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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI070654-05
Application #
8197012
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Breen, Joseph J
Project Start
2007-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$371,695
Indirect Cost
$126,670
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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
Bier, Ethan; Guichard, Annabel (2012) Deconstructing host-pathogen interactions in Drosophila. Dis Model Mech 5:48-61
Wangler, Michael F; Reiter, Lawrence T; Zimm, Georgianna et al. (2011) Antioxidant proteins TSA and PAG interact synergistically with Presenilin to modulate Notch signaling in Drosophila. Protein Cell 2:554-63
Do, Long Hoang; Bier, Ethan (2011) The Booly aliasing resource: a database of grouped biological identifiers. Bioinformation 6:83-5
Grossman, Tamar R; Gamliel, Amir; Wessells, Robert J et al. (2011) Over-expression of DSCAM and COL6A2 cooperatively generates congenital heart defects. PLoS Genet 7:e1002344
Do, Long H; Esteves, Francisco F; Karten, Harvey J et al. (2010) Booly: a new data integration platform. BMC Bioinformatics 11:513
Lee, Jun Hee; Budanov, Andrei V; Park, Eek Joong et al. (2010) Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 327:1223-8
Lee, Jun Hee; Bodmer, Rolf; Bier, Ethan et al. (2010) Sestrins at the crossroad between stress and aging. Aging (Albany NY) 2:369-74

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