This competitive renewal will build upon our previous work on the role of chemokines and their receptors in airway inflammation. Children that had experienced severe responses to RSV infections often progress into developing long-term pulmonary problems. In addition to pediatric populations, recent evidence has indicated that there is an unknown and relatively unexplored relationship to pulmonary disease in adult populations, including those with asthma and COPD. This renewal application will focus on the role of specific chemokine receptors and their ligands in RSV infection as well as the effects of RSV on exacerbation of cockroach allergen induced disease. Our hypothesis for this proposal is that RSV infection causes airways disease via the activation of CD8+ T cell responses dependent upon CCR1-mediated mechanisms, whereas resolution of disease relies upon the activation of CxCR3-mediated mechanisms. We have designed experiments using 3 specific aims to test our hypothesis and to identify the mechanisms of disease progression.
These specific aims i nclude: I. To determine what role CCR1+ T lymphocytes have on RSV-induced disease and in exacerbation of allergic airway disease;II. To establish the mechanism of CxCR3+ and its ligands in the immune response leading to the resolution of RSV-induced disease, and III. To identify the differential role of chemokines for DC subset, pDC vs. cDC, trafficking to the lungs and activation leading to altered pulmonary responses. Our studies will examine both a primary RSV-induced response as well as RSV-induced exacerbation of allergic airway disease. Determining the mechanisms that drive the early responses to RSV and mediate or alleviate severe disease will offer an excellent opportunity to target the early manifestations that have long-term detrimental effects in children, and possibly aid in attenuating progression into severe pulmonary disease. Our models have now been well characterized and allow our studies to address the cell populations involved and the relevant mechanisms that drive the detrimental responses. We will extend our hypothesis to include that CCR1+ CD8 T cells are a significant source of Th2 cytokines, especially IL-13, that lead to exacerbated allergic airway disease. The mechanism of the recruitment of CCR1+ CD8 T cells will center on the induced expression of CCR1 ligands, especially CCL5, within the airways of RSV-infected hosts. We have now also provided novel data that has identified that CxCR3-mediated mechanisms induce a critical anti-viral response via recruitment and activation of important innate cells especially plasmacytoid dendritic cells. The use of cellular transfer experiments with specific animals deficient in targeted molecules will enhance our ability to define the particular cellular mechanisms in vivo during a complex immune response. These mechanisms may be similar to those that are involved in infants, where RSV-infected children often progress into having long-term pulmonary problems and in asthmatics for exacerbated disease. Project Narrative: The coordinated production of chemokines during pulmonary inflammation leads to the recruitment of various leukocytes into the lung interstitium and airway. Identifying chemokine mediators as well as the relevant receptor during allergic and viral disease may be important for identifying therapeutics targets for treating chronic airway disease.
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