system so the initial systemic infection may occur. Anthrax lesions at any site are featured by extensive necrosis and confluent exudate containing macrophages and neutrophils.

Genetics

Bacillus anthracis genetic component includes 1 chromosome and 2 plasmids. These plasmids (pXO1 and pXO2) are fundamental to its toxicity:

• pXO1 - encodes 3 components of the anthrax exotoxin:

• Protective Antigen (PA)
• Lethal Factor (LF)
• Edema Factor (EF)

• pXO2 - encodes proteins involved in the glutamic acid capsule structure, which is responsible for conferring resistance against phagocytosis.

Transmission

The route by which anthrax is transmitted allows for its classification, it includes:

• Cutaneous anthrax - commonly requires a prior skin lesion as a prerequisite for infection
• Gastrointestinal anthrax - contracted following ingestion of contaminated food, primarily meat from an animal that died of the disease, or conceivably from ingestion of contaminated water
• Inhalational anthrax - from breathing in airborne anthrax spores
• Injection anthrax - from injection of a drug containing, or contaminated with Bacillus anthracis

Pathogenesis

B. anthracis, the causative agent of anthrax, is a spore-forming bacterium. The spores of B. anthracis, which can remain dormant in the environment for decades, are the infectious form, but this vegetative form of B. anthracis rarely causes disease. The bacterium causes disease through 2 mechanisms: toxemia and bacterial infection. Spores introduced through the skin lead to cutaneous or injection anthrax; those introduced through the gastrointestinal tract lead to gastrointestinal anthrax; and those introduced through the lungs lead to inhalation anthrax. After entering a human or animal, B. anthracis spores are believed to germinate locally or be phagocytosed by dendritic cells and macrophages. These will then carry the spores to the lymph nodes, where they germinate. B. anthracis begins to produce toxins within hours of germination. Protective antigen (PA) and edema factor (EF) combine to form edema toxin (ET), and PA and lethal factor (LF) combine to form lethal toxin (LT). After binding to surface receptors, the PA portion of the complexes facilitates translocation of the toxins to the cytosol, in which EF and LF exert their toxic effects. Bacillus anthracis disseminate to multiple organs including spleen, liver, intestines, kidneys, adrenal glands, and meninges, affecting their functioning, leading to systemic infection and a potentially fatal outcome.

The virulence factors of Bacillus anthracis are:

• Antiphagocytic capsule
• Toxins:

• PA
• LF
• EF

Bacterial Toxins

In order to infect the body, Bacillus anthracis must produce toxins. Toxins have 3 main toxic effects: edema, hemorrhage and necrosis. Besides their direct toxic effects, causing tissue damage, anthrax toxins are also responsible for interfering with cellular pathways in such way, that defense functions of the host's immune system are affected. This will ultimately allow initial systemic infection, by interfering with the immune system.

When isolated, the 3 structural elements of the anthrax exotoxins are non-toxic. However, when combined, they form virulent exotoxins:

• LF + PA = LT (Lethal Toxin)
• EF + PA = ET (Edema Toxin)

The PA is responsible for attaching the toxin to the cell, while the LF and the EF are responsible for the toxicity.

After germinating, B. anthracis produces and releases into the blood stream PA, LF and EF toxins separately. However, PA is secreted in its inactivated form (PA). In order to form exotoxin complexes with LF and EF, it must first be activated by host-cellular receptors:

• CMG2 - Capillary Morphogenesis Protein 2 (in vivo predominant toxin receptor)
• TEM8 - Tumor Endothelium Marker 8 (minor role)

CMG2 and TEM8 cleave PA into PA20 and PA63. PA63 (a C-terminal fragment) is the activated form of PA, responsible for combining with EF and LF, thereby creating the toxin oligomer PA63 oligomer receptor complex. This complex will be internalized via receptor mediated endocytosis within an endosome.

The acidic environment within the endosomes leads to the formation of a channel called PA63 oligomer channel, on the endosomal membrane. LF and EF are then released in the cytosol of the host cell, to then exert their toxic effects.

After experiments in mice, edema toxin was noted to be the major virulence factor since it caused death of mice, in much lesser dosages than lethal toxin. edema toxin is a calmodulin-dependent adenylyl cyclase known to increase intracellular cAMP, through the conversion of ATP into cAMP, thus affecting several intracellular pathways. Lethal toxin is a zinc-dependent metaloproteinase, known to interfere with the mitogen-activated protein kinase (MEK), thereby hampering with multiple intracellular mechanisms.

