Chemokine and Protein Patterns in RSV Infection

呼吸道合胞病毒（RSV）感染与哮喘的发展和严重程度有独特的联系。病毒特异性细胞免疫，特别是CTL反应，与RSV感染的免疫发病机制有关。我们已经证明，病毒诱导的气道上皮趋化因子的原型MIP-1 α的鼻咽浓度与rsv感染儿童的疾病严重程度相关，并且MIP-1 α(-/-)基因缺陷的小鼠肺部炎症显著减少。我们假设mip - α，凭借其对NK细胞和CTL的活性，作为RSV先天免疫和适应性免疫之间的桥梁，因此在限制病毒复制，诱导粘膜炎症，喘息和气道高反应性（AHR）方面发挥关键作用。在这个项目中，我们提出以下目标：1。确定MIP-1 α在控制rsv诱导的肺部炎症、AHR和疾病的病毒复制和发展中的作用。使用mip -1 α -/-小鼠，我们将验证MIP-let表达是病毒清除所必需的假设，但也与RSV感染中AHR和临床疾病的发病机制有关。2. 探讨MIP-1 et在RSV感染中对NK细胞迁移和激活的要求以及NK细胞驱动的CTL反应。我们将测试MIP-1alpha是否促进NK细胞向肺的迁移、活化和抗病毒功能，以及它是否调节NK依赖的rsv特异性CTL反应。3. 分析rsv诱导蛋白的光谱

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.