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 specialized type III secreton. A complex signaling process involving activation of small GTPases of the Rho family and c-src causes major rearrangements of the subcortical cytoskeleton, thereby allowing bacterial entry by macropinocytosis. After entry, shigellae escape to the cell cytoplasm and initiate intracytoplasmic movement through polar nucleation and assembly of actin filaments caused by bacterial surface protein IcsA, which binds and activates neuronal Wiskoff-Aldrich syndrome protein (N-WASP), thus inducing actin nucleation in an Arp 2/3-dependent mechanism. Actin-driven motility promotes efficient colonization of the host cell cytoplasm and rapid cell-to-cell spread via protrusions that are engulfed by adjacent cells in a cadherin-dependent process. Bacterial invasion turns infected cells to strongly proinflammatory cells through sustained activation of nuclear factor-kappaB. A major consequence is interleukin (IL)-8 production, which attracts polymorphonuclear 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 caspase 1-dependent process causes the release of IL-1beta and IL-18, which accounts for the initial steps of inflammation.
Sansonetti
P J
PJ
Unité de Pathogénie Microbienne Moléculaire et Unité Institut National de la Santé et de la Recherche Médicale 389, Institut Pasteur, 75724 Paris cédex 15, France. psanson@pasteur.fr
D004405:Dysentery, Bacillary / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D006790:Host-Parasite Interactions / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D012763:Shigella flexneri / Q000276:immunology / Q000472:pathogenicity; D014118:Toxins, Biological / Q000633:toxicity
D014118:Toxins, Biological