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 hostpathogen 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.

TOM1 is a PI5P effector involved in the regulation of endosomal maturation

“…This latter pathway was originally described in cells infected with the bacterium Shigella flexneri, through the injection of the virulence factor IpgD, a PI(4,5)P 2 4-phosphatase (Niebuhr et al, 2002). Upon infection with the pathogen, or expression of the bacterial lipid phosphatase, this primary pool of PI5P at the plasma membrane has been shown to induce membrane remodeling and activation of the Akt survival pathway (Niebuhr et al, 2002;Pendaries et al, 2006), to control the modulation of hemichannel opening (Puhar et al, 2013) and to alter the endocytic pathway (Ramel et al, 2011). Namely, increased levels of PI5P induce epidermal growth factor receptor (EGFR) activation independently of its ligand and impair the maturation of early endosomes to late endosomes, delaying the degradation of EGFR to maintain survival signals.…”

Bacterial Internalization, Localization, and Effectors Shape the Epithelial Immune Response during Shigella flexneri Infection

“…This puts forward the existence of alternative signaling routes for the potential mediator. One candidate could be the rapid release and paracrine action of eATP, which is known to induce both inflammation and apoptosis responses (10). Together, our findings on the bystander population emphasize its role as a potent and integral part of the host epithelial cell immune response, and it can thus be considered an "immunological compartment" that differentially senses and exhibits distinct immune responses (Fig.…”

“…During invasion, it subverts the activated host immune responses through injected bacterial effectors. The primary effector, IpgD, is an inositol 4-phosphatase that alters multiple host signaling pathways, including the release of extracellular ATP (eATP), which activates host inflammation, and the onset of the phosphatidylinositol 3-kinase (PI3K)/Akt anti-apoptotic signaling pathways (9,10). The secondary effector, OspG, has ubiquitin-binding properties that attenuate IB degradation and NF-B-dependent immune signaling (11,12).…”

Les phosphoinositides

“…Cela contribue à des signaux de survie soutenus favorisant l'infection bactérienne [11,12]. De plus, cette augmentation du taux de PtdIns5P dans la membrane plasmique entraîne la fermeture d'hémi-canaux-connexines qui, normalement, libèrent de l'ATP dans le milieu extracellulaire pour déclencher une réaction inflammatoire dirigée contre le pathogène [13]. La bactérie pathogène utilise ainsi le PtdIns5P pour détourner les réponses de la cellule hôte à son profit.…”