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Anthrax. R.C. Liddington, Nature , 415 : 373-374 (2002). Another Reason to Fear Your Mailman By Stefko Waschuk. Outline. General Information Pathogenic components Treatment / Management Therapeutic uses. General Information. From Bacillus anthracis Two primary forms

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Anthrax

Anthrax

R.C. Liddington, Nature, 415: 373-374 (2002)

Another Reason to Fear Your Mailman

By Stefko Waschuk


Outline
Outline

General Information

Pathogenic components

Treatment / Management

Therapeutic uses


General information
General Information

  • From Bacillus anthracis

  • Two primary forms

    • cutaneous anthrax (usually curable)

    • systemic anthrax (usually lethal)

  • Encoded by 2 additional plasmids in genome

    • pXO1 (184.5 kbp)

      • anthrax toxin  oedema factor (EF), lethal factor (LF), and protective antigen (PA)

    • pXO2 (95.3 kbp)

      • poly-D-glutamic acid capsule


B anthracis cycle
B. Anthracis cycle

M. Mock, A. Fouet, Annu. Rev. Microbiol.55: 647-671 (2001)


Cutaneous anthrax
Cutaneous Anthrax

  • 95% of all cases

  • Characterized by

    • tissue swelling (oedema)

    • skin lesion

    • impaired neutrophil function

  • Usually self-limiting

    • 80-90% of cases resolve without complication


Cutaneous anthrax1
Cutaneous Anthrax

T.C. Dixon. et al. New England Journal of Medicine, 341: 815-826 (1999)


Systemic anthrax
Systemic Anthrax

  • Mortality rate ~100%

  • Spores germinate within macrophage

  • Toxin released into bloodstream

    • Toxemia and septicemia

      • Shock and death


So how does it kill me
So, How Does It Kill Me?

M. Mourez et al. Trends Microbiol.10:287-293 (2002)


Requirements for pathogenesis
Requirements for Pathogenesis

  • Anthrax Toxin Receptor

  • Protective Antigen

  • Lethal Factor

    and/or

  • Oedema Factor


Anthrax toxin receptor atr
Anthrax Toxin Receptor (ATR)

  • Type I membrane protein

  • Extracellular von Willebrand factor A domain

    • Directly binds to PA

  • large extracellular domain with 3 N-linked glycosylation sites

  • Highly conserved between different species


Protective antigen pa
Protective Antigen (PA)

  • 83 kDa protein

  • 4 domains

  • Binds ATR

  • Activation requires cleavage

  • Mediates delivery of EF & LF into host cells


Protective antigen
Protective Antigen

M. Mourez et al. Trends Microbiol.10:287-293 (2002)


Mode of anthrax toxin entry
Mode of Anthrax Toxin Entry

M. Mourez et al. Nature Biotech., 19: 958-961 (2001)


Pa heptamer
PA Heptamer

M. Mourez et al. Trends Microbiol.10:287-293 (2002)


Lethal factor lf
Lethal Factor (LF)

  • 90 kDa zinc-dependent protease

  • 7 N-terminal residues critical for PA binding

  • Large homology with EF



Lethal factor structure
Lethal Factor Structure

A.D. Pannifer et al. Nature,414: 229-233 (2001)


Lethal factor
Lethal Factor

  • Surgical protease

    • Cleaves 1 specific bond near N-terminus of six known MAPKKs

      • Removes the docking sequence for MAPK

    • Lethal effects by unknown mechanism

  • Cleavage of MAPKK inhibits release of pro-inflammatory cytokines


Oedema factor ef
Oedema Factor (EF)

  • 89 kDa adenylate cyclase

  • Contributes to both cutaneous and systemic anthrax

  • Impairs phagocytosis in macrophages

  • Identical 7 PA binding residues as LF

  • Requires activation by calmodulin (CaM)


Oedema factor structure inactive

Active site in interface of CA and CB

Catalytic machinery is present, but disordered

Oedema Factor Structure (inactive)

C.L. Drum et al.Nature,415: 396-402 (2002)


Oedema factor structure active

CaM displaces helical domain

Switch B becomes ordered

binds ATP

stabilizes EF catalytic residues

Oedema Factor Structure (active)

C.L. Drum et al.Nature,415: 396-402 (2002)


More fun with cam binding
More Fun with CaM binding

  • Large binding surface stabilizes structural changes

  • ATP locked into catalytic site by salt bridge

  • Conformational changes to active site do not directly involve catalytic residues

    • become exposed to solvent in active state


Effects of ef activation
Effects of EF Activation

  • EF-CaM forms an irreversible complex

    • CaM forced into extended conformation

  • Adenylate cyclase becomes active

  • Conversion of ATP  cAMP

  • Increased [cAMP] perturbs immune effector cell functions

    • Phagocytosis

    • Chemotactic response

    • Cytokine expression


Summary anthrax toxin action
Summary: Anthrax Toxin Action

M. Mourez et al. Trends Microbiol.10:287-293 (2002)


Anthrax toxin management
Anthrax Toxin Management

  • Vaccinations

  • Antibiotics

  • Other strategies

    • Polyclonal antibodies

    • Synthetic inhibitors


Vaccinations
Vaccinations

  • Anthrax vaccine adsorbed (AVA)

  • Made from protective antigen


Antibiotics
Antibiotics

  • Ciprofloxacin Hydrochloride

    • C17H18FN3O3.HCl.H2O

  • Cutaneous Anthrax  ~100% effective

  • Systemic Anthrax  before symptomatic


Synthetic inhibitors
Synthetic Inhibitors

  • EF/LF binding analogues

  • Mutated PA

  • Soluble ATR


Ef lf binding analogues
EF/LF Binding Analogues

M. Mourez et al. Trends Microbiol.10:287-293 (2002)


Domain ii mutant pa
Domain II Mutant PA

M. Mourez et al. Trends Microbiol.10:287-293 (2002)


Domain iii mutant pa
Domain III Mutant PA

J. Mogridge et al. PNAS. 99: 7045-7048 (2002)


Soluble atr
Soluble ATR

M. Mourez et al. Trends Microbiol.10:287-293 (2002)


Therapeutic uses of anthrax
Therapeutic Uses of Anthrax

  • LFN and EFN can be bound to drugs, imported through ATR & PA

  • Cancer Treatments

    • Oncogenic proteins (Ras) activate MAPKs

    • Expression of matrix metalloproteases


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