The long-range goal of this research is to understand the mechanisms by which RV activation of macrophages leads to the exacerbation of asthma. Because virus-induced asthma has been resistant to therapy, knowledge concerning the cellular processes that are critical in its development may lead to new forms of intervention. In this regard, previous studies have implicated the macrophage as an important cell in establishing the inflammatory environment observed in RV-induced exacerbations of asthma. However, little is known about the signaling events that are initiated upon macrophage infection with RV and how these relate to cytokine/chemokine production. Moreover, it is unclear whether RV activation of macrophages is similar to that initiated by other macrophage stimuli and whether unique profiles of cell signaling are promoted by macrophage interaction with virus and virally induced factors. Thus, this application is focused on evaluating the involvement of key signaling events in RV stimulated mediator production by the macrophage, specifically IL-8, IFN-alpha, granulocyte/macrophage-colony stimulating factor (GM-CSF), IL-1beta, and TNF-alpha production (whose release is closely associated with the development of late-phase allergic reaction and asthma). In this regard, we have found that RV infection of macrophages modulates multiple signaling pathways, including the activation of the transcription factor NF-kappaB and the low molecular weight (MW) G-protein Ras, which is linked to the control of effector molecules such as the MAP kinases. Therefore, we will test the hypothesis that RV infection of macrophages initiates the release of inflammatory mediators through the action of members of the Ras superfamily, the MAP kinase family, and the transcription factors NF-KappaB and those activated by virus and virus-induced cytokines, i.e., the interferon-regulatory factors (IRF) and the STAT factors. Accordingly, we will test the following hypotheses: (1) RV interaction with macrophages regulates members of the Ras superfamily of low MW G-proteins and this process is critical for the production of the inflammatory mediators; (2) Exposure of macrophages to RV stimulates the production of inflammatory mediators through the regulation of MAP kinase cascades (ERKs, Jun kinases and/or p38 kinase); and (3) The NF-kappaB, STAT, and IRF pathways are activated as a result of macrophage exposure to RV and these pathways regulate the expression of inflammatory mediators.
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