The Shigella flexneri Type Three Secretion System Effector IpgD Inhibits T Cell Migration by Manipulating Host Phosphoinositide Metabolism

Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, Paris, France.
Cell host & microbe (Impact Factor: 12.33). 04/2011; 9(4):263-72. DOI: 10.1016/j.chom.2011.03.010
Source: PubMed


Shigella, the Gram-negative enteroinvasive bacterium that causes shigellosis, relies on its type III secretion system (TTSS) and injected effectors to modulate host cell functions. However, consequences of the interaction between Shigella and lymphocytes have not been investigated. We show that Shigella invades activated human CD4(+) T lymphocytes. Invasion requires a functional TTSS and results in inhibition of chemokine-induced T cell migration, an effect mediated by the TTSS effector IpgD, a phosphoinositide 4-phosphatase. Remarkably, IpgD injection into bystander T cells can occur in the absence of cell invasion. Upon IpgD-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP(2)), the pool of PIP(2) at the plasma membrane is reduced, leading to dephosphorylation of the ERM proteins and their inability to relocalize at one T cell pole upon chemokine stimulus, likely affecting the formation of the polarized edge required for cell migration. These results reveal a bacterial TTSS effector-mediated strategy to impair T cell function.

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Available from: Andrea Puhar, Jan 07, 2014
    • "In epithelial cells, the depletion of PI(4,5)P 2 contributes to the actin dynamics notably by disrupting the connections between cortical actin and the plasma membrane, whereas the production of PI(5)P induces activation of the PI3-kinase/Akt pathway, thereby promoting host cell survival (Niebuhr et al., 2002; Pendaries et al., 2006; Ramel et al., 2011). Recent studies indicate that IpgD prevents T cell migration at the site of infection and blocks ATP release to attenuate inflammation, suggesting that it plays a role in evading the immune response (Konradt et al., 2011; Puhar et al., 2013). Whereas the entry process into epithelial cells is rather well established , the molecular mechanism of vacuolar rupture used by Shigella remains to be defined. "
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    Cell Host & Microbe 10/2014; 16(4):517-530. DOI:10.1016/j.chom.2014.09.005 · 12.33 Impact Factor
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    • "In vitro studies have shown that Shigella triggers rapid DC pyroptosis and apoptosis (Edgeworth et al., 2002; Kim et al., 2008). We recently demonstrated that Shigella invades activated human CD4 + T cells in vitro and inhibits T cell migration toward a chemoattractant stimulus dependent on the virulence effector IpgD (Konradt et al., 2011). Additionally, Shigella impairs T cell dynamics in vivo within the site of adaptive immunity priming, i.e., the LN (Salgado-Pabón et al., 2013). "
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    • "Nunès and Guittard PI5P in T cell biology bind PI5P in order to dissect the potential functional role of PI5P and to design some potential probes for PI5P as has been done for PI(3,4,5)P 3 detection with the Akt Pleckstrin Homology (PH) domain. Finally, increase in PI5P levels could be involved; not only in T cell signaling and gene transcription, but also in T cell chemotaxis (Konradt et al., 2011) and/or other cellular processes such as vesicular trafficking and chromatin rearrangement. "
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    ABSTRACT: Phosphoinositides are critical regulators in cell biology. Phosphatidylinositol 4,5-bisphosphate, also known as PI(4,5)P2 or PIP2, was the first variety of phosphoinositide to enter in the T cell signaling scene. Phosphatidylinositol bis-phosphates are the substrates for different types of enzymes such as phospholipases C (β and γ isoforms) and phosphoinositide 3-kinases (PI3K class IA and IB) that are largely involved in signal transduction. However until recently, only a few studies highlighted phosphatidylinositol monophosphates as signaling molecules. This was mostly due to the difficulty of detection of some of these phosphoinositides, such as phosphatidylinositol 5-phosphate, also known as PI5P. Some compelling evidence argues for a role of PI5P in cell signaling and/or cell trafficking. Recently, we reported the detection of a PI5P increase upon TCR triggering. Here, we describe the current knowledge of the role of PI5P in T cell signaling. The future challenges that will be important to achieve in order to fully characterize the role of PI5P in T cell biology, will be discussed.
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