Three Models of Anthrax Toxin Effects on the MAP-Kinase Pathway and Macrophage Survival; Master's thesis

摘要

Lethal factor (LF), a component of anthrax toxin, is the primary virulence factor that allows Bacillus anthracis to evade the immune response by blocking the activation of mitogen-activated protein kinase (MAPK) enzymes. This research modifies three published MAPK models to reflect this signal inhibition and to estimate a first-order reaction rate by fitting the models to published viability data for two macrophage cell lines cultured with the LF- producing Bacillus anthracis-Vollum1B strain. One model appears to be ill- suited for this purpose because not all relevant MAPK components could be integrated into the inhibition equations. Despite different underlying parameters and values, the remaining two models display consistent behavior, due to the highly conserved signal pathway structure, and provide approximately equal rate constants and measures of the relative sensitivity between cell lines. The results demonstrate model robustness and an ability to guide experimental design toward quantifying the LF reaction rate and estimating the sensitivity of human alveolar macrophages. The models serve as a first step toward an inhalation dose-response model and, by providing a measure of differential susceptibility, can lend increased confidence in extrapolation between cell types in vitro or between species in vivo.