Subversion of mucosal barrier polarity by pseudomonas aeruginosa

Abstract

The lumenal surfaces of human body are lined by a monolayer of epithelia that together with mucus secreting cells and specialized immune cells form the mucosal barrier. This barrier is one of the most fundamental components of the innate immune system, protecting organisms from the vast environmental microbiota. The mucosal epithelium is comprised of polarized epithelial cells with distinct apical and basolateral surfaces that are defined by unique set of protein and lipid composition and are separated by tight junctions. The apical surface serves as a barrier to the outside world and is specialized for the exchange of materials with the lumen. The basolateral surface is adapted for interaction with other cells and for exchange with the bloodstream. A wide network of proteins and lipids regulates the formation and maintenance of the epithelium polarity. Many human pathogens have evolved virulence mechanisms that target this network and interfere with epithelial polarity to enhance binding to the apical surface, enter into cells, and/or cross the mucosal barrier. This review highlights recent advances in our understanding of how Pseudomonas aeruginosa, an important opportunistic human pathogen that preferentially infects damaged epithelial tissues, exploits the epithelial cell polarization machinery to enhance infection.

Keywords: Pseudomonas aeruginosa; adherens junctions; cell polarity; epithelial barrier; host–pathogen interactions; microbial pathogenesis; tight junctions.

Figure 1

Interactions of various pathogens with polarized cells. The apical surface is outlined in red and the basolateral surface in blue. The TJ (upper) and AJ (lower) are indicated by a dashed rectangle. The major components of TJs (claudin, occludin, ZO, and JAMs) and AJs (E-cadherin, b-catenin, and a-catenin) are shown. The Par3/Par6/aPKC complex is shown to associate with JAMs. Actin is associated with AJs. PI3K and PIP₃ are associated with the BL surface. (A) Illustrates relevant characteristics of EPEC-induced pedestals. PI3K, PIP₃, SHIP2, and PIP2 are recruited by Tir (the translocated intimin receptor) to the actin-containing pedestal, along with actin, Arp2/3, Nck, and N-wasp (not shown). (B) Illustrates H. pylori recruiting junctional components, including JAMs, ZO-1, and Par (not shown) to form a replicative niche at the AP surface. (C) Represents endothelial cells, shows N. meningitidis disrupting intracellular junctions and breaching the blood–brain barrier by recruiting components of the TJ and the AJ (including Par-6, aPKC, Par-3, Claudin, ZO-5, VE-cadherin, b-catenin, and p-120 catenin) to the site of binding of the bacterial microcolony at the AP surface. The loss of the TJ and AJ is illustrated by the rectangles with dotted lines.

Figure 2

Early hours of P. aeruginosa infection: subversion of host cell polarity to transform apical into a basolateral membrane. (A) Diagram of polarized epithelial cell. The apical surface is outlined in red and the basolateral surface in blue. TJ, tight junction; AJ, adherens junction; TGN, trans-Golgi network; N, nucleus. Turquoise, blue, and red curved arrows represent vesicular trafficking. PIP₃ is represented by the yellow dots. (B) Protrusion formation. An aggregate of P. aeruginosa recruits PI3K to the apical surface, generating local production of PIP₃. BL recycling of proteins is redirected to the AP surface, creating a basolateral environment at the apical surface. (C) An aggregate of P. aeruginosa is internalized into the host cell, possibly at least in part through the transient protrusion.