Modeling the effects of a Staphylococcal Enterotoxin B (SEB) on the apoptosis pathway.
BACKGROUND
The lack of detailed understanding of the mechanism of action of many biowarfare agents poses an immediate challenge to biodefense efforts. Many potential bioweapons have been shown to affect the cellular pathways controlling apoptosis 1234. For example, pathogen-produced exotoxins such as Staphylococcal Enterotoxin B (SEB) and Anthrax Lethal Factor (LF) have been shown to disrupt the Fas-mediated apoptotic pathway 24. To evaluate how these agents affect these pathways it is first necessary to understand the dynamics of a normally functioning apoptosis network. This can then serve as a baseline against which a pathogen perturbed system can be compared. Such comparisons can expose both the proteins most susceptible to alteration by the agent as well as the most critical reaction rates to better instill control on a biological network.


RESULTS
We explore this through the modeling and simulation of the Fas-mediated apoptotic pathway under normal and SEB influenced conditions. We stimulated human Jurkat cells with an anti-Fas antibody in the presence and absence of SEB and determined the relative levels of seven proteins involved in the core pathway at five time points following exposure. These levels were used to impute relative rate constants and build a quantitative model consisting of a series of ordinary differential equations (ODEs) that simulate the network under both normal and pathogen-influenced conditions. Experimental results show that cells exposed to SEB exhibit an increase in the rate of executioner caspase expression (and subsequently apoptosis) of 1 hour 43 minutes (+/- 14 minutes), as compared to cells undergoing normal cell death.


CONCLUSIONS
Our model accurately reflects these results and reveals intervention points that can be altered to restore SEB-influenced system dynamics back to levels within the range of normal conditions.
Higgs
Brandon W
BW
Emerging Technologies Office, The MITRE Corporation, McLean, VA, USA. bhiggs@mitre.org
Dileo
John
J
Chang
Wenling E
WE
Smith
Haley B
HB
Peters
Olivia J
OJ
Hammamieh
Rasha
R
Jett
Marti
M
Feidler
Jordan C
JC
D000911:Antibodies, Monoclonal / Q000276:immunology; D058846:Antibodies, Monoclonal, Murine-Derived; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D015153:Blotting, Western; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D003198:Computer Simulation; D004768:Enterotoxins / Q000276:immunology / Q000633:toxicity*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D008954:Models, Biological; D009010:Monte Carlo Method; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D013223:Statistics as Topic; D013997:Time Factors; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis; D019014:fas Receptor
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D004768:Enterotoxins; C491901:FAS protein, human; D018124:Receptors, Tumor Necrosis Factor; D051636:X-Linked Inhibitor of Apoptosis Protein; C411023:anti-Fas monoclonal antibody; D019014:fas Receptor; C031818:enterotoxin B, staphylococcal; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases