Dissecting Molecular Mechanisms of Shigella flexneri Cell-to-cell Spread

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Dissecting Molecular Mechanisms of Shigella flexneri Cell-to-cell Spread

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Title: Dissecting Molecular Mechanisms of Shigella flexneri Cell-to-cell Spread
Author: Lee, Soo Young
Citation: Lee, Soo Young. 2014. Dissecting Molecular Mechanisms of Shigella flexneri Cell-to-cell Spread. Doctoral dissertation, Harvard University.
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Abstract: Shigella is a causative agent of bacillary dysentery in humans. The ability of Shigella to disseminate in the intestinal epithelium is crucial for disease establishment. This process of cell-to-cell spread involves actin-based motility, which allows movement of Shigella through the cytoplasm, and the ability of Shigella to form filopodia-like membrane protrusions that are engulfed by adjacent cells.
Compared to the process of Shigella actin tail assembly, which requires recruitment and activation of host actin modulators such as N-WASP and Arp2/3, the mechanism of how Shigella moves from an infected cell into neighboring cells and what host factors are involved remain poorly characterized. In this dissertation, I investigate whether members of the Ena/VASP family, as key actin regulators, or Inverse-BAR (I-BAR) family proteins, as coordinators of membrane curvature and actin dynamics, are required in dissemination of S. flexneri in a cell monolayer.
Ena/VASP family proteins regulate cell migration, adhesion, shape, and cell-cell interaction. The members of the family include Vasodilator-Stimulated Phosphoprotein (VASP), Ena-VASP-like (Evl), and Mammalian enabled (Mena). We have previously shown that Mena, despite its localization to the actin tail, has no role in S. flexneri actin-based motility. Here, I investigate the role of Mena, Evl, and VASP in S. flexneri dissemination. I determine that the presence of VASP or Evl restricts cell-to-cell spread of S. flexneri. I further show evidence that the conserved EVH1 domain and phosphorylation of VASP regulate the ability of Shigella to spread.
I-BAR proteins, including IRSp53 and IRTKS, contain a conserved domain that directly binds to membrane lipids and induces convex membrane deformation. This unique property and the ability of these proteins to bind F-actin and actin modulators are necessary for the formation of actin pedestals by pathogenic E. coli and filopodia. Using cells with reduced levels of IRTKS or IRSp53, I examine the role of these proteins in cell-to-cell spread and show that neither IRTKS nor IRSp53 is required for S. flexneri spread.
Collectively, these results advance our understanding of host proteins that participate in S. flexneri dissemination.
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:13065011
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