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Modulation of Intestinal Paracellular Transport by Bacterial Pathogens

Jennifer Lising Roxas, V.K. Viswanathan

10.1002/cphy.c170034

Source: Volume 8, Issue 2, April 2018

Published online: March 2018

Full Article on Wiley Online Library



ABSTRACT

The passive and regulated movement of ions, solutes, and water via spaces between cells of the epithelial monolayer plays a critical role in the normal intestinal functioning. This paracellular pathway displays a high level of structural and functional specialization, with the membrane‐spanning complexes of the tight junctions, adherens junctions, and desmosomes ensuring its integrity. Tight junction proteins, like occludin, tricellulin, and the claudin family isoforms, play prominent roles as barriers to unrestricted paracellular transport. The past decade has witnessed major advances in our understanding of the architecture and function of epithelial tight junctions. While it has been long appreciated that microbes, notably bacterial and viral pathogens, target and disrupt junctional complexes and alter paracellular permeability, the precise mechanisms remain to be defined. Notably, renewed efforts will be required to interpret the available data on pathogen‐mediated barrier disruption in the context of the most recent findings on tight junction structure and function. While much of the focus has been on pathogen‐induced dysregulation of junctional complexes, commensal microbiota and their products may influence paracellular permeability and contribute to the normal physiology of the gut. Finally, microbes and their products have become important tools in exploring host systems, including the junctional properties of epithelial cells. © 2018 American Physiological Society. Compr Physiol 8:823‐842, 2018.

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Figure 1. Figure 1. Depletion and relocalization of TJ proteins and TJ‐associated proteins disrupts epithelial barrier. (A) Schematic, lateral view: Pathogens may relocalize TJ proteins (occludin, claudins, JAM, and ZO proteins) to intracellular sites and/or trigger their loss. (B) Schematic, en face view: Intact peripheral staining (green) of junctional proteins in uninfected cells. Junctional staining is lost and TJ protein aggregates form in the cytoplasm of infected cells. (C) Example: ZO‐1 (green) is preserved at the cell junctions of cultured human intestinal epithelial C2BBe cells. In cells infected with Yersinia enterocolitica, ZO‐1 junctional staining is lost, and cytoplasmic ZO‐1 aggregates (yellow arrowheads) are observed. DAPI (blue) stains DNA. Image obtained, with permission, from Jennifer Lising Roxas and V.K. Viswanathan.
Figure 2. Figure 2. Displaced TJ proteins may be deposited to alternate sites in host cells, including regions of bacterial attachment. (A) Schematic, lateral view: Beyond displacing proteins from the TJs, pathogens may also perturb epithelial cell polarity and, in some instances, recruit TJ proteins to sites of bacterial attachment. (B) Schematic, en face view: TJ proteins (red) are localized to the periphery of uninfected cells. In infected cells, TJ proteins may be recruited to sites of bacterial attachment. (C) Example: Occludin (red) is preserved at the cell junctions of C2BBe cells. In EPEC‐infected cells, occludin is lost from the junctions, and is recruited to regions surrounding the bacteria. Inset depicts magnified view of an EPEC microcolony (blue) surrounded by occludin stain (red). DAPI (blue) stains DNA. Image obtained, with permission, from Jennifer Lising Roxas and V.K. Viswanathan.
Figure 3. Figure 3. Pathogens may disrupt barrier function by modulating claudin expression. (A) Schematic: Normal epithelial cells with intact tight junctions express barrier‐enhancing claudins in higher abundance (green, dense solid line) compared to pore‐forming claudins (faint, blue dotted line). Pathogens may downregulate expression of barrier‐enhancing claudins (faint, green dotted line), and/or upregulate expression of pore‐forming claudins (dense, blue solid line) to increase paracellular permeability. (B) Example: Salmonella increases paracellular permeability by selectively upregulating claudin‐2 levels. Claudin‐3 is unchanged in Salmonella‐infected cells, compared to uninfected control. Image obtained, with permission, from Yong‐Guo Zhang and Jun Sun, University of Illinois at Chicago, Chicago, IL.
Figure 4. Figure 4. Pathogens may trigger contraction of the perijunctional actomyosin ring, resulting in increased paracellular permeability by the leak pathway. (A) Schematic, lateral view: Some pathogens trigger signaling pathways that activate myosin light chain kinase (MLCK) and/or Rho‐associated protein kinase (ROCK), which can both phosphorylate myosin light chain and cause actomyosin contraction. ROCK also phosphorylates myosin phosphatase target subunit 1 (MYPT1) and, thereby, inhibits MLC dephosphorylation. Alternatively, proinflammatory molecules like TNFα can also activate MLCK. (B) Schematic, en face view: Uniform distribution of TJ proteins (green) preserved at the periphery of uninfected cells. Pathogens or proinflammatory molecules like TNFα induce actomyosin contraction leading to the distortion and opening of junctional areas. Gaps may also be evident at points of cell contacts. (C) Example: Uniform ZO‐1 staining at cell periphery of cultured Caco‐2 monolayers. On the right, TNFα‐induced disruption of ZO‐1 localization, and appearance of gaps (arrowhead) at points of cell contact. Image obtained, with permission, from Ma et al. (66).
Figure 5. Figure 5. Prolonged infections, or large pathogen loads, can induce large‐scale loss of the epithelial monolayer, leading to barrier dysfunction. (A) Schematic: In healthy animals, the intestinal epithelium (a single villus is depicted) is a uniform monolayer lining the lamina propria. Disease states may result in gross epithelial erosion. (B) Example: An intact epithelial monolayer lines the intestine of uninfected rabbits. Infection with rabbit enteropathogenic Escherichia coli (REPEC) caused the gross exfoliation of intestinal epithelial cells, coincident with severe diarrhea. Image obtained, with permission, from John Scott Wilbur and V.K. Viswanathan.


