Microbes and microbial toxins: Paradigms for microbial-mucosal interactions - III. Shigellosis: from symptoms to molecular pathogenesis

Interaction of Shigella flexneri with epithelial cells includes contact of bacteria with the cell surface and release of Ipa proteins through a specia lized type III secreton. A complex signaling process involving activation o f small GTPases of the Rho family and c-src causes major rearrangements of the subcortical cytoskeleton, thereby allowing bacterial entry by macropino cytosis. After entry, shigellae escape to the cell cytoplasm and initiate i ntracytoplasmic movement through polar nucleation and assembly of actin fil aments caused by bacterial surface protein IcsA, which binds and activates neuronal Wiskoff-Aldrich syndrome protein (N-WASP), thus inducing actin nuc leation in an Arp 2/3-dependent mechanism. Actin-driven motility promotes e fficient colonization of the host cell cytoplasm and rapid cell-to-cell spr ead via protrusions that are engulfed by adjacent cells in a cadherin-depen dent process. Bacterial invasion turns infected cells to strongly proinflam matory cells through sustained activation of nuclear factor-kappaB. A major consequence is interleukin (IL)-8 production, which attracts polymorphonuc lear leukocytes (PMNs). On transmigration, PMNs disrupt the permeability of this epithelium and promote its invasion by shigellae. At the early stage of infection, M cells of the follicle-associated epithelium allow bacterial translocation. Subsequent apoptotic killing of macrophages in a caspase1-d ependent process causes the release of IL-1 beta and IL-18, which accounts for the initial steps of inflammation.