Friday, June 2, 2023
6/2/2023
PROJECT SUMMARY The intracellular bacterium Chlamydia trachomatis is a major cause of sexually transmitted disease and infectious blindness with over 150 million cases worldwide. Once inside the cell, Chlamydia replicates in a parasitic compartment called an inclusion, which is encased in actin and microtubules scaffolds. Actin scaffolds provide inclusion integrity, while microtubules (MT) control Golgi repositioning around the inclusion; both of these events are necessary for Chlamydia survival. Despite the importance of cytoskeleton rearrangements for Chlamydia's life cycle, a major gap exists regarding the molecular mechanism used by this bacterium to control the cytoskeleton. Furthermore, Chlamydia redirects multiple host organelles to its inclusion during infection. Remarkably, which cytoskeleton scaffold controls this repositioning remains to be identified. Of note, this is a key question as organelle repositioning enhances lipid and nutrient transfer to the inclusion, which then contribute to the growth of the inclusion membrane and the replication of the bacteria. Using recently established genetically-modified Chlamydia strains, we propose to study the role of novel chlamydial proteins (also called effectors) in the formation of cytoskeleton scaffolds. These effectors have been shown to interact with cytoskeleton proteins in transfected cells and are, therefore, ideal candidates to manipulate cytoskeleton during infection. Specifically, we will test the hypotheses that 1) Chlamydia builds a molecular platform composed of multiple bacterial and host proteins to coordinate actin and MT rearrangements during infection, and 2) as cytoskeletal scaffolds are woven around the inclusion, various organelles are then diverted towards the inclusion to promote Chlamydia's survival. Ultimately, this information will have a broad scientific impact as (i) It will establish the detailed mechanism used by Chlamydia to repurpose two major cytoskeleton elements for its own benefit and will provide a better understanding of disease progression; (ii) Cytoskeleton rearrangement plays a critical role in cancer development. Since Chlamydia infection has been associated with an increased risk of cancer, understanding how the cytoskeleton is reorganized during infection will shed light on this phenomenon; (iii) Understanding the mechanism that controls cytoskeleton dynamics will provide critical insight into fundamental biological pathways, and (iv) Finally, a detailed characterization of the proteins that control cytoskeletal dynamics during Chlamydia infection will provide fundamental tools to screen for the presence of similar effectors in other major human pathogens that also manipulate host cytoskeleton, in particular Salmonella, thus opening new avenues of research in molecular pathogenesis.
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