Evidence has shown that anthrax lethal toxin (LeTx) is responsible for most disease symptoms and death due to B. anthracis infection. However, the precise molecular mechanism by which lethal toxin causes disease remains a mystery. Lethal factor (L.F), the catalytic component of LeTx, is a zinc-dependent protease that has been shown to cleave MAPKKs, thus disrupting signaling through the ERK, p38, and JNK pathways. LF is able to enter and cleave MAPKK in the various tested cell types, however, only murine macrophages were shown to be sensitive to toxin induced lysis in vitro. Furthermore, macrophages from certain inbred strains of mice are resistant to toxin, but can be sensitized if activated with bacterial components, presumably via toll like receptors (TLR). We are interested in uncovering cellular mechanisms that contribute to toxin sensitivity. Here, we propose experiments designed to elucidate TLR signaling involved in sensitization of resistant macrophages as we predict this involves events that play a role upstream of toxin activity. Additionally, we will conduct somatic cell and chemical genetic screens using a toxin sensitive macrophage cell line to identify cellular factors or processes that play a role LF sensitivity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AI061847-01
Application #
6831798
Study Section
Special Emphasis Panel (ZRG1-ONC-O (29))
Program Officer
Hernandez, Milton J
Project Start
2004-08-01
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$28,513
Indirect Cost
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Sanchez, Ana M; Thomas, Diane; Gillespie, Eugene J et al. (2007) Amiodarone and bepridil inhibit anthrax toxin entry into host cells. Antimicrob Agents Chemother 51:2403-11
Nassanian, Hoorig; Sanchez, Ana M; Lo, Alice et al. (2007) Efficient construction of an inverted minimal H1 promoter driven siRNA expression cassette: facilitation of promoter and siRNA sequence exchange. PLoS One 2:e767
Banks, David J; Barnajian, Moshe; Maldonado-Arocho, Francisco J et al. (2005) Anthrax toxin receptor 2 mediates Bacillus anthracis killing of macrophages following spore challenge. Cell Microbiol 7:1173-85