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Anthrax

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

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  1. Anthrax R.C. Liddington, Nature, 415: 373-374 (2002) Another Reason to Fear Your Mailman By Stefko Waschuk

  2. Outline General Information Pathogenic components Treatment / Management Therapeutic uses

  3. 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

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

  5. 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

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

  7. Systemic Anthrax • Mortality rate ~100% • Spores germinate within macrophage • Toxin released into bloodstream • Toxemia and septicemia • Shock and death

  8. So, How Does It Kill Me? M. Mourez et al. Trends Microbiol.10:287-293 (2002)

  9. Requirements for Pathogenesis • Anthrax Toxin Receptor • Protective Antigen • Lethal Factor and/or • Oedema Factor

  10. 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

  11. Protective Antigen (PA) • 83 kDa protein • 4 domains • Binds ATR • Activation requires cleavage • Mediates delivery of EF & LF into host cells

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

  13. Mode of Anthrax Toxin Entry M. Mourez et al. Nature Biotech., 19: 958-961 (2001)

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

  15. Lethal Factor (LF) • 90 kDa zinc-dependent protease • 7 N-terminal residues critical for PA binding • Large homology with EF

  16. PA Recognition Site on LF/EF

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

  18. 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

  19. 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)

  20. 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)

  21. 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)

  22. 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

  23. 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

  24. Summary: Anthrax Toxin Action M. Mourez et al. Trends Microbiol.10:287-293 (2002)

  25. Anthrax Toxin Management • Vaccinations • Antibiotics • Other strategies • Polyclonal antibodies • Synthetic inhibitors

  26. Vaccinations • Anthrax vaccine adsorbed (AVA) • Made from protective antigen

  27. Antibiotics • Ciprofloxacin Hydrochloride • C17H18FN3O3.HCl.H2O • Cutaneous Anthrax  ~100% effective • Systemic Anthrax  before symptomatic

  28. Synthetic Inhibitors • EF/LF binding analogues • Mutated PA • Soluble ATR

  29. EF/LF Binding Analogues M. Mourez et al. Trends Microbiol.10:287-293 (2002)

  30. Domain II Mutant PA M. Mourez et al. Trends Microbiol.10:287-293 (2002)

  31. Domain III Mutant PA J. Mogridge et al. PNAS. 99: 7045-7048 (2002)

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

  33. 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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