Cutaneous or Injection Anthrax

According to animal studies, injected spores in the skin of susceptible animals (either through a lesion or by injection), germinated and gave rise, in about 2 - 4 hours, to a small edematous area containing capsulated bacilli. The following stages were noticed:

• The lesion increases in size and becomes defined by a zone of altered capillaries through dilatation, congestion and swelling of the endothelial cells, and diapedesis of neutrophils
• Macrophages and fibrin deposits appear, and the efferent lymphatics become dilated
• Continued multiplication of the bacilli in the lesion leads to fragmentation of the connective tissue, as the edema spreads extensively away from the infection site
• Necrosis and hemorrhage occur. If initial inoculation has happened with minimal number of spores, the primary lesion may be insignificant compared with that of the draining lymph nodes
• The bacilli migrate from the primary lesion, by means of the lymph vessels, to the local lymph nodes where multiplication occurs, releasing a continuous stream of organisms and toxins into the efferent lymph vessels and to the spleen and other lymphoid tissues where multiplication continues
• In animals who died following subcutaneous challenge, the local lymph nodes became haemorrhagic and edematous. Necrosis of lymphatic elements and of blood vessel walls occurs and phagocytosis of the bacilli was apparent there
• Splenic enlargement is characteristic of septicemia

Injection anthrax will have similar pathogenesis to cutaneous anthrax, but since it is injected, it can spread throughout the body faster and be harder to recognize and treat than the cutaneous form.

Inhalation Anthrax

In inhalation anthrax, the inhaled spores will be deposited in the alveoli first. From there, they will be transported, within phagocytic cells, through the lymphatic vessels to the mediastinal lymph nodes, where they will grow and cause hemorrhagic lymphadenitis. Bacteria escape from the damaged lymph nodes and invade the blood stream via the thoracic duct. Vegetative Bacillus then travel through the bloodstream and lymph vessels, potentially causing septicemia. At the same time toxins are released, causing tissue damage and hampering the immune system, in order to facilitate bacterial spread. Once the bacteremia and associated toxemia reach a critical level, the severe symptoms characteristic of the acute phase of illness are manifested. During the acute phase, damage of the lung tissue becomes apparent on the X-ray. This damage results from the action of anthrax toxin on the endothelium of the lung’s capillary bed. Primary damage of the lung is not normally a feature of the initial phase of illness and primary pulmonary infection is an uncommon presentation.

Studies in rhesus monkeys revealed that after spore inhalation, its germination might take up to 60 days. These is reason for the recommended antibiotic prophylaxis for 60 days.

Gastrointestinal Anthrax

In animal studies the intestinal lesions are focal to diffuse hemorrhagic necrotic enteritis of the small intestine. The tendency for localized lesions to develop in Peyer's patches suggests a possible role of the M cell in the uptake of the anthrax bacillus.

Gross Pathology

Cutaneous and Injection Anthrax

Cutaneous infection typically produces ulcerated lesions which are covered by a back scab and often contain numerous microorganisms. Anthrax eschars are generally seen on exposed unprotected regions of the body, mostly on the face, neck, hands and wrists. Generally cutaneous lesions are single, but sometimes two or more lesions are present.

The lesions produced by injection contrast will be similar to the ones of the cutaneous form. The difference will reside on the fact that injection anthrax can spread throughout the body faster and be harder to recognize and treat than cutaneous anthrax.

Inhalational Anthrax

Gross pathologic lesions observed in non-human primates used in aerosol challenge models of inhalation anthrax include edema, congestion, hemorrhage and necrosis in the lungs and mediastinum. Splenitis and necrotizing or hemorrhagic lymphadenitis involving the mediastinal, tracheobronchial, and other lymph nodes are common. Primary pulmonary lesions, including those of pneumonia, are occasionally observed. Meningeal involvement ranging from edema, congestion, hemorrhage, and necrosis to suppurative or hemorrhagic meningitis, usually secondary to hematogenous spread from other types of anthrax, occurs in ≤77% of animals studied. Autopsy findings for persons who died from inhalation anthrax in Sverdlovsk and in the United States are consistent with findings from the non-human primates studies. Persons who died had extensive amounts of serosanguinous fluid in pleural cavities and edema and hemorrhage of the mediastinum and surrounding soft tissues, and 48% had cerebral edema, 21% had ascites, 17% had pericardial effusions, and 14% had petechial rash. Mediastinal lymph nodes and spleen also showed hemorrhage and necrosis.

