The<i> Escherichia coli</i> heat‐labile enterotoxin induces apoptosis of immature lymphocytes <i>in vivo</i> via a glucocorticoid‐dependent pathway

Tamayo, Esther; Merino, Ramón; González-Rojas, Jovanna; Marquina, Regina; Santiuste, Inés; Amado, J. A.; Rappuoli, Rino; Giudice, Giuseppe Del; Merino, Jesús

doi:10.1002/eji.200526326

Cited by 9 publications

(33 citation statements)

References 42 publications

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“…Some studies indicate that binding of LT-B to GM1 may be sufficient for triggering apoptosis of CD8 ϩ T cells (33), while others suggest that modified LT-B constructs (e.g., H57S) still able to bind GM-1 may fail to trigger apoptosis (14). Yet other studies suggest that LT-mediated apoptosis requires the ADP-ribosylation activity of the LT-A subunit (41).…”

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confidence: 99%

EnterotoxigenicEscherichia coliModulates Host Intestinal Cell Membrane Asymmetry and Metabolic Activity

et al. 2009

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Enterotoxigenic Escherichia coli (ETEC) is a common cause of travelers' and postweaning diarrhea in humans and swine, respectively. The extent to which ETEC damages host cells is unclear. Experiments are presented that probe the ability of porcine ETEC isolates to induce apoptosis and cell death in porcine intestinal epithelial cells. Quantification of host phosphatidylserine exposure following ETEC infection suggested that ETEC induced changes in plasma membrane asymmetry, independent of the expression of the heat-labile enterotoxin. Significant host cell death was not observed. ETEC infection also caused a drastic inhibition of host esterase activity, as measured by calcein fluorescence. While ETEC infection resulted in activation of host caspase 3, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling of DNA double-strand breakage, indicative of late stages of apoptosis, was not observed. Camptothecin-induced apoptosis markedly increased subsequent ETEC adherence. Transfer of cell-free supernatants from apoptotic cells to bacterial inocula prior to infection of naïve cells increased the transcriptional activity of the regulatory region upstream of the K88ac operon and promoted subsequent adherence to host cells.Enterotoxigenic Escherichia coli (ETEC) causes childhood mortality and travelers' diarrhea in humans (36) and postweaning diarrhea in pigs (32). ETEC adherence to intestinal cells is mediated by proteinaceous, species-specific colonization factors (25). ETEC induces water and electrolyte loss from the intestine due to the activities of several enterotoxins, including the heat-labile enterotoxin (LT), the heat-stable toxins (ST), and the enteroaggregative E. coli heat-stable enterotoxin 1 (32).Bacterial pathogens often induce host cell apoptosis to promote their survival and dissemination (16,30). While several E. coli serotypes (1, 4, 9, 15) and toxins (3, 19) have been shown to induce apoptosis of epithelial cells, the extent to which ETEC damages host cells is unclear. The prototypic ETEC isolate H10407 was cytotoxic to but failed to induce apoptosis in the macrophage cell line J774 (as measured by DNA fragmentation) (24). The extent to which LT induces apoptosis has also received considerable attention due to interest in the receptor-binding subunit (LT-B) as a mucosal adjuvant. LT-B induces apoptosis of CD8 ϩ but not CD4 ϩ T cells (37). Some studies indicate that binding of LT-B to GM1 may be sufficient for triggering apoptosis of CD8 ϩ T cells (33), while others suggest that modified LT-B constructs (e.g., H57S) still able to bind GM-1 may fail to trigger apoptosis (14). Yet other studies suggest that LT-mediated apoptosis requires the ADP-ribosylation activity of the LT-A subunit (41).Overall, the roles of ETEC and LT in mediating apoptosis have not been defined clearly and remain somewhat controversial. The goals of this study were therefore to quantify the ability of ETEC to damage porcine intestinal epithelial cells, to clarify the role of LT in these processes, and to me...

