Respiratory viral infection: a potential "missing link" in the pathogenesis of COPD

Abstract

Chronic obstructive pulmonary disease (COPD) is currently the third most common cause of global mortality. Acute exacerbations of COPD frequently necessitate hospital admission to enable more intensive therapy, incurring significant healthcare costs. COPD exacerbations are also associated with accelerated lung function decline and increased risk of mortality. Until recently, bacterial pathogens were believed to be responsible for the majority of disease exacerbations. However, with the advent of culture-independent molecular diagnostic techniques it is now estimated that viruses are detected during half of all COPD exacerbations and are associated with poorer clinical outcomes. Human rhinovirus, respiratory syncytial virus and influenza are the most commonly detected viruses during exacerbation. The role of persistent viral infection (adenovirus) has also been postulated as a potential pathogenic mechanism in COPD. Viral pathogens may play an important role in driving COPD progression by acting as triggers for exacerbation and subsequent lung function decline whilst the role of chronic viral infection remains a plausible hypothesis that requires further evaluation. There are currently no effective antiviral strategies for patients with COPD. Herein, we focus on the current understanding of the cellular and molecular mechanisms of respiratory viral infection in COPD.

FIGURE 1

Protease/anti-protease imbalance and oxidative stress are viable pro-inflammatory mechanisms that contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke and inhaled noxious agents activate epithelial cells and macrophages to release several chemotactic factors (including interferon-γ-induced protein 10 (IP10), monokine-induced by interferon-γ (MIG), I-TAC, interleukin (IL)-6, IL-8 and leukotriene B₄ (LTB₄)), which attract and activate key inflammatory cells that accumulate within the airway mucosa in COPD. Sustained activation of innate and adaptive immune responses leads to airway influx of neutrophils and CD8 cytotoxic T-cells (TC1 cells)/CD4 T-helper 1 (Th1) cells. In a sub-group of COPD patients, increased Th2 signalling may be present and numerous therapies targeted at Th2 cytokines have been studied. Mepolizumab (IL-5) has shown minor reduction in acute exacerbations of COPD whilst benralizumab (IL5Ra) and navarixin (CXCR2) have shown a modest effect on forced expiratory volume in 1 s. COPD inflammatory mediators sustain the inflammatory process in COPD leading to elastin degradation and emphysema. Neutrophil elastase also causes mucus hypersecretion. Epithelial cells and macrophages also release transforming growth factor (TGF)-β, which stimulates fibroblast proliferation resulting in small airway fibrosis and remodelling. The finding of CD8⁺ T- and B-cells organised into follicles within the airway epithelium in COPD may represent an increased “immune surveillance” of the airway fuelling the hypothesis that an additional aetiological factor, other than exposure to inhaled noxious agents, is necessary in order to develop COPD. Chronic viral infection might serve as an additional host aetiological factor (the “missing link”) in the development of COPD, whilst increased susceptibility to acute viral-induced exacerbations leads to incremental disease progression. CTGF: connective tissue growth factor; CPE: cytopathogenic effect; TNF: tumour necrosis factor.

FIGURE 2

Mechanisms of virus-induced airway inflammation in chronic obstructive pulmonary disease (COPD). COPD exacerbations are associated with increased expression of cytokines and chemokines, including tumour necrosis factor (TNF)-α, interleukin (IL)-6, interferon (IFN)-γ-induced protein 10 (IP10), leukotriene B₄ (LTB₄), monokine-induced by IFN-γ (MIG), IFN-inducible T-cell-α chemoattractant and RANTES, growth regulated gene α (GRO-α) and epithelial-neutrophil activating peptide (ENA-78). These cytokines and chemokines attract various inflammatory cells such as neutrophils, T-cells, macrophages and dendritic cells. Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) promote the release of matrix proteins from fibroblasts/myofibroblasts, which enhance the production of matrix metalloproteinases (i.e. MMP-9) from airway epithelial cells leading to airway remodelling. Respiratory viruses preferentially target airway epithelial cells leading to epithelial cell sloughing, Goblet cell hyperplasia (mucus plug), microvascular dilatation, oedema and immune cell infiltration. Consequently, there is increased impaired mucociliary clearance and increased susceptibility to bacterial infection. Cigarette smoke contributes to impaired host innate antiviral immunity through the reduction of IFNs and IFN-stimulated gene production, and induces inflammatory mediators in the airway and increased epithelial cell apoptosis via the activation of nuclear factor (NF)-κB. In addition, dysregulated adaptive immunity may also be an important disease mechanism that may render patients with COPD more susceptible to acute viral infection. GM-CSF: granulocyte-macrophage colony stimulating factor; ICAM: intracellular adhesion molecule; TGF: transforming growth factor; I-TAC: interferon-inducible T-cell alpha chemoattractant; ISG: interferon stimulated genes; Th1: T-helper cell type 1.