Cytokine Subversion—and inducible transient organogenesis—

by Bacillus anthracis

Tom KeplerCenter 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

Application

macrophageintoxicated mbacillus

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

• kepler@duke.edu

• 919 681 0620