CHLAMYDIAL INVASION OF NON-PHAGOCYTIC CELLS

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DESCRIPTION (provided by applicant): 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.