cytokine subversion — and inducible transient organogenesis— by bacillus anthracis
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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. - PowerPoint PPT PresentationTRANSCRIPT
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Cytokine Subversion—and inducible transient organogenesis—
by Bacillus anthracis
Tom KeplerCenter for Bioinformatics & Computational Biology
Duke University Medical Center
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Outline
• B. anthracis
• Cytokines– TNF
• Spatial organization– Inducible Transient Organogenesis
• Model and Results
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Mathematical Modeling and Category A pathogens
• Little/No Human data– Naturally rare– No experimentation
• Diversity among animal models
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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.
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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
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MAP Kinase Pathway
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Cytokines
• Communication molecules– Proliferation– Differentiation– Regulation of Movement
• Pro-inflammatory– TNF, IL1, IL6, …
• Anti-inflammatory– IL10, IL4
• Chemoattractant• Viral subversion
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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
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Pathogen subversion of cytokines
• Viruses
• Bacteria
• Anti-inflammatory
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Inducible Transient Organogenesis
• Germinal center– Synovial GC
• Granuloma
• Thymus– Transplantation observations (M.L. Markert)
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Lymph Node Germinal Center
Mantle
Light Zone
Dark Zone
T (paracortical) Zone
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Germinal Center-like structure in rheumatoid synovium
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Application
macrophageintoxicated mbacillus
lethal toxin
TNF
B. anthracis - macrophage spatial interaction dynamics
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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
• 919 681 0620