Rhinovirus (RV) is a single-stranded RNA virus responsible for most common colds, and an important trigger of chronic obstructive pulmonary disease (COPD) exacerbations. However, little information exists regarding interactions between viruses and bacteria in the pathogenesis of COPD exacerbations. We have found in cultured airway epithelial cells that infection with H. influenzae and P. aeruginosa, respectively, induces additive and synergistic increases in IL-8 expression following infection with RV serotype 39. We offer the general hypotheses that: 1) bacterial infection and squamous differentiation increase access of RV to its receptors by increasing receptor expression and degrading tight junctions; and 2) bacterial and RV infection share common biochemical signaling pathways involved in airway inflammation. Together, these hypotheses provide a mechanism for RV-induced COPD exacerbations. To test these, we propose the following:
Specific Aim 1 : Determine cellular mechanisms underlying the additive and/or synergistic effects of bacteria and RV on airway epithelial cell responses. We hypothesize that: 1) bacterial infection increases the pro-inflammatory response of airway epithelia to RV infection; 2) bacterial infection increases airway epithelial cell ICAM-1 and Toll-like receptor (TLR)-3 expression, leading to exaggerated responses to RV; and 3) bacterial infection increases the susceptibility to RV infection by degrading tight junctions.
Specific Aim 2 : Identify the biochemical signaling pathways mediating RV39-induced IL-8 expression in human bronchial epithelial cells. We hypothesize that: 1) activation of the PI 3-kinase, ERK and TLR3 pathways is required for maximal RV39-induced IL-8 expression; 2) maximal NF-icB transactivation requires PI 3-kinase-dependent activation of NADPH oxidase; 3) ERK regulates RV39- induced IL-8 expression via activation of the AP-1 promoter site.
Specific Aim 3 : Examine the signaling mechanisms responsible for the cooperative effects of bacteria and RV on airway epithelial cell IL-8 expression, and whether bacterial and RV1B infection have additive or synergistic effects on airway inflammation in vivo. We hypothesize that: 1) synergistic responses in IL-8 expression are mediated by increased AP-1 activation; 2) RV1B infection of mouse airways is sufficient to induce airway inflammation; and 3) RV1B and bacterial infection have synergistic effects on airway inflammation in vivo. Understanding viral-induced exacerbations of chronic obstructive pulmonary disease (COPD) will lead to improvements in the treatment of this disease, thereby increasing survival and quality of life for patients.
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