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Cytokine Subversion — and inducible transient organogenesis— by Bacillus anthracis

Cytokine Subversion — and inducible transient organogenesis— by Bacillus anthracis. Tom Kepler Center for Bioinformatics & Computational Biology Duke University Medical Center. Outline. B. anthracis Cytokines TNF Spatial organization Inducible Transient Organogenesis Model and Results.

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Cytokine Subversion — and inducible transient organogenesis— by Bacillus anthracis

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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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