Gastrointestinal Anthrax

On gastrointestinal infection the typical eschar may occur on different locations:

• Oropharynx
• Stomach
• Duodenum
• Ileum
• Caecum

According to the location of the eschar, gastrointestinal anthrax may be divided in 2 categories: oropharyngeal and abdominal.

As the eschar progresses, symptoms will appear as a result of the necrosis of the lesion, coupled with severe intestinal and mesenteric edema and lymph node enlargement in the mesentery.

Microscopic Pathology

Anthrax lesions at any site are characterized by extensive necrosis and confluent exudate, containing macrophages and neutrophils. In histopathological specimens or culture media, the presence of large boxcar-shaped Gram-positive bacilli in chains, suggests the diagnosis.

Cutaneous or Injection Anthrax

Histologic examination of skin lesions caused by cutaneous anthrax revealed:

• Tissue necrosis
• Edema
• Lymphocytic infiltrates
• No liquefaction
• No abscess formation (lesion is not suppurative)
• Focal points of hemorrhage
• Thrombosis
• Bacilli in subcutaneous tissue, revealed by Gram staining

Inhalation Anthrax

Histologic evaluation of affected tissues revealed:

• Numerous necrotic foci of hemorrhage in the mediastinum or hilar and peribronchial lymph nodes
• Pulmonary infection may also result in interstitial pneumonia associated with:

• Vasculitis
• Edema
• Infiltrating macrophages and neutrophils

• Bacilli are most likely to be observed in the alveolar capillaries and venules and, to a lesser degree, within the alveolar space and draining lymph nodes

Gastrointestinal Anthrax

Histologic evaluation of affected tissues revealed:

• Edema
• Mucosal necrosis
• Inflammatory infiltrates
• Peritoneal fluid may reveal gram-positive bacilli
• Occasionally mediastinal widening

