Anthrax
Sponsored Links
This presentation is the property of its rightful owner.
1 / 33

Anthrax PowerPoint PPT Presentation


  • 116 Views
  • Uploaded on
  • Presentation posted in: General

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

Download Presentation

Anthrax

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


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

    • 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

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


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 Anthrax

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


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?

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


Requirements for Pathogenesis

  • Anthrax Toxin Receptor

  • Protective Antigen

  • Lethal Factor

    and/or

  • Oedema Factor


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)

  • 83 kDa protein

  • 4 domains

  • Binds ATR

  • Activation requires cleavage

  • Mediates delivery of EF & LF into host cells


Protective Antigen

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


Mode of Anthrax Toxin Entry

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


PA Heptamer

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


Lethal Factor (LF)

  • 90 kDa zinc-dependent protease

  • 7 N-terminal residues critical for PA binding

  • Large homology with EF


PA Recognition Site on LF/EF


Lethal Factor Structure

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


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)

  • 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)


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)


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

  • 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

  • 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

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


Anthrax Toxin Management

  • Vaccinations

  • Antibiotics

  • Other strategies

    • Polyclonal antibodies

    • Synthetic inhibitors


Vaccinations

  • Anthrax vaccine adsorbed (AVA)

  • Made from protective antigen


Antibiotics

  • Ciprofloxacin Hydrochloride

    • C17H18FN3O3.HCl.H2O

  • Cutaneous Anthrax  ~100% effective

  • Systemic Anthrax  before symptomatic


Synthetic Inhibitors

  • EF/LF binding analogues

  • Mutated PA

  • Soluble ATR


EF/LF Binding Analogues

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


Domain II Mutant PA

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


Domain III Mutant PA

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


Soluble ATR

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


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


  • Login