Shigella, a Category B agent, is responsible for an estimated 1.1 million deaths annually. An in-depth understanding of the pathogen-host interaction is essential to the treatment and development of new therapeutics against diseases. Shigella pathogenesis involves bacterial invasion of the colonic epithelium and subsequent intercellular spread. One aspect of this process that is poorly understood is the spread of Shigella from one cell into an adjacent uninfected cell. I propose the first genome-wide analysis of host cell factors required for S. flexneri pathogenesis, with a particular focus on the factors required for S. flexneri intercellular spread.
My Specific Aims are: 1) to identify host factors necessary for S. flexneri spread via a genome-wide siRNA screen, 2) to characterize the pathways engaged by S. flexneri during intercellular spread. My approach is highly likely to identify novel factors in the mammalian cell that contribute to S. flexneri pathogenesis, and perhaps the pathogenesis of other Category A-C pathogens. Furthermore, I expect that a screen for small molecule inhibitors of S. flexneri spread currently being carried out in the Goldberg laboratory will generate complementary data, which together with the data generated here, might allow us both to identify small molecule inhibitors of specific pathways critical to S. flexneri and to characterize the mechanism of action of these molecules. These approaches may lead to the development of therapeutic agents for the treatment of Shigella infection. Lay summary: The intestinal bacterium Shigella causes 1.1 million deaths annually and is a potential agent of bioterrorism. A better understanding of the methods by which Shigella causes disease allows the development of preventative and therapeutic agents against Shigella. I propose a large-scale analysis of human proteins that participate in Shigella disease and a detailed investigation of the method in which Shigella interacts with these proteins. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI073035-02
Application #
7469523
Study Section
Special Emphasis Panel (ZRG1-F13-P (20))
Program Officer
Mills, Melody
Project Start
2007-07-01
Project End
2009-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$51,278
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Lu, Richard; Herrera, Bobby Brooke; Eshleman, Heather D et al. (2015) Shigella Effector OspB Activates mTORC1 in a Manner That Depends on IQGAP1 and Promotes Cell Proliferation. PLoS Pathog 11:e1005200