Anthrax Virulence

Anthrax Virulence

1. Multicomponent anthrax toxin: consists of 3 distinct antigenic componenet

   • Edema Factor (EF)
     • inherent adenylate cyclase and works additively with lethal factor
     • increases cAMP production
     • immunosuppressive effect
     • Necessary for edema producing activity of the toxin
   • Lethal Factor (LF)
     • immunosuppressive effect
     • damages endothelial cell function and causes cell apoptosis
     • dirupts downstream cell signalling
     • Essential for the lethal effect of anthrax toxin
     • Zn++ dependant protease that induces sytokine production in macrophages & lymphocytes
     • Crystal structure is a member of the mitogen-activated protein kinase (MAPKK) family of enzymes
       • Known to disrupt cellular signaling
   • Protective Antigen (PA)
     • binding domain that allows toxins to enter host cell
       • Binding domain of anthrax toxin which has 2 active domians: EF & LF
     • induces protective antitoxic antibodies
     • Anthrax toxin receptor
       • Human receptor for anthrax PA demonstrated to be a type I membrane protein that bind directly to PA
   • mediates toxigenic stage
   • production mediated by temperature-sensitive plasmid, pXO1
   • each component of the toxin is a thermolabile protein
   • Apart from their antigenicity, each of the 3 factors exhibits no significant biological activity.
     • Combination of 2 or 3 of the toxin components yeild the following results in experimental animals
       • PA+LF combine to produce lethal activity
       • EF+PA produce edema
         • elevates cAMP to extraordinary levels in susceptiable cells.
         • Intracellular changes in cAMP affect changes in membrane permeability & may account for edema
         • In macrophages & neutrophils: additioanl effect is depletion of ATP reserves which are needed for the engulfment process.
         • 1 effect of toxin is to impair activity of regional phagocytes duuring infectious process
       • EF+LF is inactive
         • Phagocytosis by opsonized or heat-killed B. antheacis cells is not inhibited by either EF or LF
           • BUT a combination of EF+LF inhibits engulfment of bacteria & the oxidative burst in the pmns
         • increased levels of cAMP in neutrophils
         • Studies suggest that 2 active components increase host susceptibilty to infection
           • Supressing neutrophil function & impairing host resistance
       • PA+LF+ED produces edema & necrosis & is lethal
     • Experiments suggest anthrax toxin has the familiar A-B enzymatic binding structure of bacteriual exotoxins
       • PA acting as the B fragment & either EF or LF acting as the active A fragment

2. Poly-D-Glutamyl Capsule

   • Capsule production depends on plasmid pXO2
     • Transefered to nonencapsulated B. anthracis via transduction produces an encapsulated phenotype
     • detection of capsular material used to distinguish from closest relatives
   • single antigenic type capsule consisting of D-glutamate polypeptide
   • capsule itself is none toxic
     • Prevents phagocytosis when in vegetative form.
     • function to protect organism against complement & bactericidal components of serum & phagocytes
     • Protect against phagocytic engulfment& destruction
   • Play most important during role establishment of infection
     • Mediates the invasive stage of the infection
     • less significant role in the terminal phase of disease, which are mediated by anthrax toxin

3. Host immune response

   • EF & LF inbihits CT4 T-cell proliferation, neutrophile phagocytosis, cytokine production, IL-2 production & causes macrophage lysis.
   • macrophages ingest spores & transport them to regional lymphnodes
     • Spores used macrophage tobypass immune system
   • Produced anti-protective antigen IgG to combat toxins by neutralizing lethal factor
   • PA-specific IgG memory B cells are prodcued in infected

4. Coordinates expression of virielnce factors in response to environmental signal

   • Toxin protiens & antiphagocytic capsule are produced in response to growth in increased atmospheric CO2
     • CO2 signal is thought to be of physiological significance for a pathogen which invades mammalian host tissue

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