Modulation of epithelial cell polarity by bacterial pathogens

Abstract

Epithelial cells constitute a physical barrier that aids in protecting the host from microbial pathogens. Polarized epithelial cells contain distinct apical and basolateral membrane domains separated by intercellular junctions, including tight junctions (TJs), which contribute to the maintenance of apical-basal polarity. Polarity complexes also contribute to the establishment of TJ formation. Several pathogens perturb epithelial TJ barrier function and structure in addition to causing a loss of apical-basal polarity. Here, we review the impact of pathogenic bacteria on the disruption of cell-cell junctions and epithelial polarity.

Keywords: EPEC; apical-basal polarity; enteropathogenic Escherichia coli; tight junctions.

Figure 1

EPEC induces formation of aberrant TJ strands in the lateral membrane. Freeze–fracture images of control uninfected T84 cells immuno-gold labelled for claudin-1 and occludin (A and C, respectively). The apical (AP) and the basolateral (BL) membrane domains of EPEC-infected T84 cells show few (arrows) and ectopic (arrowheads) TJ strands along the lateral membrane, as indicated in the immuno-gold label for claudin-1 and occludin (B and D, respectively). This image was reproduced from Ref. 23 with the express written permission of the publisher.

Figure 2

Model demonstrating the potential effect of pathogens on apical–basal polarity. A monolayer of epithelial cells forms a barrier separating the internal contents of the body from the external environment. The membranes of polarized epithelial cells have differing protein and lipid compositions. The apical membrane faces the lumen, and the basolateral domain is in contact with the underlying basement membrane. (A) The apical polarity complexes Crb and Par localize to TJs, while Scrib/Lgl/Dl resides below the TJ along the lateral membrane. (B) EPEC, through a T3SS, injects bacterial effectors (EspF, Map, EspG, Tir, etc.) into host cells. The effectors redistribute TJ proteins (ZO-1, claudin-1, and occludin), interact with and recruit the IF proteins (CK-8/18) to the pedestal formation, modulate the activity of Par polarity proteins (aPKC and CDC42), and redistribute basolateral proteins (β1-integrin and Na⁺/K⁺ ATPase) to the apical domain. All of these events result in a loss of both barrier function and apical–basal polarity. (C) Y. pseudotuberculosis redistributes ZO-1 and occludin from the TJ region and β1-integrin from the basolateral membrane, leading to disrupted barrier function. (D) H. pylori disrupts the organization of apical junctions via the interaction of CagA with ZO-1, JAM, and E-cadherin, causing their recruitment to the apical membrane. CagA binds to PAR1b, PKC, and PRK2, perturbing cell polarity, as demonstrated by the redistribution of the apical protein gp135 to the basolateral compartment. (E) P. aeruginosa increases the activation of PI3K and the generation of membrane PIP3-rich structures, which accumulate F-actin, RAC1, basolateral constituents (β1-integrin, β-catenin, and nectin), and Par polarity proteins (PAR3/PAR6/PKC). The altered composition of the apical membrane suggests that P. aeruginosa inverts epithelial cell polarity. (F) N. meningitidis forms bacterial aggregates in the apical domain of endothelial cells, which leads to an “ectopic early junction–like domain” enriched in F-actin, Par proteins (PAR3 and PAR6), adherens junction proteins (VE-cadherin, β-catenin, and p-120), as well as TJ proteins (ZO-1, ZO-2, and claudin-5). N. meningitidis perturbs cell–cell junctions through the formation of gaps through the lateral membrane of infected cells.