Image Gallery

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  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Sterne strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on sheep blood agar (SBA) medium, for a 48 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Sterne strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on sheep blood agar (SBA) medium, for a 24 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Low-power magnification of 5X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Sterne strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on sheep blood agar (SBA) medium, for a 24 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Sterne strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on polymyxin B - lysozyme - EDTA – thallous acetate agar (PLET) medium, for a 24 hour time period, at a temperature of 37°C”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Sterne strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on phenylethyl alcohol agar (PEA) medium, for a 48 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Sterne strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on phenylethyl alcohol agar (PEA) medium, for a 24 hour time period, at a temperature of 37°.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 5X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Sterne strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on phenylethyl alcohol agar (PEA) medium, for a 24 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Sterne strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on mannitol, egg yolk, polymyxin agar (MEP) medium, for a 24 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 5X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Sterne strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on mannitol, egg yolk, polymyxin agar (MEP) medium, for a 24 hour time period, at a temperature of 37°C. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Sterne strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on colistin-naladixic acid agar (CNA) medium, for a 48 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Sterne strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on colistin-naladixic acid agar (CNA) medium, for a 24 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Sterne strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on mannitol, egg yolk, polymyxin agar (MEP) medium, for a 48 hour time period, at a temperature of 37°C. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on polymyxin B - lysozyme - EDTA – thallous acetate agar (PLET) medium, for a 48 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on sheep blood agar (SBA) medium, for a 48 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on sheep blood agar (SBA) medium, for a 24 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 5X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on sheep blood agar (SBA) medium, for a 24 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on polymyxin B - lysozyme - EDTA – thallous acetate agar (PLET) medium, for a 48 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on polymyxin B - lysozyme - EDTA – thallous acetate agar (PLET) medium, for a 24 hour time period, at a temperature of 37°C. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on phenylethyl alcohol agar (PEA) medium, for a 48 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on phenylethyl alcohol agar (PEA) medium, for a 48 hour time period, at a temperature of 37°C. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on phenylethyl alcohol agar (PEA) medium, for a 24 hour time period, at a temperature of 37°C. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on phenylethyl alcohol agar (PEA) medium, for a 24 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on mannitol, egg yolk, polymyxin agar (MEP) medium, for a 48 hour time period, at a temperature of 37°C. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on colistin-naladixic acid agar (CNA) medium, for a 48 hour time period, at a temperature of 37°C. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on colistin-naladixic acid agar (CNA) medium, for a 24 hour time period, at a temperature of 37°C. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Low-power magnification of 10X of a digital Keyence scope, this photograph depicts the colonial growth displayed by Pasteur strain members of the Gram-positive bacterium, Bacillus anthracis, which were cultured on colistin-naladixic acid agar (CNA) medium, for a 24 hour time period, at a temperature of 37°C. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Magnification of 10X, this image depicts a number of Gram-positive Bacillus anthracis bacterial colonies of the Sterne-strain, which had been cultivated on a blood agar plate (BAP), and incubated for a 24 hour time period at a temperature of 35 °C. Of particular note was the classic “ground glass” texture exhibited by the colonies, resembling a pile of glass shards. As they continued to grow, and their edges touched, you can see that these colonies had coalesced, destroying their originally well-demarcated borders.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Magnification of 10X, this image depicts a number of Gram-positive Bacillus anthracis bacterial colonies of the Sterne-strain, which had been cultivated on a blood agar plate (BAP), and incubated for a 24 hour time period at a temperature of 35 °C. Of particular note was the classic “ground glass” texture exhibited by the colonies, resembling a pile of glass shards. As they continued to grow, and their edges touched, you can see that these colonies had coalesced, destroying their originally well-demarcated borders.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Magnification of 30X, this image depicts a single Gram-positive Bacillus anthracis bacterial colony of the Sterne-strain, which had been cultivated on a blood agar plate (BAP), and incubated for a 24 hour time period at a temperature of 35 °C. Of particular note was the classic “ground glass” texture exhibited by the colony, resembling a pile of glass shards. In the background, you’ll note that as these colonies continued to grow, and their edges touched, they coalesced, destroying their originally well-demarcated borders.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Magnification of 20X, this image depicts a number of Gram-positive Bacillus anthracis bacterial colonies of the Sterne-strain, which had been cultivated on a blood agar plate (BAP), and incubated for a 24 hour time period at a temperature of 35 °C. Of particular note was the classic “ground glass” texture exhibited by the colonies, resembling a pile of glass shards. As they continued to grow, and their edges touched, you can see that these colonies had coalesced, destroying their originally well-demarcated borders.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Hematoxylin-eosin-stained (H&E) photomicrograph of a tissue specimen harvested from the bronchus of a deceased 60 year-old man, revealed cytoarchitectural changes associated with a case of inhalation anthrax, due to Gram-positive Bacillus anthracis bacteria.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Colonial morphology displayed by Gram-positive, Pasteur strain, Bacillus anthracis bacteria, which was grown on a medium of phenylethyl alcohol agar (PEA), for a 24 hour time period, at a temperature of 37°C”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Colonial morphology displayed by Gram-positive, Pasteur strain, Bacillus anthracis bacteria, which was grown on a medium of phenylethyl alcohol agar (PEA), for a 24 hour time period, at a temperature of 37°C. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Light colonial growth displayed by Gram-positive, Pasteur strain, Bacillus anthracis bacteria, which was grown on a medium of MacConkey agar, for a 24 hour time period, at a temperature of 37°C. