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
    • "T cells are a key component of the adaptive immune system and are required for protective immunity against many bacterial pathogens45678910. Recent studies have shown that a number of bacterial pathogens, including Salmonella Typhimurium, can directly inhibit T cells11121314151617, providing insight into the types of strategies used by pathogenic bacteria to overcome pathways of the adaptive immune system. Salmonellae are a leading cause of morbidity and mortality in humans worldwide18192021. "
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    ABSTRACT: Salmonellae are pathogenic bacteria that induce immunosuppression by mechanisms that remain largely unknown. Previously, we showed that a putative type II l-asparaginase produced by Salmonella Typhimurium inhibits T cell responses and mediates virulence in a murine model of infection. Here, we report that this putative l-asparaginase exhibits l-asparagine hydrolase activity required for Salmonella Typhimurium to inhibit T cells. We show that l-asparagine is a nutrient important for T cell activation and that l-asparagine deprivation, such as that mediated by the Salmonella Typhimurium l-asparaginase, causes suppression of activation-induced mammalian target of rapamycin signaling, autophagy, Myc expression, and l-lactate secretion. We also show that l-asparagine deprivation mediated by the Salmonella Typhimurium l-asparaginase causes suppression of cellular processes and pathways involved in protein synthesis, metabolism, and immune response. Our results advance knowledge of a mechanism used by Salmonella Typhimurium to inhibit T cell responses and mediate virulence, and provide new insights into the prerequisites of T cell activation. We propose a model in which l-asparagine deprivation inhibits T cell exit from quiescence by causing suppression of activation-induced metabolic reprogramming.
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    • "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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    ABSTRACT: Shigella enters epithlial cells via internalization into a vacuole. Subsequent vacuolar membrane rupture allows bacterial escape into the cytosol for replication and cell-to-cell spread. Bacterial effectors such as IpgD, a PI(4,5)P2 phosphatase that generates PI(5)P and alters host actin, facilitate this internalization. Here, we identify host proteins involved in Shigella uptake and vacuolar membrane rupture by high-content siRNA screening and subsequently focus on Rab11, a constituent of the recycling compartment. Rab11-positive vesicles are recruited to the invasion site before vacuolar rupture, and Rab11 knockdown dramatically decreases vacuolar membrane rupture. Additionally, Rab11 recruitment is absent and vacuolar rupture is delayed in the ipgD mutant that does not dephosphorylate PI(4,5)P2 into PI(5)P. Ultrastructural analyses of Rab11-positive vesicles further reveal that ipgD mutant-containing vacuoles become confined in actin structures that likely contribute to delayed vacular rupture. These findings provide insight into the underlying molecular mechanism of vacuole progression and rupture during Shigella invasion.
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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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    ABSTRACT: Antibody-mediated immunity to Shigella, the causative agent of bacillary dysentery, requires several episodes of infection to get primed and is short-lasting, suggesting that the B cell response is functionally impaired. We show that upon ex vivo infection of human colonic tissue, invasive S. flexneri interacts with and occasionally invades B lymphocytes. The induction of a type three secretion apparatus (T3SA)-dependent B cell death is observed in the human CL-01 B cell line in vitro, as well as in mouse B lymphocytes in vivo. In addition to cell death occurring in Shigella-invaded CL-01 B lymphocytes, we provide evidence that the T3SA needle tip protein IpaD can induce cell death in noninvaded cells. IpaD binds to and induces B cell apoptosis via TLR2, a signaling receptor thus far considered to result in activation of B lymphocytes. The presence of bacterial co-signals is required to sensitize B cells to apoptosis and to up-regulate tlr2, thus enhancing IpaD binding. Apoptotic B lymphocytes in contact with Shigella-IpaD are detected in rectal biopsies of infected individuals. This study therefore adds direct B lymphocyte targeting to the diversity of mechanisms used by Shigella to dampen the host immune response.
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