Chlamydia trachomatis is a Gram-negative obligate intracellular pathogen that is the causative agent of a wide spectrum of human diseases including trachoma and the sexually transmitted disease chlamydia. Successful infection of cells by chlamydia involves attachment, invasion, establishment of a protective vacuole called an inclusion, and inhibition of lysosomal fusion. With the advent of the C. trachomatis genome sequence and new cell biological and proteomic tools, the mechanisms involved in these processes are just beginning to be revealed, advancing our knowledge of chlamydia-host cell interactions. The long term goal is to define the molecular and biochemical mechanisms important for the successful establishment of infection by chlamydia. This proposal will specifically address the process of invasion. It is hypothesized that chlamydia uses multiple pathways of invading non-phagocytic cells. A recently identified molecule termed Tarp has been demonstrated to be translocated from the infecting elementary body across the host plasma membrane and into the cytosol where it is tyrosine phosphorylated by unknown host kinases, and recruit actin. As a phosphoprotein, Tarp may act as a signaling platform to recruit a number of adapter and effector molecules that mediate actin cytoskeletal remodeling.
Specific Aim 1 will address the Rac GTPase dependent pathway and focus on the potential downstream mediators of actin recruitment.
Specific Aim 2 will focus on the Tarp protein, the tyrosine kinase(s) responsible for its phosphorylation, the binding partners, their roles in chlamydial invasion, and the potential relationship of Tarp with the Rac GTPase.
Specific Aim 3 will address the potential mechanism of actin recruitment by the Chlamydophila caviae Tarp homolog, which does not contain the multiple repeat sequences present in C. trachomatis serovars L2 and D. These studies would not only reveal important insights into the biology of chlamydia, but also the cellular process of signaling to the actin cytoskeleton that chlamydia subverts to facilitate its infection. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI065545-04
Application #
7393732
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Hiltke, Thomas J
Project Start
2005-07-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$226,954
Indirect Cost
Name
U of L Imperial Col of Sci/Technlgy/Med
Department
Type
DUNS #
227092590
City
London
State
Country
United Kingdom
Zip Code
SW7 2-AZ
Nogueira, Ana T; Pedrosa, Antonio T; Carabeo, Rey A (2018) Manipulation of the Host Cell Cytoskeleton by Chlamydia. Curr Top Microbiol Immunol 412:59-80
Brinkworth, Amanda J; Wildung, Mark R; Carabeo, Rey A (2018) Genomewide Transcriptional Responses of Iron-Starved Chlamydia trachomatis Reveal Prioritization of Metabolic Precursor Synthesis over Protein Translation. mSystems 3:
Nogueira, Ana T; Braun, Kristin M; Carabeo, Rey A (2017) Characterization of the Growth of Chlamydia trachomatis in In Vitro-Generated Stratified Epithelium. Front Cell Infect Microbiol 7:438
Pokorzynski, Nick D; Thompson, Christopher C; Carabeo, Rey A (2017) Ironing Out the Unconventional Mechanisms of Iron Acquisition and Gene Regulation in Chlamydia. Front Cell Infect Microbiol 7:394
Thwaites, Tristan R; Pedrosa, Antonio T; Peacock, Thomas P et al. (2015) Vinculin Interacts with the Chlamydia Effector TarP Via a Tripartite Vinculin Binding Domain to Mediate Actin Recruitment and Assembly at the Plasma Membrane. Front Cell Infect Microbiol 5:88
Thwaites, Tristan; Nogueira, Ana T; Campeotto, Ivan et al. (2014) The Chlamydia effector TarP mimics the mammalian leucine-aspartic acid motif of paxillin to subvert the focal adhesion kinase during invasion. J Biol Chem 289:30426-42
Thompson, Christopher C; Nicod, Sophie S; Malcolm, Denise S et al. (2012) Cleavage of a putative metal permease in Chlamydia trachomatis yields an iron-dependent transcriptional repressor. Proc Natl Acad Sci U S A 109:10546-51
Fields, Kenneth A; Heinzen, Robert A; Carabeo, Rey (2011) The obligate intracellular lifestyle. Front Microbiol 2:99
Brinkworth, Amanda J; Malcolm, Denise S; Pedrosa, António T et al. (2011) Chlamydia trachomatis Slc1 is a type III secretion chaperone that enhances the translocation of its invasion effector substrate TARP. Mol Microbiol 82:131-44
Carabeo, Rey (2011) Bacterial subversion of host actin dynamics at the plasma membrane. Cell Microbiol 13:1460-9

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