Digging through the Obstruction: Insight into the Epithelial Cell Response to Respiratory Virus Infection in Patients with Cystic Fibrosis

Abstract

Respiratory virus infections are common but generally self-limiting infections in healthy individuals. Although early clinical studies reported low detection rates, the development of molecular diagnostic techniques by PCR has led to an increased recognition that respiratory virus infections are associated with morbidity and acute exacerbations of chronic lung diseases, such as cystic fibrosis (CF). The airway epithelium is the first barrier encountered by respiratory viruses following inhalation and the primary site of respiratory viral replication. Here, we describe how the airway epithelial response to respiratory viral infections contributes to disease progression in patients with CF and other chronic lung diseases, including the role respiratory viral infections play in bacterial acquisition in the CF patient lung.

FIG 1

Epithelial responses to respiratory virus infection in AECs from healthy persons and cystic fibrosis (CF) patients. In CF patient AECs, mutations in the CF transmembrane conductance regulator (CFTR) ion channel lead to reduced chloride (Cl⁻) secretion and increased sodium (Na⁺) uptake, resulting in a depleted airway surface liquid (ASL) level and increased mucus buildup, impairing mucociliary clearance of pathogens from the airway. CF and non-CF AECs recognize viral infection through PRRs, which lead to the production of type I and III IFNs (IFN-β and -λ, respectively). These molecules are secreted from AECs and act in an autocrine and paracrine manner to signal through their cognate receptors, the IFN-α/β receptor (IFNAR) and the IFN-λ receptor (IFNλR), respectively, to induce the expression of antiviral mediators (i.e., ISGs). CF patient AECs have defects in ISG production, resulting in an increased viral burden. The innate immune response to respiratory viral infection also enhances bacterial colonization and P. aeruginosa biofilm growth.