Anthrax toxins - MegaMicro

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Anthrax toxins

Micro > Bacteriology > Pathogenic mechanisms > Toxins
Source organism: Bacillus anthracis
Structure of toxin
·         Three-protein exotoxin: A2B
o   Activity domains:
§ Anthrax Edema Factor (EF)
§ Anthrax Lethal Factor (LF)
o   Binding component:
§ Protective Antigen (PA)
o   Toxin variation

§ Edema toxin: PA+EF
§ Lethal toxin: PA+LF

Mechanism:
·         Toxin entry into cell:
o   PA binds to an anthrax toxin receptor on the cell membrane and forms a pre-pore
§ Surface of pre-pore can bind up to 4 molecules of LF or EF
§ Assembled complex is endocytosed and carried to an acidic compartment of the cell
·         Low pH converts the pre-pore into a cation-selective channel
§ EF & LF are driven through the channel by a pH gradient exposing the factors to the cytosol

·         Enzymatic mechanisms of EF & LF:
o   EF acts as a Ca2+-calmodulin dependent adenylate cyclase to increase cAMP in the cell
§ Increase in cAMP disrupts water homeostasis leading to disruption of intracellular ion regulation and resulting in edema
o   LF acts as a Zn2+-dependent endoprotease that cleaves the N-terminus of MAPKK
§ This leads to inhibition of the kinases causing altered signaling pathways and eventually apoptosis
§ Apoptosis of macrophages allows the organism to evade the immune system
Prevention:
·         Spores are destroyed by boiling but can survive for years in dry dirt
·         Tetracycline can be used as a prophylaxis against anthrax
·         Vaccinations are available against bacillus anthracis

Disease produced: Three presentations

o   Pulmonary anthrax is caused through inhalation of spores
§ Spores germinate and replicate in the respiratory tract allowing the bacteria to enter the blood stream and release their toxins systemically
§ Spores can be taken up by macrophages in the lungs and brought to the hilar and mediastinal lymph nodes resulting in widening of the mediastinum
§ Presents with:
·         Fever
·         Dyspnea
·         Non-productive cough
§ Very high mortality rate (85%+)

o   GI anthrax is caused through ingestion of contaminated meat
§ Spores germinate and replicate in the GI tract
§ The bacteria then secrete toxins that cause necrotic lesions in the throat and intestines
§ The bacteria can disseminate into the blood causing systemic infection
§ Can also lead to dysentery and vomiting of blood
§ High mortality rate

o   Cutaneous anthrax is caused by inoculation of an abrasion or wound with spores
§ Spores germinate and replicate in the wound  followed by secretion of toxinf, causing the “classic” painless black lesion with a ring of edema
§  This form of anthrax is usually not fatal if treated and often affects people who work in the hides and wool industry

Related concepts
1.       Anthrax Toxin
2.       Edema Factor
3.       Lethal Factor
4.       Bacillus Anthracis

 
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