Subversion of mucosal barrier polarity by Pseudomonas aeruginosa

Review Article published: 26 May 2011 doi: 10.3389/fmicb.2011.00114 Subversion of mucosal barrier polarity by Pseudomonas aeruginosa Joanne Engel1,2* and Yonatan Eran1 1 2 Department of Medicine, University of California at San Francisco, San Francisco, CA, USA Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, CA, USA Edited by: Dara Frank, Medical College of Wisconsin, USA Reviewed by: Steve Blanke, University of Illinois at Urbana-Champaign, USA Lee-Ann H. Allen, University of Iowa, USA *Correspondence: Joanne Engel, University of California San Francisco, Box 0654, 513 Parnassus Avenue, San Francisco, CA 94143-0654, USA. e-mail: 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, microbial pathogenesis, host–pathogen interactions, cell polarity, epithelial barrier, tight junctions, adherens junctions The mucosal barrier The mucosal surfaces of our body are a primary component of our innate immune system and serve as a barrier against endogenous microflora as well as against external pathogens. This barrier is made of polarized epithelial cells, specialized immune cells, and secreted mucus. Many pathogens have evolved strategies to circumvent this barrier, including entering into cells or traveling through them by transcytosis, crossing through intercellular junctions, or directly disrupting the barrier by killing cells in the epithelium (Kazmierczak et al., 2001a). The mucosal barrier epithelium is comprised of one or more layers of epithelial cells that have specialized and distinct apical and basolateral surfaces, separated by tight junctions (TJs), that form selective permeability barriers between biological compartments (Wang and Margolis, 2007; Martin-Belmonte and Mostov, 2008). The apical surface faces the lumen of the cavity, while the basolateral surface faces adjoining cells and the underlying basement membrane. The apical and basolateral membrane domains are distinguished by unique assemblies of proteins and lipids, creating specific membrane domains with distinct roles in formation and maintenance of barrier function, as well as the myriad of physiological barrier functions, such as nutrient exchange. The apical surface contains transporters and enzymes that are specialized to interact with the external environment. The outer leaflet of the apical surface is highly enriched in glycosphingolipids and cholesterol. The basolateral plasma membrane of the epithelial cell contains many transporters and receptors that are involved in uptake of nutrients and hormones from the circulation. The basolateral surface can be divided into lateral domains, which contact other www.frontiersin.org cells, and basal domains, which contact the basement membrane and blood vessels. The lateral surface contains specialized cell–cell contact domains, including TJs and adherens junctions (AJs). The TJ is located at the apical-most region of the lateral surface and defines the boundary between the apical and basolateral surfaces (Ebnet, 2008). The TJ serves two functions. First, it acts as a “gate” or “barrier” to prevent paracellular diffusion between the cells. This function enables the epithelial monolayer to restrict permeability to solutes or larger particles, including pathogens. Second, the TJ acts as a fence to prevent diffusion or intermixing of plasma membrane components between the apical and basolateral domains. The TJ contains three classes of integral membrane proteins: occludins, claudins, and JAMs, each of which forms homophilic interactions that are responsible for gate function of the TJ. The TJ is attached to the cytoskeleton by a set of adaptor proteins including zonula occludens protein 1 (ZO-1). The AJ lies underneath the TJ. The AJ consists mainly of classical cadherin family members and nectins, which are integral membrane proteins whose large extracellular domains interact in a homophilic or heterophilic manner to connect adjacent cells. Cadherins are linked to the cytoskeleton through β-catenin, α-catenin, and p120-catenin. In addition to providing the structural “linking” of neighboring cells, cadherins function as organizing nodes for multiprotein complexes that regulate cell–cell contacts, an essential function for morphogenesis and remodeling of tissues and organs (Meng and Takeichi, 2009). A wide network of proteins and lipids regulates the formation and maintenance of epithelial cell polarity. The first step in the formation of apical–basolateral polarity is the formation of May 2011 | Volume 2 | Article 114 | 1 Engel and Eran cell–cell junctions. E-cadherins from adjacent cells interact to c reate homophilic intercellular adhesions. Activation of small Rho GTPase family members, leads to cytoskeleton rearrangement and recruitment of structural and regulatory proteins, resulting in the formation of mature TJs and AJs (Iden and Collard, 2008). Junction maturation is coupled to the development of apical–basolateral asymmetry in the cell, where the newly formed AJ serves as a site for basolateral protein sorting (Yeaman et al., 2004). Maintenance of cell polarity and junction integrity involves continuous sensing of external cues such as extracellular matrix content and cell–cell contacts. These cues are translated into cellular signals that are received by a regulatory core of three protein complexes: Par3/Par6/ aPKC, the Crumbs complex (Crumbs-3, PALS1, and PATJ), and the Scribble complex (Scribble, LGL1/2, and DLG1). The mutually exclusive localization of these three complexes helps to stabilize apical–basolateral polarity (Bryant and Mostov, 2008; Iden and Collard, 2008). In addition to (...truncated)