Figure 1. Depletion and relocalization of TJ proteins and TJ‐associated proteins disrupts epithelial barrier. (A) Schematic, lateral view: Pathogens may relocalize TJ proteins (occludin, claudins, JAM, and ZO proteins) to intracellular sites and/or trigger their loss. (B) Schematic, en face view: Intact peripheral staining (green) of junctional proteins in uninfected cells. Junctional staining is lost and TJ protein aggregates form in the cytoplasm of infected cells. (C) Example: ZO‐1 (green) is preserved at the cell junctions of cultured human intestinal epithelial C2BBe cells. In cells infected with Yersinia enterocolitica, ZO‐1 junctional staining is lost, and cytoplasmic ZO‐1 aggregates (yellow arrowheads) are observed. DAPI (blue) stains DNA. Image obtained, with permission, from Jennifer Lising Roxas and V.K. Viswanathan.


Figure 2. Displaced TJ proteins may be deposited to alternate sites in host cells, including regions of bacterial attachment. (A) Schematic, lateral view: Beyond displacing proteins from the TJs, pathogens may also perturb epithelial cell polarity and, in some instances, recruit TJ proteins to sites of bacterial attachment. (B) Schematic, en face view: TJ proteins (red) are localized to the periphery of uninfected cells. In infected cells, TJ proteins may be recruited to sites of bacterial attachment. (C) Example: Occludin (red) is preserved at the cell junctions of C2BBe cells. In EPEC‐infected cells, occludin is lost from the junctions, and is recruited to regions surrounding the bacteria. Inset depicts magnified view of an EPEC microcolony (blue) surrounded by occludin stain (red). DAPI (blue) stains DNA. Image obtained, with permission, from Jennifer Lising Roxas and V.K. Viswanathan.


Figure 3. Pathogens may disrupt barrier function by modulating claudin expression. (A) Schematic: Normal epithelial cells with intact tight junctions express barrier‐enhancing claudins in higher abundance (green, dense solid line) compared to pore‐forming claudins (faint, blue dotted line). Pathogens may downregulate expression of barrier‐enhancing claudins (faint, green dotted line), and/or upregulate expression of pore‐forming claudins (dense, blue solid line) to increase paracellular permeability. (B) Example: Salmonella increases paracellular permeability by selectively upregulating claudin‐2 levels. Claudin‐3 is unchanged in Salmonella‐infected cells, compared to uninfected control. Image obtained, with permission, from Yong‐Guo Zhang and Jun Sun, University of Illinois at Chicago, Chicago, IL.


Figure 4. Pathogens may trigger contraction of the perijunctional actomyosin ring, resulting in increased paracellular permeability by the leak pathway. (A) Schematic, lateral view: Some pathogens trigger signaling pathways that activate myosin light chain kinase (MLCK) and/or Rho‐associated protein kinase (ROCK), which can both phosphorylate myosin light chain and cause actomyosin contraction. ROCK also phosphorylates myosin phosphatase target subunit 1 (MYPT1) and, thereby, inhibits MLC dephosphorylation. Alternatively, proinflammatory molecules like TNFα can also activate MLCK. (B) Schematic, en face view: Uniform distribution of TJ proteins (green) preserved at the periphery of uninfected cells. Pathogens or proinflammatory molecules like TNFα induce actomyosin contraction leading to the distortion and opening of junctional areas. Gaps may also be evident at points of cell contacts. (C) Example: Uniform ZO‐1 staining at cell periphery of cultured Caco‐2 monolayers. On the right, TNFα‐induced disruption of ZO‐1 localization, and appearance of gaps (arrowhead) at points of cell contact. Image obtained, with permission, from Ma et al. (66).


