Chapter 16 : Enteric Pathogens That Affect Intestinal Epithelial Tight Junctions

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This chapter covers the effects of both enteric pathogens such as bacterial and viral pathogens on intestinal epithelial tight junction (TJs). The author and his research group have shown that enteropathogenic (EPEC)-induced myosin light chain (MLC) phosphorylation is one way that this pathogen disrupts the TJ barrier; other researchers have shown the same for enterohemorrhagic (EHEC). Several microbes elaborate proteases. In this era of attention to host-pathogen interactions, the functional impact of some of these bacterial products is becoming apparent. An interesting paradigm has emerged over the past few years—the exploitation of TJ transmembrane proteins as microbial receptors. First, several claudin isoforms were shown to function as receptors for enterotoxin (CPE), the toxin responsible for the diarrhea associated with type A food poisoning. Second, three unrelated viruses have now been shown to use TJ transmembrane proteins as receptors. The most recent studies identifying TJ proteins as receptors for both viruses and a bacterial toxin exemplify exploitation. Diarrhea benefits the host by flushing the organisms from the intestinal lumen. At the same time, diarrhea serves as a means of transmission of the pathogen.

Citation: Hecht G. 2003. Enteric Pathogens That Affect Intestinal Epithelial Tight Junctions, p 267-284. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch16

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Bacterial Proteins
Type III Secretion System
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Image of FIGURE 1

Schematic of TJ structure. TJs are macromolecular structures consisting of both transmembrane-spanning proteins, such as occludin, and a number of claudin isoforms. Two additional integral membrane proteins with a single transmembrane domain (not shown) are JAM and CAR. These molecules contribute to the barrier function of TJs. In addition to the transmembrane proteins, a number of other proteins form an intracellular plaque that likely aids in the targeting of transmembrane proteins. A number of signaling molecules also localize to the TJ and likely contribute to the regulation of permeability. The exact roles of these signaling molecules have not been defined. (Modified from L. L. Mitic and J. M. Anderson, 60:121–142, 1998.)

Citation: Hecht G. 2003. Enteric Pathogens That Affect Intestinal Epithelial Tight Junctions, p 267-284. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch16
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Image of FIGURE 2

Type III secretion system of EPEC. Most gram-negative enteric pathogens, including EPEC, EHEC, and , , and spp., express a type III secretory system through which effector molecules can be directly delivered into host cells. Of particular relevance to EPEC is the translocated intimin receptor (Tir), which is tyrosine phosphorylated once inside the host cell and inserted into the host cell membrane where it serves as a receptor for the outer membrane EPEC adhesin, intimin. Effector molecules, such as EspF, are also injected into host cells where they perturb physiologic processes. (Modified from D. L. Goosney, S. Gruenheid, and B. B. Finlay, . 16:173–189, 2000.)

Citation: Hecht G. 2003. Enteric Pathogens That Affect Intestinal Epithelial Tight Junctions, p 267-284. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch16
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Image of FIGURE 3

Under normal conditions, TJs provide a barrier to the paracellular space, thus preventing free access of bacteria or their products to the underlying compartments. Pathogens, however, can disrupt the TJ barrier by indirect and direct mechanisms. Examples of indirect perturbation of TJs include contraction of the perijunctional actomyosin ring through the activation of MLCK and subsequent phosphorylation of MLC. Redistribution of TJ proteins likely occurs as a consequence of cytoskeletal contraction through the numerous interactions that exist between TJ proteins and actin or myosin. The transepithelial migration of inflammatory cells, in particular neutrophils, occurs across TJs and opens, at least temporarily, these structures. One example of a more direct effect is the dephosphorylation of occludin by EPEC ( ). Less-or nonphosphorylated forms of occludin dissociate from the TJ and thereby alter paracellular permeability.

Citation: Hecht G. 2003. Enteric Pathogens That Affect Intestinal Epithelial Tight Junctions, p 267-284. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch16
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