Virus-induced modulation of lower airway diseases: pathogenesis and pharmacologic approaches to treatment

Abstract

Uncomplicated upper respiratory viral infections are the most common cause of days lost from work and school and exert a major economic burden. In susceptible individuals, however, common respiratory viruses, particularly human rhinoviruses, also can have a major impact on diseases that involve the lower airways, including asthma, chronic obstructive pulmonary diseases (COPD) and cystic fibrosis (CF). Respiratory virus-induced wheezing illnesses in early life are a significant risk factor for the subsequent development of asthma, and virus infections may also play a role in the development and progression of airway remodeling in asthma. It is clear that upper respiratory tract virus infections can spread to the lower airway and trigger acute attacks of asthma, COPD or CF. These exacerbations can be life-threatening, and exert an enormous burden on health care systems. In recent years we have gained new insights into the mechanisms by which respiratory viruses may induce acute exacerbations of lower airway diseases, as well as into host defense pathways that may regulate the outcomes to viral infections. In the current article we review the role of viruses in lower airway diseases, including our current understanding on pathways by which they may cause remodeling and trigger acute exacerbations. We also review the efficacy of current and emerging therapies used to treat these lower airway diseases on the outcomes due to viral infection, and discuss alternative therapeutic approaches for the management of virus-induced airway inflammation.

Keywords: Airway remodeling; Asthma; Epithelial cells; Human rhinovirus; Innate immunity.

Fig. 1

Release of remodeling mediators from human airway epithelial cells upon infection with HRV. Release of growth factors of the transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) families could contribute to remodeling via regulation of fibroblast/myofibroblast release of matrix proteins that can lead to thickening of the lamina reticularis. Matrix metalloproteinase-9 (MMP-9) may regulate matrix protein turnover. Vascular endothelial growth factor can regulate angiogenesis, while increased release of MUC5AC may enhance mucus production.

Fig. 2

Regulation of airway epithelial cell antiviral immunity upon infection with HRV. Release of nitric oxide (NO) can inhibit both replication of HRV and viral induced chemokine production. Induction of interferon-stimulated genes (ISG) in the intracellular compartment may regulate viral replication, while secreted ISGs may exert immunomodulatory effects. Chemokine production can be both proinflammatory and antimicrobial via release of secondary mediators or recruitment of dendritic cells.

Fig. 3

Potential target sites for the development of therapeutics to regulate viral exacerbations of lower airway diseases. Approaches have targeted: 1) Viral binding or internalization. 2) Viral replication. 3) Signaling downstream from pattern recognition receptors. 4) Release or binding of specific proinflammatory mediators, or supplementation of interferons or specific ISGs and 5) modulation of specific antiviral immune responses. Abbreviations: HRV, Human rhinovirus; ICAM-1, intercellular adhesion molecule-1; dsRNA, double-stranded RNA; TLR3, toll-like receptor 3; RIG-1, retinoic acid inducible gene-I; mda-5, melanoma differentiation-associated gene-5; TRIF, TIR-domain-containing adapter-inducing interferon-β; RIP-1, receptor interacting protein-1; IPS-1, interferon-β promoter stimulating protein-1; TRAF-3, TNF receptor-associated factor-3; FADD, fas-associated protein with death domain; IRF, interferon regulatory factor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; ISG, interferon-stimulated gene.