Figure 5. Prolonged infections, or large pathogen loads, can induce large‐scale loss of the epithelial monolayer, leading to barrier dysfunction. (A) Schematic: In healthy animals, the intestinal epithelium (a single villus is depicted) is a uniform monolayer lining the lamina propria. Disease states may result in gross epithelial erosion. (B) Example: An intact epithelial monolayer lines the intestine of uninfected rabbits. Infection with rabbit enteropathogenic Escherichia coli (REPEC) caused the gross exfoliation of intestinal epithelial cells, coincident with severe diarrhea. Image obtained, with permission, from John Scott Wilbur and V.K. Viswanathan.
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Teaching Material

J. L. Roxas, V. K. Viswanathan. Modulation of Intestinal Paracellular Transport by Bacterial Pathogens. Compr Physiol. 8: 2018, 823-842.

Didactic Synopsis

Major Teaching Points:

  • Paracellular transport is the passive movement of ions, solutes and water via the spaces between cells. This process is regulated by the tight junction complex.
  • There are two recognized modes of paracellular transport—the pore and leak pathways—that are independently, and sometimes opposingly, regulated.
  • The high-capacity pore pathway is ion- and size-selective, and is gated by the claudin family of proteins. The low-capacity, charge-insensitive, leak pathway permits passage of larger molecules.
  • Many pathogenic microbes and their products target tight junctions, and alter their composition and function. The consequent perturbation of paracellular permeability contributes to disease symptoms, including diarrhea.
  • Concomitant with altered permeability, the loss of epithelial cell polarity, and the potential passage of toxins and microbes into the lamina propria may exacerbate disease.
  • Commensal and probiotic microbes and their products can mitigate pathogen-induced perturbations of paracellular permeability, although the molecular mechanisms are not always well defined.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: Understanding how relocalization and depletion of TJ proteins by pathogens impact cell permeability. TJ proteins are enriched at the cell junctions of uninfected epithelial monolayers with intact barrier. Pathogens may disrupt epithelial barrier by relocalizing TJ proteins and TJ-associated proteins away from cell junctions to intracellular sites and/or triggering their degradation [(A) and (B)]. Yersinia enterocolitica-mediated relocalization and depletion the TJ-associated protein ZO-1 is shown as an example in (C).

Figure 2. Teaching points: Continuation of the concept presented in Figure 1 on the fate of relocalized TJ proteins. Displaced or relocalized TJ proteins and TJ-associated proteins during infection may be deposited at alternate sites in host cells, including regions near bacteria [(A) and (B)]. (C) For example, EPEC displaces occludin from its anchorage at cell junctions. Occludin is deposited at regions surrounding attached bacteria. ZO-1 (not shown in figure) is also recruited around EPEC microcolonies and to actin tails of invading Shigella and Listeria (37).

Figure 3. Teaching points: Understanding how pathogens can increase cell permeability via modulation of claudin expression. The TJ pore pathway is gated by claudins. The schematic in (A) represents an en face view of claudins staining at the cell junctions. Barrier-enhancing claudins are expressed in high abundance in normal cells with intact barrier function, while pore-forming claudins are at relatively lower abundance. Pathogens may disrupt tight junctions by selectively modulating claudin expression. (B) Salmonella selectively modulates expression of pore-forming claudin-2 to increase paracellular permeability (131).

Figure 4. Teaching points: Understanding that actomyosin contraction may open tight junctions and increase paracellular permeability. Schematic in (A) shows two signaling pathways leading to actomyosin contraction. Pathway 1: Pathogens like EPEC activate myosin light chain kinase (MLCK). MLCK can phosphorylate myosin light chain (MLC) and lead to actomyosin contraction. Pathway 2: Pathogens may also activate Rho/ROCK signaling pathway. Rho-mediated ROCK activation can lead to MLC phosphorylation and consequent actomyosin contraction. ROCK also phosphorylates MYPT1, a regulatory subunit of myosin light chain phosphatase, and thereby inhibits MLC dephosphorylation. Pathogens may also trigger inflammation. During inflammation, proinflammatory cytokines like TNFα can also activate MLCK and promote actomyosin contraction. Actomyosin contraction leads to distortion and formation of gaps in cell junctions, as depicted in (B) and (C).

Figure 5. Teaching points: Understanding that large-scale loss of epithelial monolayer that may occur during infection perturbs barrier function. A single layer of epithelial cells lines the intestines, forming a barrier to protect the underlying tissue. With prolonged infection or high pathogen burdens, large-scale epithelial erosion can occur and severely compromise barrier function (A). As an example, gross exfoliation of intestinal epithelial cells was observed in a REPEC-infected rabbit that suffered from severe diarrhea (B).


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Article Title: Modulation of Intestinal Paracellular Transport by Bacterial Pathogens
 

How to Cite

Jennifer Lising Roxas, V.K. Viswanathan. Modulation of Intestinal Paracellular Transport by Bacterial Pathogens. Compr Physiol 2018, 8: 823-842. doi: 10.1002/cphy.c170034