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Connexin-dependent inter-cellular communication increases invasion and dissemination of Shigella in epithelial cells

Nature Cell Biology volume 5, pages 720–726 (2003)Cite this article

Abstract

Shigella flexneri, the causative agent of bacillar dystentery, invades the colonic mucosa where it elicits an intense inflammatory reaction responsible for destruction of the epithelium1,2. During cell invasion, contact with host cells activates the type-III secretion of the Shigella IpaB and IpaC proteins3,4. IpaB and IpaC are inserted into host cell plasma membranes and trigger initial signals that result in actin polymerization, while allowing cytosolic access of other bacterial effectors that further reorganize the cytoskeleton5,6. After internalization, Shigella moves intracellularly and forms protrusions that infect neighbouring cells, promoting bacterial dissemination across the epithelium2,6. Here, we show that during cell invasion, Shigella induces transient peaks in intracellular calcium concentration that are dependent on a functional type-III secretory apparatus. In addition, Shigella invasion induces the opening of Connexin 26 (Cx26) hemichannels in an actin- and phospholipase-C-dependent manner, allowing release of ATP into the medium. The released ATP, in turn, increases bacterial invasion and spreading, as well as calcium signalling induced by Shigella. These results provide evidence that pathogen-induced opening of connexin channels promotes signalling events that favour bacterial invasion and dissemination.

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Figure 1: Shigella cell-to-cell spreading is enhanced in connexin transfectants.
Figure 2: Invasive Shigella induces calcium responses.
Figure 3: Shigella induces ATP release in HCx26 cells.
Figure 4: ATP stimulates Shigella-induced foci of actin polymerization.
Figure 5: ATP stimulates cell-to-cell spreading of Shigella.

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Acknowledgements

The authors wish to thank H. Yamasaki for his interest in this study. We thank L. Venance for helpful suggestions on the carbenoxolone experiments. P.S. is a Howard Hughes Medical Institute Scholar. This work was supported in part by a grant from the Programme de Recherche Fondamentale en Microbiologie Maladies Infectieuses et Parasitaires from the Ministère de la Recherche et de la Technologie and a Programme Transversal de Recherches (PTR no 54) from the Institut Pasteur to G.T.V.N.

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Authors and Affiliations

  1. Unité de Pathogénie Microbienne Moléculaire, Inserm U389, Institut Pasteur, Paris, 75724, France

    Guy Tran Van Nhieu, Caroline Clair & Philippe Sansonetti

  2. Unité de Neurovirologie et Régénération du Système Nerveux, Institut Pasteur, Paris, 75724, France

    Roberto Bruzzone

  3. Laboratoire des Biomembranes et Signalisation Cellulaire, CNRS-UMR 6558 – LBSC, Université de Poitiers, Poitiers, France

    Marc Mesnil

  4. Unité de Signalisation Cellulaire et Calcium, Inserm U442, IBAIC, Université de Paris-Sud, Orsay, France

    Laurent Combettes

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Correspondence to Guy Tran Van Nhieu.

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Van Nhieu, G., Clair, C., Bruzzone, R. et al. Connexin-dependent inter-cellular communication increases invasion and dissemination of Shigella in epithelial cells. Nat Cell Biol 5, 720–726 (2003). https://doi.org/10.1038/ncb1021

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