How Shigella Utilizes Ca(2+) Jagged Edge Signals during Invasion of Epithelial Cells.

Guy Tran Van Nhieu,Mariette Bonnet

doi:10.3389/fcimb.2016.00016

Abstract

Shigella, the causative agent of bacillary dysentery invades intestinal epithelial cells using a type III secretion system (T3SS). Through the injection of type III effectors, Shigella manipulates the actin cytoskeleton to induce its internalization in epithelial cells. At early invasion stages, Shigella induces atypical Ca2+ responses confined at entry sites allowing local cytoskeletal remodeling for bacteria engulfment. Global Ca2+ increase in the cell triggers the opening of connexin hemichannels at the plasma membrane that releases ATP in the extracellular milieu, favoring Shigella invasion and spreading through purinergic receptor signaling. During intracellular replication, Shigella regulates inflammatory and death pathways to disseminate within the epithelium. At later stages of infection, Shigella downregulates hemichannel opening and the release of extracellular ATP to dampen inflammatory signals. To avoid premature cell death, Shigella activates cell survival by upregulating the PI3K/Akt pathway and downregulating the levels of p53. Furthermore, Shigella interferes with pro-apoptotic caspases, and orients infected cells toward a slow necrotic cell death linked to mitochondrial Ca2+ overload. In this review, we will focus on the role of Ca2+ responses and their regulation by Shigella during the different stages of bacterial infection.

Highlights

Shigella, the causative agent of bacillary dysentery, invades the colonic mucosa, where it induces a strong inflammatory response responsible for massive destruction of the epithelium (Ashida et al, 2015)
Shigella-infected epithelial cells do not die from apoptosis but from a slow necrotic death associated with plasma membrane (PM) permeabilization and increased cytosolic Ca2+ (Carneiro et al, 2009; Dupont et al, 2009, Figure 2)
Local Ca2+ signals affect the dynamics of cytoskeletal reorganization to promote bacterial invasion

Summary

Introduction

The causative agent of bacillary dysentery, invades the colonic mucosa, where it induces a strong inflammatory response responsible for massive destruction of the epithelium (Ashida et al, 2015). Shigella induces local and global Ca2+ responses dependent on InsP3-mediated signaling with a pattern that differs significantly from classical agonist-induced Ca2+ response (Tran Van Nhieu et al, 2003, 2013, Figure 1B). ATP signaling increases the number of bacteria captured and entering the cell at a given site, as well as bacterial invasion in neighboring cells at early stage of infection (Romero et al, 2011, Figure 1B).

Results

Conclusion