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Light colonial growth displayed by Gram-positive, Pasteur strain, Bacillus anthracis bacteria, which was grown on a medium of MacConkey agar, for a 24 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Light colonial growth displayed by Gram-positive, Pasteur strain, Bacillus anthracis bacteria, which was grown on a medium of CNA agar, for a 24 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Light colonial growth displayed by Gram-positive, Pasteur strain, Bacillus anthracis bacteria, which was grown on a medium of CNA agar, for a 24 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Colonial morphology displayed by Gram-positive, Pasteur strain, Bacillus anthracis bacteria, which was grown on a medium of chocolate agar, for a 24 hour time period, at a temperature of 37°C.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Bacillus anthracis bacterial colonies, which had been allowed to grow on sheep’s blood agar (SBA) for a 24 hour period. In this particular view you’ll note the appearance of what is termed a "plaque" (arrowhead), which represents an area where the bacteria had been lysed, or destroyed by the application of a localized amount of gamma phage-containing solution. Highly specific toB. anthracis, these gamma phage viruses, i.e., bacteriophages, attacked the B. anthracis bacteria, subsequently leaving this circular plaque devoid of bacterial organisms. The specificity of these gamma phages to B. anthracis makes this a positive test for the presence of this bacterium.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Bacillus anthracis bacterial colonies, which had been allowed to grow on sheep’s blood agar (SBA) for a 24 hour period. Note the classical appearance exhibited in the colonial morphology including a ground-glass, non-pigmented texture with accompanying “comma” projections from some of the individual rough-edged colonies. In this particular view, you’ll note that a “tenacity test” had been performed using an iinoculating loop, which proved positive for B. anthracis, causing the “colony to ‘stand up’ like beaten egg white”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Bacillus anthracis bacterial colonies, which have been allowed to grow on sheep’s blood agar (SBA) for a 24 hour period. Note the classical appearance exhibited in the colonial morphology including a ground-glass, non-pigmented texture with accompanying “comma” projections from some of the individual rough-edged colonies. In this particular view, you’ll note that a “tenacity test” had been performed using an iinoculating loop, which proved positive for B. anthracis, causing the “colony to ‘stand up’ like beaten egg white”.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Bacillus anthracis bacterial colonies, which have been allowed to grow on sheep’s blood agar (SBA) for a 24 hour period. Note the classical appearance exhibited in the colonial morphology including a ground-glass, non-pigmented texture with accompanying “comma” projections from some of the individual rough-edged colonies. In this particular view, you’ll note that a “tenacity test” had been performed using an iinoculating loop, which proved positive for B. anthracis, causing the “colony to ‘stand up’ like beaten egg white”.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Bacillus anthracis bacterial colonies, which have been allowed to grow on sheep’s blood agar (SBA) for a 24 hour period. Note the classical appearance exhibited in the colonial morphology including a ground-glass, non-pigmented texture with accompanying “comma” projections from some of the individual rough-edged colonies.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Bacillus anthracis bacterial colonies, which have been allowed to grow on sheep’s blood agar (SBA) for a 24 hour period. Note the classical appearance exhibited in the colonial morphology including a ground-glass, non-pigmented texture with accompanying “comma” projections from some of the individual rough-edged colonies. See PHIL 11748 for a higher magnification of these colonies.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Magnification of 6,408X, this scanning electron micrograph (SEM) depicted spores from the Aimes strain of Bacillus anthracis bacteria. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Magnification of 31,207X, this scanning electron micrograph (SEM) depicted spores from the Sterne strain of Bacillus anthracis bacteria. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Magnification of 12,483X, this scanning electron micrograph (SEM) depicted spores from the Sterne strain of Bacillus anthracis bacteria.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Gram-positive, endospore-forming Bacillus anthracisbacteria. B. anthracis is the pathologic microorganism responsible for the disease “anthrax”, an acute infectious disease, which most commonly occurs in wild and domestic vertebrates (cattle, sheep, goats, camels, antelopes, and other herbivores), but it can also occur in humans when they are exposed to infected animals, or tissue from infected animals.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Gross pathologic posterior oblique view of a chimpanzee's lungs that had contracted fatal inhalation anthrax.” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Micrograph revealing submucosal hemorrhage in the small intestine, in a case of fatal human anthrax; H&E stain; Mg. 240X.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Micrograph revealing submucosal hemorrhage in the small intestine, in a case of fatal human anthrax; H&E stain; Mg. 240X.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Female patient shown here on the 24th day of a Bacillus anthracis infection involving her left eye.” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Female patient shown here on the 5th day of a Bacillus anthracis infection involving her left eye.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Female patient is shown here on the 5th day of a Bacillus anthracis infection involving her left eye.” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Symptoms of cutaneous anthrax due to B. anthracis”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Symptoms of cutaneous anthrax due to B. anthracis.” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Blood agar culture plate growing B. anthracis and other soil flora.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Hematoxylin-eosin stained (H&E) stained photomicrograph revealing some of the histopathologic changes associated with this Bacillus anthracis bacterial infection.” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Brain section through the ventricles revealing an inter ventricular hemorrhage as consequence of virulence factors of Bacillus anthracis (edema toxin, lethal toxin, and antiphagocytic capsular antigen). The toxins are responsible for the primary clinical manifestations of hemorrhage, edema, and necrosis”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Agar culture plate is growing Bacillus anthracis colonies.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Blood agar culture plate growing B. anthracis and other soil flora.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Cutaneous anthrax lesion on the arm of a 50 year old female.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  High magnification of 12,483X, this scanning electron micrograph (SEM) depicted spores from the Sterne strain of Bacillus anthracis bacteria.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Magnification of 12,483X, this scanning electron micrograph (SEM) depicted spores from the Sterne strain of Bacillus anthracis bacteria. ”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Magnification of 12,483X, this scanning electron micrograph (SEM) depicted spores from the Sterne strain of Bacillus anthracis bacteria.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Magnification of 6,408X, this scanning electron micrograph (SEM) depicted spores from the Aimes strain of Bacillus anthracis bacteria.