Cytokine Subversion

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Cytokine Subversionand inducible transient
organogenesisby Bacillus anthracis

• Tom Kepler
• Center 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
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Germinal Center-like structure in rheumatoid
synovium
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B. anthracis - macrophage spatial interaction
dynamics
macrophage
lethal toxin
intoxicated mf
bacillus
TNF
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Postdoctoral and Predoctoral Opportunities at
CB2

• Duke University Medical Center
• Center for Bioinformatics and Computational
  Biology
• New PhD program starting 2003
• Postdoctoral Fellows Sought
• kepler_at_duke.edu
• 919 681 0620