Shigella is a gram-negative enteropathogenic bacterium responsible for dysentery in humans. The type III secretion system (T3SS) encoded on a large plasmid is a key virulence factor of Shigella. Upon epithelial contact, the T3SS allows the translocation of effector proteins into the target cells subverting host cell signal transduction pathways. These T3SS effectors reorganize the actin cytoskeleton through the targeting of RhoGTPases and tyrosine kinase signaling, leading to localized membrane ruffling and subsequent bacterial invasion of host cells. Recent evidence indicate that as opposed to what is observed in non-polarized cells, the coordinated activity of the T3SS effectors, IpgB1 and IpgB2 that activate RhoGTPases, is required for invasion of polarized intestinal epithelial cells that form highly organized intercellular junctions. Adherens junctions (AJs) are regulated by Rho GTPases and tyrosine kinases. In particular, the disruption of AJs linked to epithelial-to-mesenchymal transition (EMT) implicates signaling processes that are reminiscent to those observed during Shigella invasion. These results suggest that the diversion of AJs by these Shigella effectors is necessary for bacterial invasion. In this proposal, we will characterize signaling events mediated by T3SS effectors leading to the transient activation of an EMT-like pathway implicating RhoGTPases and tyrosine kinase signaling, accounting for the breaching of the epithelial barrier by this enteroinvasive bacterial pathogen. This proposal which addresses a key process of bacterial pathogenesis in a relevant epithelial cell system is likely to have profound implications on our understanding of mechanisms underlying the regulation of the epithelial barrier homeostasis and its manipulation by invasive pathogens.
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