MOLECULAR AND CELLULAR MECHANISMS OF INVASION OF THE INTESTINAL BARRIER BY ENTERIC PATHOGENS - THE PARADIGM OF SHIGELLA

The pathogenesis of bacillary dysentery can be studied at different le vels of integration of the cellular components that constitute the col onic mucosal barrier. We considered the interaction of Shigella flexne ri in three experimental systems that provide complementary informatio n and a scheme of events occurring in human colorectal mucosa as Shige lla invasion proceeds. Interaction of S. flexneri with individual epit helial cells shows a series of events in which the bacterium, upon con tact with the cell surface, releases a set of Ipa proteins (i.e. invas ins) through a specialized, activable, type-III secretory apparatus (i .e. Mxi/Spa). Via a complex signaling process, these invasins cause ma jor rearrangements of the subcortical cytoskeletal network which allow bacterial entry by a macropinocytotic event. Then the bacterium lyses its phagocytotic vacuole and initiates intracytoplasmic movement, due to polar assembly of actin filaments caused by a bacterial surface pr otein, IcsA. This allows very efficient colonization of the host cell cytoplasm and passage to adjacent cells via protrusions which are engu lfed by a cadherin-dependent process. However, when invasive Shigella are deposited on the apical side of polarized monolayers of human colo nic cells, they appear unable to invade, indicating that bacteria need to reach the subepithelial area to invade the epithelium. In this sys tem, it has been shown that transepithelial signaling caused by apical bacteria induces adherence and transmigration of basal polymorphonucl ears (PMN), thus disrupting the monolayer permeability and facilitatin g bacterial invasion. LPS accounts for a large part of this transepith elial signalization to PMN. Such a process could account for invasion in intestinal crypts. Finally, models of infection, such as the rabbit ligated intestinal loop show that initial bacterial entry occurs esse ntially via M cells of the follicular associated epithelium. It then c auses apoptosis of macrophages located in the follicular dome, inducin g release of IL-IP which, in turn, initiates inflammation, leading to destabilization of the epithelial structures as modeled above. These d ata can now be used to understand the mechanisms of mucosal protection against bacillary dysentery.