The long-range goal of this research proposal is to elucidate how rhinovirus (RV) activation of macrophages contributes to the exacerbations of asthma. Virus-induced asthma is resistant to therapy; therefore knowledge about the cellular processes 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 microenvironment observed in RV-induced exacerbations of asthma. However, little is known about how signaling events initiated by major and minor group rhinoviruses contribute to proinflammatory cytokine/chemokine production. In addition, it is unclear whether major and minor group rhinoviruses activate macrophages via the same signaling pathways because they have different cellular receptors. Thus, this proposal is focused on evaluating the involvement of key signaling events in RV-stimulated mediator production by the macrophage, specifically, MCP-1, RANTES and IFN-a. In this regard, we have found that major and minor group rhinoviruses modulate multiple signaling pathways in different ways including the activation of the low molecular weight G-proteins, Ras and Rac, p38 MAP kinase, and the JNK MAP kinase. In light of our preliminary studies, we will test the following hypotheses 1) Major and minor group rhinovirus interaction with macrophages differentially regulates members of the Ras superfamily of low MW G-proteins and this process is critical for the production of the inflammatory mediators MCP-1, RANTES and IFN-a. 2) Exposure of macrophages to major and minor group rhinovirus stimulates the production of inflammatory mediators, MCP-1, RANTES and IFN-a, through the regulation of MAP kinase cascades (Jun kinases (JNKs) and/or p38 kinase). ? ? ?
| Schuler, Bryce A; Schreiber, Michael T; Li, Luyuan et al. (2014) Major and minor group rhinoviruses elicit differential signaling and cytokine responses as a function of receptor-mediated signal transduction. PLoS One 9:e93897 |
| Schreiber, Michael T; Schuler, Bryce; Li, LuYuan et al. (2013) Activation of the small G-protein Rac by human rhinovirus attenuates the TLR3/IFN-? axis while promoting CCL2 release in human monocyte-lineage cells. Innate Immun 19:278-89 |
| Albright, Catherine J; Hall, David J (2011) An exercise in molecular epidemiology: human rhinovirus prevalence and genetics. Biochem Mol Biol Educ 39:426-31 |
