A Shigella effector dampens inflammation by regulating epithelial release of danger signal ATP through production of the lipid mediator PtdIns5P

Immunity. 2013 Dec 12;39(6):1121-31. doi: 10.1016/j.immuni.2013.11.013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • Cells, Cultured
  • Dysentery, Bacillary / immunology*
  • Dysentery, Bacillary / metabolism*
  • Enterobacteriaceae / immunology
  • Enterobacteriaceae Infections / immunology
  • Enterobacteriaceae Infections / metabolism
  • HeLa Cells
  • Humans
  • Inflammation / metabolism*
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Male
  • Phosphatidylinositol Phosphates / genetics
  • Phosphatidylinositol Phosphates / metabolism*
  • Polymerase Chain Reaction
  • Rabbits
  • Shigella flexneri / genetics
  • Shigella flexneri / metabolism*

Substances

  • Phosphatidylinositol Phosphates
  • phosphatidylinositol 5-phosphate
  • Adenosine Triphosphate