Airway Epithelial Cell Junctions as Targets for Pathogens and Antimicrobial Therapy

Abstract

Intercellular contacts between epithelial cells are established and maintained by the apical junctional complexes (AJCs). AJCs conserve cell polarity and build epithelial barriers to pathogens, inhaled allergens, and environmental particles in the respiratory tract. AJCs consist of tight junctions (TJs) and adherens junctions (AJs), which play a key role in maintaining the integrity of the airway barrier. Emerging evidence has shown that different microorganisms cause airway barrier dysfunction by targeting TJ and AJ proteins. This review discusses the pathophysiologic mechanisms by which several microorganisms (bacteria and viruses) lead to the disruption of AJCs in airway epithelial cells. We present recent progress in understanding signaling pathways involved in the formation and regulation of cell junctions. We also summarize the potential chemical inhibitors and pharmacological approaches to restore the integrity of the airway epithelial barrier. Understanding the AJCs-pathogen interactions and mechanisms by which microorganisms target the AJC and impair barrier function may further help design therapeutic innovations to treat these infections.

Keywords: adherens junction; airway epithelial cells; antimicrobial therapy; apical junctional complex; bacterial infection; epithelial barrier dysfunction; permeability; tight junction; trans-epithelial electrical resistance; viral infection.

Figure 1

Schematic diagram illustrating the structure of apical junction complexes in the airway epithelium. In the human airway epithelium, the surface mucus layers and the physical barrier formed by airway epithelial cells serve as the first line of defense against the external environment. The apical junctional complexes (AJCs) between adjacent epithelial cells establish cell polarity and restrict epithelial permeability via maintaining cell–cell contact. AJCs are located on the top lateral membranes between neighboring cells and include tight junctions (TJs) and adherens junctions (AJs). The inset shows an enlarged illustration of several protein components of TJ and AJ. Claudin, occludin, and junctional adhesion molecule (JAM) are examples of TJ transmembrane proteins. E-cadherin and nectin are shown as examples of the AJ transmembrane proteins. These proteins interact with cytoplasmic adapter proteins, such as zonula occludens (ZO-1/2/3) and β-catenin, to connect to the prejunctional actin cytoskeleton. The assembly and remodeling of the filamentous actin (F-actin) network are critical for the epithelial barrier function and are regulated by key organizers such as cortactin and actin-related protein-2/3 (Arp2/3) complex. This image was created with BioRender.com.

Figure 2

Disrupted epithelial barrier induced by invading microorganisms. Bacterial and viral infection can cause AJC disassembly and barrier disruption, the consequent increase in epithelial permeability will allow or exacerbate secondary invasions of allergens and pathogens into the subepithelial space. Multiple molecular pathways have been implicated in mediating or contributing to pathogen-induced AJC disassembly. Some examples are protein kinase C/D (PKC/D) activation, reactive oxygen species (ROS) generation, and rearrangement of the F-actin cytoskeleton. Therapeutics such as agonists and antagonists have been investigated and/or proposed to restore the epithelial barrier function caused in infected epithelial cells. Refer to Table 1; Table 2 for detailed information about the critical pathways and potential therapeutics. cAMP, cyclic adenosine monophosphate; HRV, human rhinovirus; IAV, influenza A virus; MERS-CoV, Middle East respiratory syndrome coronavirus; RSV, respiratory syncytial virus; SARS-CoV, severe acute respiratory syndrome coronavirus; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2. This image was created with BioRender.com.