Rhinovirus and Innate Immune Function of Airway Epithelium

Abstract

Airway epithelial cells, which lines the respiratory mucosa is in direct contact with the environment. Airway epithelial cells are the primary target for rhinovirus and other inhaled pathogens. In response to rhinovirus infection, airway epithelial cells mount both pro-inflammatory responses and antiviral innate immune responses to clear the virus efficiently. Some of the antiviral responses include the expression of IFNs, endoplasmic reticulum stress induced unfolded protein response and autophagy. Airway epithelial cells also recruits other innate immune cells to establish antiviral state and resolve the inflammation in the lungs. In patients with chronic lung disease, these responses may be either defective or induced in excess leading to deficient clearing of virus and sustained inflammation. In this review, we will discuss the mechanisms underlying antiviral innate immunity and the dysregulation of some of these mechanisms in patients with chronic lung diseases.

Keywords: COPD; ER stress; antiviral responses; asthma; autophagy; dsRNA; rhinovirus.

Figure 1

Proximal airway mucosa showing different type of airway epithelial cells with airway surface liquid, submucosal gland and professional innate immune cells in the submucosa.

Figure 2

Overview of innate immune responses of airway epithelial cells to RV. Airway epithelial cells show replication-independent CXCL responses which occurs as a result of activation PI-3 kinase/AP1 following binding and endocytosis of RV. Interaction of RV with TLR2 may induce CXCL-8 and NOS-2 expression via MyD88 signaling pathway. NOS-2 generates nitric oxide by catalysis of arginine. CXCL responses are also elicited when TLR3 binds to RV dsRNA via NF-κB. In contrast, RV-stimulated IFN and CXCL-10 responses are primarily due to dsRNA generated during RV replication. Binding of dsRNA to TLR3 induces IFNs via TBK1/IKKi/IRF3 activation. On the other hand, cytoplasmic receptors MDA5 or RIG-I upon binding to dsRNA translocate and interact with MAVS expressed on mitochondria. This interaction triggers activation of TBK1/IKKε to induce expression of IFNs and CXCL-10 via IRF3 and IRF1/NF-κB, respectively. During viral replication, accumulation of RV proteins and RV genome activates ER stress and induces autophagy. These processes degrade RV proteins to limit virion assembly.

Figure 3

Dysregulated IFN responses in COPD airway epithelial cells. Type I and III IFNs bind to their respective receptors and stimulate the expression of ISGs as well amplify the expression of IFNs through activation of JAK-STAT pathway. RV interaction with TLR2 induces the expression of SIRT-1, which inhibits STAT activation to limit amplification of IFNs and the expression of ISGs and this arm is dysregulated in COPD. Shown in the figure is binding of IFN-β to its receptors, IFNAR1 and IFNAR2. Interaction of IFN-λs with its receptors IFNLR1 and IL10R2 activates JAK-STAT signaling similar to IFN-β.