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Photomicrograph of Bacillus anthracis bacteria using Gram-stain technique”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis taken from the peritoneum using a Hiss capsule stain.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Photomicrograph of Bacillus anthracis bacteria taken from heart blood, and using Carbol Fuchsin stain.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis positive encapsulation test is demonstrated using two different agar media”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Photomicrograph demonstrating a positive Gram stain with Bacillus anthracis”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax lesion on the skin of the forearm caused by the bacterium Bacillus anthracis”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax lesion on the neck”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax lesion on volar surface of right forearm”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis tenacity positive on sheep blood agar.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis tenacity positive on sheep blood agar”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis tenacity positive on sheep blood agar”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis Avirulent Pasteur Strain, Non-hemolytic on sheep blood agar” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis spores seen under phase contrast microscopy”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis spores seen under phase contrast microscopy”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis spores seen under phase contrast microscopy”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis spores seen under phase contrast microscopy”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "B. anthracis Direct Fluorescent Antibody (DFA) capsule stain”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "B. anthracis Direct Fluorescent Antibody (DFA) capsule stain.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "B. anthracis Direct Fluorescent Antibody (DFA) capsule stain.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "B. anthracis Direct Fluorescent Antibody (DFA) cell wall stain.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "B. anthracis Direct Fluorescent Antibody (DFA) cell wall stain.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis gamma phage lysis on sheep blood agar.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis Indian Ink capsule stain.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis M'Fadyean capsule stain”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis capsule production on bicarbonate agar medium”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Hemorrhagic lymph node due to inhalation anthrax”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Transmission electron micrograph of Bacillus anthracis.” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Transmission electron micrograph of Bacillus anthracis”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Transmission electron micrograph of Bacillus anthracis”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Transmission electron micrograph of Bacillus anthracis.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Transmission electron micrographic image of Bacillus anthracis”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Transmission electron micrograph of Bacillus anthracis”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Confocal micrograph of Bacillus anthracis”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Numerous rod-shaped Bacillus anthracis bacteria, some that had linked together to form chains, while others remained solitary”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax, skin of left forearm”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax, skin of right forearm, 4th day”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Necrosis of lymph node due to anthrax”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax, skin of face, 13th day”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax, skin of face, 11th day”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax, skin of face, 8th day”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax, skin of face, 6th day”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax, skin of face, 4th day”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax, skin of right forearm, 7th day.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax, skin of right forearm, 5th day”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax, skin of right forearm, 12th day.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Cutaneous anthrax lesion on neck of man”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Cutaneous anthrax, lesion on the left forearm”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis from agar culture Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Dr. LaForce”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Photomicrograph of lung tissue demonstrating pneumonia in a case of fatal human inhalation anthraxAdapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Bacillus anthracis in lung Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Meningeal hemorrhage due to anthrax”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Photomicrograph of meninges demonstrating hemorrhage due to fatal inhalation anthrax”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Severe hemorrhagic necrosis of lymph node due to anthrax”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Mild meningitis with hemorrhage due to Bacillus anthracis”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Photomicrograph of serohemorrhagic meningitis in a case of fatal human anthrax with the presence ofBacillus anthracis.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Blood agar plate culture of Bacillus anthracis, with a positive gamma phage test”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Sheep blood agar plate culture of Bacillus anthracis and Bacillus cereus”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Gross pathology of fixed, cut brain showing hemorrhagic meningitis due to inhalation anthrax.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Gross pathology of fixed, cut brain showing hemorrhagic meningitis due to inhalation anthrax.”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax skin lesion on face of man. Cutaneous”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Anthrax skin lesion on neck of man. Cutaneous”Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Gram-stained photomicrograph revealing numerous rod-shaped Bacillus anthracis bacteria that had linked together to form long filamentous chains.” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "Gram-stained photomicrograph revealing numerous rod-shaped Bacillus anthracis bacteria that had linked together to form long filamentous chains.” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "hematoxylin-eosin (H&E)-stained photomicrograph of a small intestinal tissue sample revealed the presence of histopathologic changes indicative of marked mucosal and submucosal hemorrhage, with accompanying arteriolar degeneration in a case of fatal human anthrax.” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  ".” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• "Gram-stained photomicrograph revealing numerous rod-shaped Bacillus anthracis bacteria that had linked together to form long filamentous chains.” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[20]

  "Gram-stained photomicrograph revealing numerous rod-shaped Bacillus anthracis bacteria that had linked together to form long filamentous chains.” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  "” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  ".” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• "” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[20]

  "” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• "” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[20]

  "” Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.