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, which are fundamental for its toxicity. The spores of B. anthracis are the infectious form and can remain dormant in the environment for decades. The disease may be transmitted through the skin, gastrointestinal or respiratory systems. The bacterium causes disease through 2 mechanisms: toxemia and bacterial infection.[1] B. anthracis begins to produce toxins within hours of germination.[2] 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), the active toxins. Bacterial toxins have a direct cytotoxic effect by interfering with cellular pathways, being also responsible for weakening the immune system, so the initial systemic infection may occur. Anthrax lesions at any site are characterized by lymphadenopathy, extensive edema, necrosis and confluent exudate containing macrophages and neutrophils. If not stopped, the infection may affect different organs, causing septicemia and potentially death.

Genetics

The genetic component of Bacillus anthracis includes 1 chromosome and 2 plasmids. These plasmids (pXO1 and pXO2) are fundamental for its toxicity:[1]

  • pXO1 - encodes 3 components of the anthrax exotoxins:
  • Protective Antigen (PA)
  • Lethal Factor (LF)
  • Edema Factor (EF)

Transmission

The route of transmission of anthrax allows for its classification into the following:[3]

  • 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 the 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.[4] The bacterium causes disease through 2 mechanisms: toxemia and bacterial infection.[1] 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.[5][1] B. anthracis begins to produce toxins within hours of germination.[2] 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.[6] Bacillus anthracis disseminate to multiple organs including spleen, liver, intestines, kidneys, adrenal glands, and meninges, affecting their normal functions and leading to systemic infection with a potentially fatal outcome.[7][8][3]

The virulence factors of Bacillus anthracis are:

  • PA
  • LF
  • EF

Bacterial Toxins

In order to infect the body, Bacillus anthracis must produce toxins. These toxins have 3 main toxic effects: edema, hemorrhage, and necrosis. Besides their direct toxic effects responsible for 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.[1]

When isolated, the 3 structural elements of the anthrax exotoxins are non-toxic. However, when combined, they form virulent exotoxins:[1]

  • 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.[1]

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 the exotoxin complexes with LF and EF, it must first be activated by host-cellular receptors:[1]

  • CMG2 - Capillary Morphogenesis Protein 2 (predominant toxin receptorin vivo)
  • 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.[1]

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.[1]

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 multiple intracellular mechanisms.[1]

Cutaneous or Injection Anthrax

According to animal studies, spores that enter the skin of susceptible animals (either through a lesion or by injection) germinate and give rise, in about 2 - 4 hours, to a small edematous area containing capsulated bacilli. The following stages are noticed:[3]

Injection anthrax will have similar pathogenesis to cutaneous anthrax, but since it is injected, it can spread throughout the body faster and it becomes harder to recognize and treat than the cutaneous form.[9]

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 to facilitate bacterial spread.[10][11][12]

Once the bacteremia and associated toxemia reach a critical level, the severe symptoms that are 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.[13][11][12]

Studies in rhesus monkeys revealed that after spore inhalation, its germination might take up to 60 days. This is the reason why antibiotic prophylaxis is recommended for 60 days.[11]

Gastrointestinal Anthrax

In animal studies, the intestinal lesions caused by ingested anthrax spores range from 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.[3]

Gross Pathology

Cutaneous and Injection Anthrax

Cutaneous infection typically produces ulcerated lesions which are covered by a 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.[14][15]

The lesions produced by injection anthrax 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.[9]

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.[16] 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.[17] Autopsy findings from persons who died from inhalation anthrax in Sverdlovsk and in the United States[18] are consistent with findings from the non-human primates studies. Persons who died had extensive amounts of serosanguinous fluid in pleural cavities, edema, and hemorrhage of the mediastinum and surrounding soft tissues. 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.[16][19]

Gastrointestinal Anthrax

On gastrointestinal infection the typical eschar may occur on different locations, including:[11]

