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

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

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.

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

MAP Kinase Pathway

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

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

Pathogen subversion of cytokines Viruses Bacteria Anti-inflammatory

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

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

Germinal Center-like structure in rheumatoid synovium

macrophage intoxicated m  bacillus lethal toxin TNF B. anthracis - macrophage spatial interaction dynamics

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