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Cytokine Subversion and Organogenesis by Bacillus anthracis: Modeling and Results

Explore the subversion of cytokines by B. anthracis, inducible transient organogenesis, and mathematical modeling. Learn about the lifecycle, biochemistry, toxins, and spatial interactions with macrophages. Discover opportunities at Duke University Medical Center.

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Cytokine Subversion and Organogenesis by Bacillus anthracis: Modeling and Results

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  1. Cytokine Subversion—and inducible transient organogenesis—by Bacillus anthracis Tom Kepler Center for Bioinformatics & Computational Biology Duke University Medical Center

  2. Outline • B. anthracis • Cytokines • TNF • Spatial organization • Inducible Transient Organogenesis • Model and Results

  3. Mathematical Modeling and Category A pathogens • Little/No Human data • Naturally rare • No experimentation • Diversity among animal models

  4. Bacillus anthracis: lifecycle • Endospore • Dormant and highly resistant for decades • Upon exposure to low pH, amino acids (e.g., macrophage phagosomes), germinates. • Vegetative bacillus • Grows within the host, eventually killing it. • No host-host transmission • Upon exposure to air, sporulates.

  5. B. anthracis: biochemistry • Toxins • Protective Antigen • Heptameric binding to host cell surface receptors • Mediates entry of EF and LF into host cell • Edema Factor • ATP → cAMP • Inhibits neutrophil phagocytosis • Lethal Factor • Cleaves MAPKK • Induces ROI, TNF, IL6

  6. MAP Kinase Pathway

  7. Cytokines • Communication molecules • Proliferation • Differentiation • Regulation of Movement • Pro-inflammatory • TNF, IL1, IL6, … • Anti-inflammatory • IL10, IL4 • Chemoattractant • Viral subversion

  8. TNF • Produced by monocytes/macrophages upon bacterial stimulation • Low dose: chemoattraction, activation • High dose: necrosis, apoptosis: Shock • Soluble TNF receptor from cleavage of aggregated receptor

  9. Pathogen subversion of cytokines • Viruses • Bacteria • Anti-inflammatory

  10. Inducible Transient Organogenesis • Germinal center • Synovial GC • Granuloma • Thymus • Transplantation observations (M.L. Markert)

  11. Mantle Light Zone Dark Zone T (paracortical) Zone Lymph Node Germinal Center

  12. Germinal Center-like structure in rheumatoid synovium

  13. B. anthracis - macrophage spatial interaction dynamics macrophage lethal toxin intoxicated mf bacillus TNF

  14. Postdoctoral and Predoctoral Opportunities at [CB]2 • Duke University Medical Center • Center for Bioinformatics and Computational Biology • New PhD program starting 2003 • Postdoctoral Fellows Sought • kepler@duke.edu • 919 681 0620

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