Respiratory Syncytial Virus (RSV) infections have been uniquely linked to the development and the severity of asthma. Virus-specific cellular immunity, particularly the CTL response, is implicated in the immunopathogenesis of RSV infection. We have shown that nasopharyngeal concentrations of MIP-1alpha, a prototype of viral-inducible airway epithelial chemokines, correlate with the degree of illness severity in RSV-infected children and that mice genetically deficient in MIP-1 alpha (-/-) have a striking reduction in lung inflammation. We hypothesize that MIP-alpha, by virtue of its activity on both NK cells and CTL, functions as a bridge between innate and adaptive immunity to RSV, thus playing a crucial role in restricting viral replication, yet inducing mucosal inflammation, wheezing and airway hyperresponsiveness (AHR). In this project we propose the following aims: 1. Identify the contribution of MIP-1 alpha in the control of viral replication and development of RSV-induced lung inflammation, AHR and illness. Using MIP-1alpha -/- mice, we will test the hypothesis that MIP-let expression is necessary for viral clearance, but also linked to the pathogenesis of AHR and clinical illness in RSV infections. 2. Investigate the requirement of MIP-1 et for the migration and activation of NK cells and NK-cell driven CTL responses in RSV infection. We will test whether MIP-1alpha promotes NK cell migration to the lung, activation, and antiviral function and whether it regulates NK-dependent RSV-specific CTL responses. 3. Analyze the spectrum of RSV-inducible proteins in the lung of mice, either control or MIP-1 alpha deficient, using a high-throughput proteomics approach with 2D SDS-PAGE and MALDI-TOF mass spectroscopy. We will generate databases of lung proteins from RSV-infected mice to identify downstream proteins/mediators affected by MIP-let-dependent pathways. 4. Analyze whether distinct protein patterns at the airway mucosal site can discriminate between infants with different severity of illness or degree of chemokine response following naturally-acquired RSV infection. By the high-throughput proteomics approach we will identify specific proteins or protein patterns in nasopharyngeal secretions that may contribute to the pathogenesis or severity of RSV-induced disease, and are associated with greater production of MIP-1alpha or other epithelial-derived chemokines. These studies will contribute to the identification of new strategies to promptly recognize, prevent, or early treat the most severe clinical forms of RSV infection in infancy, thus reducing the long-term burden of recurrent wheezing and asthma.
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