Molecular mechanisms used by Chlamydia trachomatis to manipulate membrane fusion

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? DESCRIPTION (provided by applicant): The intracellular bacterium Chlamydia trachomatis is a major cause of sexually transmitted diseases and infectious blindness worldwide. The survival of Chlamydia in host cells largely relies on two fundamental processes 1) protecting its infectious intracellular compartment (so-called inclusion) from lysosomal killing and 2) hijacking host compartments to acquire lipids and material necessary for inclusion growth. Furthermore, C. trachomatis induces the homotypic fusion of its inclusions to promote its infectivity. To execute these events, C. trachomatis has evolved to be extraordinarily efficient at manipulating host vesicular trafficking and membrane fusion. Despite the importance of this intimate connection between host and Chlamydia, very little is known regarding the impact of this bacterium on the host membrane fusion machinery, the so-called SNAREs. In particular, it is not known whether Chlamydia extensively interferes with SNAREs to control host vesicular trafficking and promote its survival inside the cell. Using an innovative multidisciplinary approach, we will determine whether C. trachomatis (i) uses a series of SNARE-like proteins to specifically block endocytic/lysosomal host SNARE complexes and protect its inclusion from destruction and (ii) uses host SNAREs involved in the secretory pathway to induce fusion with host vesicles and promote the homotypic fusion of its inclusions. Ultimately, this information will guide the development of novel therapeutics that interfere with the establishment of the inclusion. Furthermore, the detailed characterization of chlamydial SNARE-like proteins will give scientists the fundamental tools to screen for their presence in other major human pathogens, including Salmonella typhi, and Mycobacterium tuberculosis, thus opening new avenues of research in infectious diseases.
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