Microsimulation of anthracis-immune system interaction

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DESCRIPTION (provided by applicant): This project will develop a realistic microsimulation of the pathogenesis of B. anthracis infection and the immune response mounted against it. This computational model is intended to complement the ongoing in vitro and animal studies and provide a means to integrate the information obtained in these various experiments. The investigators will study the transient functional reorganization of the immune system in response to B. anthracis infection. Anthrax lethal toxin appears to act largely by cleaving proteins in the signaling cascade that controls the synthesis of pro-inflammatory cytokines including TNF and IL-1 [beta]. This interference results in the overproduction of these cytokines, which are a key component of the host antibacterial response, but also mediate shock and cytotoxicity. It is not simply the overproduction of pro-inflammatory cytokines per se that drives the pathogenesis of anthrax, but the dysregulation of the normal transient reorganization of the immune system of which TNF and IL-1[beta] are a key part. The microsimulation will be constructed as a modular and multi-scale realistic computational model providing the means to explore this hypothesis, design experimental tests for its falsification and examine its implications for the design of novel therapies.