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