Viral-associated exacerbations of asthma and COPD

Abstract

Exacerbations of asthma and chronic obstructive pulmonary disease are major burdens on the healthcare system, and contribute significantly to the mortality and morbidity associated with these diseases. Upper respiratory viral infections are associated with the majority of such disease exacerbations. The past few years have seen advances in the mechanisms by which viral infections induce pro-inflammatory chemokine production, and in our understanding of host antiviral and anti-inflammatory defence pathways that might regulate responses to infection. A more comprehensive understanding of the molecular basis of these processes could elucidate new therapeutic approaches to reduce the devastating impact that these exacerbations have on quality of life and healthcare costs.

Figure 1

Mechanisms of virus-associated exacerbations of asthma and COPD. Viral infection of the epithelium results in the upregulation of ICAM-1. Pro-inflammatory mediators are also released that recruit inflammatory cells such as neutrophils and monocytes, which then differentiate into macrophages, lymphocytes and eosinophils. These inflammatory cells also release inflammatory mediators such as chemokines, cytokines, matrix metalloproteinases (MMPs) and reactive oxygen species (ROS), which perpetuate the inflammatory response culminating in an exacerbation.

Figure 2

Overview of the intracellular signalling pathway stimulated by rhinovirus. HRV binds to ICAM-1 on the surface of epithelial cells. The virus becomes internalised and, during replication, produces dsRNA. dsRNA can then bind TLR3, which activates Toll/IL-1-containing adaptor inducing interferon β (TRIF) and subsequently either interferon regulatory factor (IRF) or NF-κB. dsRNA can also bind either RIG-I or mda-5, resulting in the activation of IRF- or NF-κB-mediated pathways. It is thought that activation of IRF and NF-κB stimulates the production of the anti-viral response. FADD, Fas-associated death domain protein; IKK, inhibitor of NF-κB kinase family; IPS-1, interferon-β promoter stimulator 1; MAVS, mitochondrial antiviral signalling; RIP-1, kinase receptor interacting protein-1; TBK, TANK-binding kinase; TRAF, tumor necrosis factor receptor-associated factor; VISA, virus-induced signalling adaptor.