Bacterial pathogens and the toxins they produce are a leading cause of disease and mortality in the developing world and can be used as agents for bioterrorism. Since the host target proteins for many of these toxins have been highly conserved during the course of evolution, model organisms such as Drosophila melanogaster provide effective tools for analyzing the molecular mechanism of toxin action and for identifying new host targets mediating their toxicity. Bacillus anthracis, the causative agent of anthrax, produces two exotoxins, Lethal factor (LF) and Edema factor (EF), which are required for bacterial pathogenicity. Although a great deal is known about the structures and enzymatic activities of anthrax toxins, much less is understood about the cellular mechanisms by which these toxins cause disease. It is also unclear whether LF has additional targets and whether LF and EF function in a concerted fashion or act via separate mechanisms. In this grant, we propose to use Drosophila to analyze the function of the anthrax LF and EF toxins. We will focus on analyzing novel toxin induced phenotypes and identifying targets mediating these effects. In addition, we will analyze the basis for strong genetic synergism between LF and EF as well as the opposing lethal and heart disrupting activities of these toxins in adult flies. Finally, we will collaborate with other groups to determine whether the LF and EF act similarly in vertebrates.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Breen, Joseph J
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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Guichard, Annabel; Nizet, Victor; Bier, Ethan (2014) RAB11-mediated trafficking in host-pathogen interactions. Nat Rev Microbiol 12:624-34
Guichard, Annabel; Cruz-Moreno, Beatriz; Cruz-Moreno, Beatriz Cruz et al. (2013) Cholera toxin disrupts barrier function by inhibiting exocyst-mediated trafficking of host proteins to intestinal cell junctions. Cell Host Microbe 14:294-305
Guichard, Annabel; Nizet, Victor; Bier, Ethan (2012) New insights into the biological effects of anthrax toxins: linking cellular to organismal responses. Microbes Infect 14:97-118
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