title: A Shigella effector dampens inflammation by regulating epithelial release of danger signal ATP through production of the lipid mediator PtdIns5P.
abstract: Upon infection with Shigella flexneri, epithelial cells release ATP through connexin hemichannels. However, the pathophysiological consequence and the regulation of this process are unclear. Here we showed that in intestinal epithelial cell ATP release was an early alert response to infection with enteric pathogens that eventually promoted inflammation of the gut. Shigella evolved to escape this inflammatory reaction by its type III secretion effector IpgD, which blocked hemichannels via the production of the lipid PtdIns5P. Infection with an ipgD mutant resulted in rapid hemichannel-dependent accumulation of extracellular ATP in vitro and in vivo, which preceded the onset of inflammation. At later stages of infection, ipgD-deficient Shigella caused strong intestinal inflammation owing to extracellular ATP. We therefore describe a new paradigm of host-pathogen interaction based on endogenous danger signaling and identify extracellular ATP as key regulator of mucosal inflammation during infection. Our data provide new angles of attack for the development of anti-inflammatory molecules.
authors: Inserm U786, Unité de Pathogénie Microbienne Moléculaire, 75724 Paris Cedex 15, France; Institut Pasteur, Unité de Pathogénie Microbienne Moléculaire, 75724 Paris Cedex 15, France. Electronic address: andrea.puhar@pasteur.fr.
authors: Andrea
authors: A
authors: Puhar
authors: Inserm U1048, I2MC, 31432 Toulouse Cedex 4, France; Université Toulouse 3, I2MC, 31432 Toulouse Cedex 4, France.
authors: Hélène
authors: H
authors: Tronchère
authors: Inserm U1048, I2MC, 31432 Toulouse Cedex 4, France; Université Toulouse 3, I2MC, 31432 Toulouse Cedex 4, France; CHU Toulouse, Laboratoire d'Hématologie, 31432 Toulouse Cedex 4, France.
authors: Bernard
authors: B
authors: Payrastre
authors: Inserm U1050, Equipe Communication Intercellulaire et Infections Microbiennes, CIRB, 75231 Paris Cedex 5, France; CNRS UMR7241, Equipe Communication Intercellulaire et Infections Microbiennes, CIRB, 75231 Paris Cedex 5, France; Collège de France, Equipe Communication Intercellulaire et Infections Microbiennes, CIRB, 75231 Paris Cedex 5, France.
authors: Guy Tran Van
authors: GT
authors: Nhieu
authors: Inserm U786, Unité de Pathogénie Microbienne Moléculaire, 75724 Paris Cedex 15, France; Institut Pasteur, Unité de Pathogénie Microbienne Moléculaire, 75724 Paris Cedex 15, France. Electronic address: philippe.sansonetti@pasteur.fr.
authors: Philippe J
authors: PJ
authors: Sansonetti
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004405:Dysentery, Bacillary / Q000276:immunology* / Q000378:metabolism*; D004755:Enterobacteriaceae / Q000276:immunology; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011817:Rabbits; D012763:Shigella flexneri / Q000235:genetics / Q000378:metabolism*
chemical_list: D018129:Phosphatidylinositol Phosphates; C113567:phosphatidylinositol 5-phosphate; D000255:Adenosine Triphosphate