The airway epithelium: soldier in the fight against respiratory viruses

Abstract

The airway epithelium acts as a frontline defense against respiratory viruses, not only as a physical barrier and through the mucociliary apparatus but also through its immunological functions. It initiates multiple innate and adaptive immune mechanisms which are crucial for efficient antiviral responses. The interaction between respiratory viruses and airway epithelial cells results in production of antiviral substances, including type I and III interferons, lactoferrin, β-defensins, and nitric oxide, and also in production of cytokines and chemokines, which recruit inflammatory cells and influence adaptive immunity. These defense mechanisms usually result in rapid virus clearance. However, respiratory viruses elaborate strategies to evade antiviral mechanisms and immune responses. They may disrupt epithelial integrity through cytotoxic effects, increasing paracellular permeability and damaging epithelial repair mechanisms. In addition, they can interfere with immune responses by blocking interferon pathways and by subverting protective inflammatory responses toward detrimental ones. Finally, by inducing overt mucus secretion and mucostasis and by paving the way for bacterial infections, they favor lung damage and further impair host antiviral mechanisms.

FIG. 1.

Defenses of the healthy epithelium (the healthy soldier). Epithelial cells act as a barrier against respiratory viruses. The mucociliary apparatus (ciliary movement of mucus) and tight junctions (TJs) add mechanical, biological, and chemical protection. The airway epithelium also regulates both innate and adaptive immune responses, through production of antiviral substances such as IFNs, lactoferrin, β-defensins, and nitric oxide (NO) in the mucus layer and production of cytokines and chemokines which recruit and activate immune cells in the submucosa.

FIG. 2.

Key airway signaling pathways induced by respiratory viruses. TLR3 is expressed in intracellular endosomes and recognizes viral ssRNAs, such as those of rhinovirus, RSV, and influenza virus. TLR3 activates IRF-3 via the Toll/IL-1 receptor domain-containing adaptor (TRIF), resulting in IFN-β and IFN-λ1 production. TLR3 also activates IRF-7 and NF-κB through MyD88 activation. Activation of NF-κB and IRF-7 leads to the production of proinflammatory cytokines and the production of IFN-α, -λ1, and -λ2/3, respectively. Other endosomal TLRs (TLR7/8 and TLR9) detect ssRNAs and dsRNAs, such as those of influenza virus and adenovirus. Both TLR7/8 and TLR9 signal through a MyD88-dependent pathway, leading to the activation of NF-κB and IRF-7. TLR4 is expressed on the cell surface and responds to the RSV fusion protein. TLR4 signals through MyD88 to activate NF-κB and through TRIF to activate IRF-7. The two RNA helicases RIG-I and MDA5 detect viral replication products in the cytosol to activate IRF-3 via the adaptor protein IPS-1/MAVS/VISA/Cardif.

FIG. 3.

The airway epithelium under attack (the wounded soldier). Most respiratory viruses have elaborated strategies to evade antiviral mechanisms, for instance, by interfering with IFN signaling. During viral infection, the epithelium can be injured (through cytotoxic effects, disruption of tight junctions, or interference with epithelial repair), with the consequence of a loss of integrity and protection. Furthermore, respiratory viruses can lead to perturbed (skewed or exaggerated) inflammatory responses. Respiratory viruses might also facilitate bacterial colonization, with further negative consequences for the affected individual.

FIG. 4.

Examples of immune response disruption by respiratory viruses. Respiratory viruses are able to modulate the immune response by interfering with antiviral signaling pathways. They can inhibit IFN synthesis, for instance, by blocking IRF-3 activation (RSV and parainfluenza virus) or by interfering with RIG-1/MDA5 signaling (rhinovirus, RSV, and influenza virus). They can interfere with the production of antiviral molecules by blocking IFN signaling, for instance, through inhibition of STAT-1/2 activation (RSV, parainfluenza virus, and human metapneumovirus [hMPV]), or can directly inhibit antiviral proteins (influenza virus). They can interfere with NF-κB signaling (rhinovirus, RSV, and influenza virus), resulting in an excessive production of proinflammatory cytokines and in mucus hypersecretion. They are also able to induce bacterial adherence through an upregulation of host surface receptors such as PAF-r, CEACAM-1, and ICAM-1.