Macrophage-Dependent Immunopathogenesis of Anthrax

University Of Illinois At Chicago, Chicago IL

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Abstract

Bacillus anthracis can induce a bacteremic phase of infection that is associated with a shock syndrome and a high-level rate of mortality. Most research in this field is focused on toxin production and function. Relatively little is known about the immunopathogenesis of the disease process related to macrophage infection, activation and sensitization to toxin-mediated triggering. Studies using other intracellular pathogens suggest that infection induced macrophage activation is an independent process from toxin-induced triggering of the shock syndrome. The working hypothesis for this proposal is that Bacillus anthracis induces a similar, 2-step process of macrophage activation followed by toxin triggering and that these are two, independent stages of macrophage- related immunopathogenesis of the shock syndrome. The objectives of this project are to establish an animal model of Bacillus anthracis-induced priming and toxin-induced triggering of the shock syndrome to test the hypothesis that these are independent processes. Contrasts will be made with the well-establish model of BCK-induced priming and endotoxin-induced triggering of the shock response. In vitro corollaries of infection-induced macrophage activation will test the phenotypic and functional changes of macrophage function following Bacillus anthracis infection in vivo and in vitro. Preliminary studies will test the linkage between infection-induced macrophage activation and triggering of the NF kappa B-dependent transcription response. Complementary in vitro studies will be used to test the prediction that toxin-induced triggering of activated macrophage populations will result in changes in toxin receptor expression, cytokine production and nitric oxide production and NF kappa B activation. The long-term objective is to develop an animal model and in vitro cell systems to test the functional relationships between Bacillus anthracis- induced macrophage activation and toxin-mediated triggering of activated macrophage functions that in part mediate the shock syndrome. This information will be used to seem molecular interventions that reduce or abrogate the shock response to this infection.