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EnterotoxigenicEscherichia coliModulates Host Intestinal Cell Membrane Asymmetry and Metabolic Activity

et al. 2009

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“…As LT promotes an intense T-cell apoptosis [3,16], we explored whether the maintenance in the number of CD4…”

Section: Resultsmentioning

confidence: 99%

“…Both toxins consist of a monomeric A subunit with enzymatic activity and of a homo-pentameric ring of B subunits that bind to the cell surface ganglioside GM1. The enzymatic activity of these toxins results in a persistent activation of adenylate cyclase and the increase of cytosolic cAMP [2], which disrupts cell homeostasis with a variety of toxic effects [2,3]. The high toxicity of LT and CT has stimulated the search for mutants with low or no toxicity retaining their immunostimulatory capacity.…”

Section: Introductionmentioning

confidence: 99%

“…Both toxins induce the maturation of DC, increasing their antigen presentation capability, their migration to the lymph nodes and their interaction with naive T cells [14]. In addition, CT and LT may act directly on lymphocytes inducing their activation and/or cell death [3,15,16]. We have previously shown that administration of LT promotes an intense but incomplete apoptosis of lymphocytes [5,16].…”

Section: Introductionmentioning

confidence: 99%

“…This, together with the capacity of the toxin to stimulate the remaining lymphocytes [15], may explain the apparent paradox that an agent with such a potent pro-apoptotic activity can be an adjuvant. An interesting observation is that the LT-mediated cell death is only observed after its systemic administration [3], suggesting that the immunomodulatory properties of LT are highly influenced by the route of toxin delivery. Because of the glucocorticoid-mediated effect of LT on apoptosis [3,16], our interest was focused on the glucocorticoid-induced TNFR-related protein (GITR), a member of the TNFR superfamily that is constitutively expressed at high levels in Treg and at low levels on conventional CD4…”

Section: Introductionmentioning

confidence: 99%

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GITR contributes to the systemic adjuvanticity of the Escherichia coli heat‐labile enterotoxin

et al. 2010

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The Escherichia coli heat-labile enterotoxin (LT) possesses a powerful mucosal and systemic adjuvant effect. However, little is known about the cellular and molecular basis of the immunostimulatory activity of LT at the mucosal level, and even less information is available on the mechanisms underlying its systemic adjuvant activity. In this study, we show that distinct mechanisms are responsible for the parenteral and mucosal adjuvanticity of LT. Indeed, the systemic administration of LT upregulates the expression of glucocorticoid-induced TNFR-related protein (GITR), but not other activation markers, in naive T cells. Using WT and GITR-deficient mice and LT and its enzymatically inactive mutant LTK63 as adjuvants, we show that the induction of GITR expression in T cells accounts for the systemic immunostimulatory capacity of LT, which requires an intact enzymatic activity. In contrast, the mucosal administration of LT does not induce GITR expression on Peyer's patche T cells and accordingly no differences are observed in the mucosal adjuvanticity of LT between WT and GITR-deficient mice. Altogether, our results demonstrate the distinct effect of LT after parenteral administration when compared with the mucosal delivery, and describe a new mechanism of LT adjuvanticity related to its ability to induce the expression of GITR in CD4 1 T cells.

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Involvement of the intrinsic and extrinsic cell‐death pathways in the induction of apoptosis of mature lymphocytes by the Escherichia coli heat‐labile enterotoxin

et al. 2009

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Escherichia coli heat-labile enterotoxin (LT) exhibits a broad range of immunomodulatory activities, including the induction of lymphocyte-programmed cell death. In previous studies, we have demonstrated that in vivo LT promotes apoptosis of immature T and B cells through the stimulation of endogenous glucocorticoids. In the present study, we show that the extrinsic cell-death pathway as well as the apoptosis-inducing factor do not participate in the LT-induced elimination of thymocytes. In contrast to developing lymphocytes, LT promotes the death of mature lymphocytes by both glucocorticoid-and Fas death receptor/Fas ligand-dependent mechanisms. However, the dependency of these mechanisms in the LT-induced cell-death activity seems to be different among CD4 + and CD8 + T cells. Altogether, our study shows that the same bacterial toxin can induce apoptosis of lymphoid cells through several mechanisms depending on the status of differentiation of these cells.

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The Escherichia coli heat‐labile enterotoxin induces apoptosis of immature lymphocytes in vivo via a glucocorticoid‐dependent pathway

Cited by 9 publications

References 42 publications

EnterotoxigenicEscherichia coliModulates Host Intestinal Cell Membrane Asymmetry and Metabolic Activity

EnterotoxigenicEscherichia coliModulates Host Intestinal Cell Membrane Asymmetry and Metabolic Activity

GITR contributes to the systemic adjuvanticity of the Escherichia coli heat‐labile enterotoxin

Involvement of the intrinsic and extrinsic cell‐death pathways in the induction of apoptosis of mature lymphocytes by the Escherichia coli heat‐labile enterotoxin

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