1. Overview of structural and functional mechanisms by which enterovirulent bacteria cause diarrhea.
Overview of structural and functional mechanisms by which enterovirulent bacteria cause diarrhea. The intestinal epithelium consists of a single layer of highly polarized epithelial cells. The tight junction, a component of the apical junctional complex, seals the paracellular space between epithelial cells. Specific structural proteins compose the cytoskeleton and microtubule networks, which play pivotal roles in the polarized organization of intestinal cells. The brush border at the apical domain and basolateral cell domain contains proteins and transporters exerting specific intestinal functions. The intestinal epithelial barrier plays an essential role in maintaining immune homeostasis. The intestinal microbiota resides in the lumen, outside the mucus layer. Goblet cells secrete mucins which, combined with membrane-bound mucins, act as a physicochemical barrier and protect the epithelial cell surface. Antimicrobial peptides secreted by Paneth cells and enterocytes are localized within the mucus layer, forming the first chemical defense system against unwanted enteric pathogens. The lamina propria, located beneath the basement membrane, contains immune and dendritic cells. Enterovirulent bacteria use their adhesive factors to interact with the brush border membrane by hijacking membrane-bound molecules as receptors. Structural and functional brush border injuries results in adhesin/receptor interaction or T3SS-translocated bacterial effectors activating cell signaling pathways that lead to the cytoskeleton-dependent attachment/effacement (A/E) lesion of brush border microvilli or shedding of microvilli, which in turn results in the disappearance of brush border-associated proteins exerting specific intestinal functions. On the other hand, secreted cytotonic toxins, by binding to membrane-bound receptors, by endocytosis and retrograde traffic, or by T3SS-translocated bacterial effectors, activate signaling pathways for deregulating membrane-associated proteins controlling nutrient transport or functioning as ions and water channels. Moreover, secreted cytotoxic toxins after endocytosis induce cytoskeleton- or caspase-dependent cell death. In addition, via T3SS-translocated bacterial effectors or secreted toxins, enteric pathogens also target the junctional domain of polarized epithelial cells, inducing structural and functional lesions at the tight junctions and leading to a fault in the intestinal epithelial barrier. Invasive enterovirulent bacteria cross the epithelial cell membrane via a massive membrane rearrangement, penetrate into the host cells, and pursue sophisticated intracellular lifestyles within vacuoles containing bacteria. Other enteroinvasive bacteria, after escape from the vacuole, engage in actin-based movements within the cell cytoplasm for the penetration of neighboring cells via bacterium-induced transpodia. Adhering and invading enterovirulent bacteria trigger cellular defense responses, including, for example, the enhanced production/secretion of mucus and the production of proinflammatory cytokines and chemokines activating, in turn, immune cells of lamina propria. Moreover, some enterovirulent bacteria act to produce a loss of the first line of intestinal defenses by modifying the resident microbiota composition or altering the secretory process of mucus from goblet cells.
Vanessa Liévin-Le Moal, and Alain L. Servin Microbiol. Mol. Biol. Rev. 2013; doi: /MMBR