Host epithelial-viral interactions as cause and cure for asthma

Abstract

Research on the pathogenesis of asthma has concentrated on initial stimuli, genetic susceptibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth muscle) as critical steps leading to disease. Recent evidence indicates that the innate immune cell response to respiratory viruses also contributes to the development of inflammatory airway disease. We further develop this concept by raising the issue that the interaction between host airway epithelial cells and respiratory viruses is another aspect of innate immunity that is also a critical determinant of asthma. We also introduce a rationale for how antiviral performance at the epithelial cell level might be improved to prevent acute infectious illness and chronic inflammatory disease caused by respiratory viruses.

Fig. 1. Conventional scheme for how respiratory viruses trigger chronic asthma

Critical steps leading from initial respiratory virus infection to chronic inflammatory disease include viral properties, genetic susceptibility, altered immune program, and end-organ dysfunction. The immune program was felt to depend on the development of an adaptive immune response involving antigen-presenting cells (especially conventional dendritic cells (cDCs), memory cells (especially T cells and B cells), and effector cells (especially eosinophils and mast cells). End-organ dysfunction involves a transition from epithelial precursor cells such ciliated cells and Clara cells to mucous cells (mucous cell metaplasia, MCM) and increased mass and contractility of airway smooth muscle cells (airway hyperreactivity, AHR). Modified from ref. [5].

Fig. 2. Time course for immune events after respiratory viral infection

Viral replication leads to increased viral levels followed by innate and adaptive immune responses that eventually clear virus to noninfectious levels. The acute illness is followed by the development of acute and chronic disease that are both characterized by airway hyperreactivity (AHR) and mucous cell metaplasia (MCM). Acute disease is manifest at 3 weeks after viral inoculation and is driven by an adaptive immune response that includes cDCs and Th2 cells with IgE–high-affinity IgE receptor interaction and CCL28 production. Chronic disease is fully manifest at 7 weeks after inoculation and is driven by an innate immune response that includes cDCs, iNKT cells, and M2 cells with semi-invariant TCR–CD1d interaction and IL-13 production. Modified from ref. [5].

Fig. 3. Scheme for virus-induced IFN production and signal transduction

Viral replication causes Toll-like receptor (TLR) 3, 7, 8, and 9, melanoma differentiation-associated gene 5 (MDA5), retinoic acid-inducible gene I (RIG-I), and protein kinase R (PKR)-dependent production of three types of IFNs that trigger IFN signaling. IFN-γ signaling begins when IFN-γ dimer binds to its heterodimeric receptor (IFNGR) and triggers activation of Jak1 and Jak2 tyrosine kinases and consequent receptor phosphorylation. This step enables recruitment of STAT1 and subsequent release of the phosphorylated STAT1-homodimer. Activated Stat1 homodimer translocates to the nucleus where it binds to the gamma-activation site (GAS) and activates (in concert with p300) transcription of interferon-stimulated genes (ISGs). IFN-λ- and IFN-α/β-driven gene expression is initiated by activation of the IFN-λ receptor (IL-10R2/IL-28AR)) or IFN-α/β receptor (IFNAR) and subsequent activation of IL10R2- or IFNAR1-associated Tyk2 and IFNLR1- or IFNAR2-associated Jak1 with consequent IL-10R2 or IFNAR1 phosphorylation and recruitment of STAT2. Phosphorylation of Stat2 enables recruitment of Stat1 and release of the phosphorylated STAT1-STAT2-heterodimer. This heterodimer in concert with IRF-9 forms a complex that binds to the interferon stimulated response element (ISRE) and increases ISG transcription. SOCS1 and STAT1β (a truncated form of STAT1) decrease signaling as indicated. Asthma may down-regulate these pathways by direct or indirect actions on IFN production or signaling as indicated. Modified from ref. [33].

Fig. 4. Revised scheme for how viruses might trigger chronic asthma

This scheme is modified from the conventional scheme depicted in Fig. 1 to include the control of viral level in airway epithelial cells based on IFN production and signaling. The diagram also indicates proposed strategies for therapeutic intervention, including an antiviral approach that aims to improve epithelial control of viral levels.