According to the location of the eschar, gastrointestinal anthrax may be divided in 2 categories: oropharyngeal and abdominal.[11]

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.[11]

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 reveals:[20]

Inhalation Anthrax

Histologic evaluation of affected tissues reveals:

Gastrointestinal Anthrax

Histologic evaluation of affected tissues revealed:[20]

Gallery

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 (2014) "Anthrax lethal and edema toxins in anthrax pathogenesis". Trends in Microbiology 22 (6): 317–325. doi:10.1016/j.tim.2014.02.012. ISSN 0966842X.
  2. 2.0 2.1 (1999) "Understanding Bacillus anthracis pathogenesis". Trends in Microbiology 7 (5): 180–182. doi:10.1016/S0966-842X(99)01507-3. ISSN 0966842X.
  3. 3.0 3.1 3.2 3.3 Anthrax in Humans and Animals.
  4. (2008) "Anthrax". Journal of the American Veterinary Medical Association 233 (1): 63–72. doi:10.2460/javma.233.1.63. ISSN 0003-1488.
  5. (1957) "The pathogenesis of anthrax following the administration of spores by the respiratory route". The Journal of Pathology and Bacteriology 73 (2): 485–494. doi:10.1002/path.1700730219. ISSN 0368-3494.
  6. (2004) "The roles of anthrax toxin in pathogenesis". Current Opinion in Microbiology 7 (1): 19–24. doi:10.1016/j.mib.2003.12.001. ISSN 13695274.
  7. Rubin, Raphael (2012). Rubin's pathology : clinicopathologic foundations of medicine. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 1605479683. 
  8. Kumar, Vinay (2014). Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Elsevier/Saunders. ISBN 0323266169. 
  9. 9.0 9.1 Anthrax Symptoms.
  10. Turnbull, Peter (2008). Anthrax in humans and animals. Geneva, Switzerland: World Health Organization. ISBN 9789241547536. 
  11. 11.0 11.1 11.2 11.3 11.4 11.5 Spencer RC (2003). "Bacillus anthracis.". J Clin Pathol 56 (3): 182-7. PMID 12610093.
  12. 12.0 12.1 Friedlander AM, Welkos SL, Pitt ML, Ezzell JW, Worsham PL, Rose KJ et al. (1993). "Postexposure prophylaxis against experimental inhalation anthrax.". J Infect Dis 167 (5): 1239-43. PMID 8486963.
  13. Turnbull, Peter (2008). Anthrax in humans and animals. Geneva, Switzerland: World Health Organization. ISBN 9789241547536. 
  14. Rubin, Raphael (2012). Rubin's pathology : clinicopathologic foundations of medicine. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 1605479683. 
  15. Kumar, Vinay (2014). Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Elsevier/Saunders. ISBN 0323266169. 
  16. 16.0 16.1 (2003) "Pathology and Pathogenesis of Bioterrorism-Related Inhalational Anthrax". The American Journal of Pathology 163 (2): 701–709. doi:10.1016/S0002-9440(10)63697-8. ISSN 00029440.
  17. (2010) "Pathology of Inhalational Anthrax Animal Models". Veterinary Pathology 47 (5): 819–830. doi:10.1177/0300985810378112. ISSN 0300-9858.
  18. A. A. Abramova & L. M. Grinberg (January-February 1993). "[Pathology of anthrax sepsis according to materials of the infectious outbreak in 1979 in Sverdlovsk (macroscopic changes)]". Arkhiv patologii 55 (1): 12–17. PMID 7980032.
  19. A. A. Abramova & L. M. Grinberg (January-February 1993). "[Pathology of anthrax sepsis according to materials of the infectious outbreak in 1979 in Sverdlovsk (macroscopic changes)]". Arkhiv patologii 55 (1): 12–17. PMID 7980032.
  20. 20.0 20.1 (1999) "Anthrax". New England Journal of Medicine 341 (11): 815–826. doi:10.1056/NEJM199909093411107. ISSN 0028-4793.
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