Shigella Invasion
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Shigella Invasion
Bacterial pathogens possess highly specialized adaptive processes that enable their penetration of the host intestinal epithelium and cause disease. Once bound to the epithelial surface, bacteria may colonize and establish a permanent residence in the gut. Some Gram-negative pathogenic bacteria have acquired sophisticated molecular syringes, such as Type-III or Type-IV secretion systems, which are multisubunit molecular machines that span the bacterial and host membranes and translocate effectors directly into host cells. Shigella flexneri is a Gram-negative facultative intracellular pathogen causing disease by invading the colonic mucosa. When Shigella reaches the colon, the bacteria are translocated through the epithelial barrier by way of the M-Cells of the Peyers patches, which overlay the solitary lymphoid nodules. M-Cells allow intact S. flexneri to traverse into the underlying subepithelial pocket where macrophages reside. These macrophages engulf S. flexneri, but instead of successfully destroying the bacteria, these cells rapidly undergo apoptosis. Before cell death, infected macrophages release IL-1Beta through the direct activation of Caspase1 by S. flexneri. The proinflammatory nature of IL-1Beta results in the recruitment of polymorphonuclear cells that infiltrate the infected site and destabilize the epithelium. Loss of integrity of the epithelial barrier allows more bacteria to traverse into the subepithelial space and gain access to the basolateral pole of the epithelial cells. S. flexneri can then invade epithelial cells, spread from cell to cell, and disseminate throughout the tissue (Ref.1). IL-8 is also a major secreted product of S. flexneri infected epithelial cells. This proinflammatory chemokine is a potent chemoattractant for polymorphonuclear cells and can direct recruitment of these cells into the infected site and their infiltration of the epithelial layer. An important transcriptional regulator of IL-8 gene expression is NF-KappaB (Nuclear Factor Kappa-B) involved in the inducible expression of a number of genes whose products, including many Cytokines/Chemokines, cell adhesion molecules, and acute phase response proteins involved in the inflammatory response.

The pathogens released from the killed macrophages also enter into enterocytes from the basolateral surface by inducing membrane ruffles and macropinocytosis. These localized changes in the host cytoskeleton lead to the formation of filopodia that coalesce and trap the pathogen within a membrane-bound vacuole that is rapidly lysed, thereby providing the bacterium with access to the host cell cytoplasm. Unlike Salmonella, however, Shigella rapidly lyses the surrounding vacuole and is released into the cytosol, where it grows and divides. Once the microbe has escaped from the vacuole, it quickly becomes coated with filamentous actin and ultimately forms an actin tail at one pole of the bacterium. This actin polymerization propels the bacterium through the cytoplasm and when the pathogen reaches the plasma membrane of the cell, it forms a long protrusion into the neighboring cell, which subsequently internalizes the microbe. The bacterium again breaks out of the vacuole, thereby starting a new cycle of infection in a new host cell. This process allows Shigella to move from cell to cell without ever contacting the extracellular milieu (Ref.2). During entry, the Shigella Type-III secretion apparatus (the Mxi/Spa translocon) allows the insertion of a pore that contains the invasion plasmid antigens, IpaB, IpaC and IpaD proteins into cell membranes. Insertion of this complex allows translocation of the carboxy-terminus moiety of IpaC, and other Shigella effectors, such as IpaA, into the cell cytosol. IpaC triggers actin polymerization and the formation of filopodial and lamellipodial extensions dependent on the CDC42 and RacGTPases. IpaA, on the other hand, binds to the focal adhesion protein vinculin and induces depolymerization of actin filaments. IpaA and the GTPase Rho are not required for Actin polymerization at the site of bacterial contact with the cell membrane, but allow the transformation of the IpaC-induced extensions into a structure that is productive for bacterial entry. Rho is required for the recruitment at entry foci of ezrin, a cytoskeletal linker required for Shigella entry, and also of coractin and Src tyrosine kinase. Several host cytoskeletal proteins are involved in tail formation, including Alpha-Actinin, Filamin, Fimbrin, VASP (Vasodilator-Stimulated Phosphoprotein), Vinculin, and N-WASP (Neural-Wiskott-Aldrich syndrome protein) (Ref.3). Intracellular motility of Shigella is also caused by the polar expression of IcsA/VirG, an outer membrane protein that binds N-WASP and activates the recruitment and binding of the ARP2/3 (Actin Related Protein) complex. This complex (IcsA, N-WASP, and ARP2/3) is necessary and sufficient to cause Actin nucleation-polymerisation and to promote bacterial motility in the cytoplasm. Shigella utilizes an additional means to affect the Actin cytoskeleton. The Shigella effector VirA binds Tubulin and promotes microtubule destabilization around the site of bacterial entry into the host cells. This ability in turn lead to microtubule growth and the stimulation of Rac1 activity, thus evoking local membrane ruffling, required for efficient bacterial entry into the host cells (Ref.4).

S. flexneri is the etiological agent of a self-limiting gastroenteritis called shigellosis in humans, characterized by severe localized inflammation and ulceration of the colonic mucosa. Shigellosis most often targets young children in underdeveloped countries. Colonic biopsies from infected patients reveal massive inflammatory cell infiltration, tissue edema, and regions where the epithelium is completely destroyed. Prior to development of dysentery, early inflammatory lesions of the colorectal mucosa often resemble aphthoid ulcers with the presence of a lymphoid follicle. No specific adherence system mediating the interaction between Shigella and the luminal side of M-Cells has been identified so far. However, invasive Shigella translocate much more efficiently through M-Cells than a non-invasive mutant. The acute recto-colitis that follows epithelial invasion by Shigella is a paradigm of this process (Ref.5).