Airway epithelial cells from patients with COPD show higher baseline levels of cytokine expression and increased susceptibility to RV infection, despite an increased IFN response.

Rhinovirus (RV), a single-stranded RNA picornavirus, is the most frequent cause of asthma exacerbations. We previously demonstrated in human bronchial epithelial cells that melanoma differentiation-associated gene (MDA)-5 and the adaptor protein for Toll-like receptor (TLR)-3 are each required for maximal RV1B-induced interferon (IFN) responses. However, in vivo, the overall airway response to viral infection likely represents a coordinated response integrating both antiviral and pro-inflammatory pathways. We examined the airway responses of MDA5- and TLR3-deficient mice to infection with RV1B, a minor group virus which replicates in mouse lungs. MDA5 null mice showed a delayed type I IFN and attenuated type III IFN response to RV1B infection, leading to a transient increase in viral titer. TLR3 null mice showed normal IFN responses and unchanged viral titers. Further, RV-infected MDA5 and TLR3 null mice showed reduced lung inflammatory responses and reduced airways responsiveness. Finally, RV-infected MDA5 null mice with allergic airways disease showed lower viral titers despite deficient IFN responses, and allergic MDA5 and TLR3 null mice each showed decreased RV-induced airway inflammatory and contractile responses. These results suggest that, in the context of RV infection, binding of viral dsRNA to MDA5 and TLR3 initiates pro-inflammatory signaling pathways leading to airways inflammation and hyperresponsiveness.

Rhinovirus (RV) is a common cause of asthma exacerbations. The signaling mechanisms regulating RV-induced airway epithelial cell responses have not been well studied. We examined the role of phosphatidylinositol (PI) 3-kinase in RV-induced interleukin (IL)-8 expression. Infection of 16HBE14o؊ human bronchial epithelial cells with RV39 induced rapid activation of PI 3-kinase and phosphorylation of Akt, a downstream effector of PI 3-kinase. RV39 also colocalized with cit-Akt-PH, a citrogen-tagged fluorescent fusion protein encoding the pleckstrin homology domain of Akt, indicating that 3-phosphorylated PI accumulates at the site of RV infection. Inhibition of PI 3-kinase and Akt attenuated RV39-induced NF-B transactivation and IL-8 expression. Inhibition of PI 3-kinase also blocked internalization of labeled RV39 into 16HBE14o؊ cells, suggesting that the requirement of PI 3-kinase for RV39-induced IL-8 expression, at least in part, relates to its role in viral endocytosis. Rhinovirus (RV)2 is a single-stranded RNA virus from the Picornaviridae family responsible for the majority of common colds. Viral infections trigger the majority of asthma exacerbations (1, 2), and RV accounts for 60% of virus-induced exacerbations (1). RV is also an important trigger of chronic obstructive pulmonary disease (COPD) exacerbations (3, 4). The precise mechanisms by which RV induces asthma or COPD exacerbations are unknown, but numerous studies suggest a role for IL-8, a CXC chemokine with the neutrophil-attractant Glu-Leu-Arg (ELR) motif. IL-8 and neutrophils are found in the nasal secretions and sputum of patients with RV-induced asthma exacerbations (5-9). Further, the number of neutrophils correlates with the level of IL-8 (7, 9). RV induces IL-8 expression in cultured airway epithelial cells (10 -12). Increased neutrophil and IL-8 levels are a feature of asthma (13,14) and COPD exacerbations (15-17). Together, these data suggest that RV may stimulate asthma exacerbations by inducing bronchial epithelial cell production of IL-8, leading to a neutrophilic inflammatory response.The human RVs include more than 100 serotypes that are divided into two groups based on their cellular receptors. Intercellular adhesion molecule (ICAM)-1 is the airway epithelial cell receptor for major subgroup RVs (e.g. RV14, RV16, and RV39), whereas the low density lipoprotein receptor functions as the receptor for minor subgroup RVs (e.g. RV1B and RV2). Thus, antibodies to ICAM-1 inhibit major subgroup RV infection of epithelial cells (18).ICAM-1 is a type I transmembrane glycoprotein belonging to the immunoglobulin superfamily. In endothelial cells, ICAM-1 cross-linking increases phosphorylation and activation of pp60 Src (19,20) and pp125 focal adhesion kinase (21). The p85 regulatory subunit of class 1A PI 3-kinase serves as a substrate for both Src (22) and focal adhesion kinase (23, 24), suggesting that ICAM-1 ligation by RV could also activate PI 3-kinase. Other viruses with different membrane receptors also activate PI 3-kinase. Adenovirus atta...

Viral infection is associated with approximately one-half of acute exacerbations of chronic obstructive pulmonary disease (COPD), which in turn, accelerate disease progression. In this study, we infected mice exposed to a combination of elastase and LPS, a constituent of cigarette smoke and a risk factor for development of COPD, with rhinovirus serotype 1B, and examined animals for viral persistence, airway resistance, lung volume, and cytokine responses. Mice exposed to elastase and LPS once a week for 4 wk showed features of COPD such as airway inflammation and obstruction, goblet cell metaplasia, reduced lung elastance, increased total lung volume, and increased alveolar chord length. In general, mice exposed to elastase or LPS alone showed intermediate effects. Compared with rhinovirus (RV)-infected PBS-exposed mice, RV-infected elastase/LPS-exposed mice showed persistence of viral RNA, airway hyperresponsiveness, increased lung volume, and sustained increases in expression of TNFalpha, IL-5, IL-13, and muc5AC (up to 14 days postinfection). Furthermore, virus-induced IFNs, interferon response factor-7, and IL-10 were deficient in elastase/LPS-treated mice. Mice exposed to LPS or elastase alone cleared virus similar to PBS-treated control mice. We conclude that limited exposure of mice to elastase/LPS produces a COPD-like condition including increased persistence of RV, likely due to skewing of the immune response towards a Th2 phenotype. Similar mechanisms may be operative in COPD.