Chemokine and Protein Patterns in RSV Infection

RSV 感染中的趋化因子和蛋白质模式

• 批准号: 7392737
• 负责人: Roberto P Garofalo
• 金额: $ 22.09万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392737
• 关键词: Abbreviations; Acute; Affect; Allergens; Animal Model; Animals; Antiviral Agents; Asthma; Biochemical Pathway; Biological Markers; Bronchiolitis; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CCL3 gene; CD8B1 gene; Cells; Cellular Immunity; Characteristics; Chemokine, Other; Chemotactic Factors; Child; Class; Clear Cell; Clinical; Collaborations; Constriction procedure; Cytotoxic T-Lymphocytes; Databases; Development; Disease; Elements; Employee Strikes; Enzyme-Linked Immunosorbent Assay; Eosinophil cationic protein; Epithelial; Epithelial Cells; Event; Fingerprint; Genomics; Grant; Hand; Hospitalized Child; Human; Human Metapneumovirus; Immune; Immune response; Immune system; Immunity; Immunoassay; In Vitro; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Inherited; Interferons; Knockout Mice; Knowledge; Link; Lower respiratory tract structure; Lung; Lung Inflammation; Lymphocyte Function; Macrophage Inflammatory Protein-1; Macrophage Inflammatory Proteins; Major Histocompatibility Complex; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Modeling; Mucositis; Mucous Membrane; Mus; NK Cell Activation; Natural Killer Cells; Pathogenesis; Pathology; Pathway interactions; Pattern; Peptides; Play; Pneumonia; Polyacrylamide Gel Electrophoresis; Preparation; Process; Production; Protein Databases; Protein Secretion; Proteins; Proteomics; Publications; Recurrence; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Respiratory physiology; Respiratory syncytial virus; Respiratory syncytial virus RSV proteins; Role; Sampling; Series; Severities; Severity of illness; Shapes; Small Inducible Cytokine A3; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectrum Analysis; Structure of parenchyma of lung; Symptoms; T-Lymphocyte; Testing; Time; Transcriptional Regulation; Upper Respiratory Infections; Validation; Viral; Virus; Virus Diseases; Wheezing; airway hyperresponsiveness; airway inflammation; atopy; base; cell motility; chemokine; cytokine; cytotoxic; design; in vivo; infancy; insight; lung injury; migration; mouse model; mucosal site; prevent; programs; prototype; research study; response; tissue culture; two-dimensional; virus pathogenesis

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.

呼吸道合胞病毒(RSV)感染与哮喘的发生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，鼻咽中MIP-1α的浓度与RSV感染儿童的疾病严重程度相关，MIP-1α是病毒诱导的呼吸道上皮趋化因子的原型，并且MIP-1α(-/-)基因缺陷的小鼠的肺部炎症显著减少。我们推测，MIP-α通过其在NK细胞和CTL上的活性，在RSV天然免疫和获得性免疫之间发挥桥梁作用，从而在限制病毒复制、诱导粘膜炎症、喘息和呼吸道高反应性(AHR)方面发挥关键作用。在本项目中，我们提出了以下目标：1.确定MIP-1α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。利用MIP-1α/-小鼠，我们将检验这一假设，即MIP-let的表达对于病毒清除是必要的，但也与呼吸道合胞病毒感染的AHR和临床疾病的发病机制有关。2.探讨呼吸道合胞病毒感染时MIP-1 ET对NK细胞迁移和激活及NK细胞驱动的CTL反应的要求。我们将测试MIP-1α是否促进NK细胞向肺的迁移、激活和抗病毒功能，以及它是否调节NK依赖的RSV特异性CTL反应。3.分析呼吸道合胞病毒诱导的蛋白质谱 利用高通量蛋白质组学方法，结合2D SDS-PAGE和MALDI-TOF质谱学，对对照或MIP-1α缺陷小鼠的肺组织进行了研究。我们将建立RSV感染小鼠的肺蛋白质数据库，以确定受MIP-let依赖通路影响的下游蛋白质/介质。4.分析呼吸道粘膜部位不同的蛋白质模式是否可以区分自然获得的RSV感染后不同疾病严重程度或趋化因子反应程度的婴儿。通过高吞吐量 蛋白质组学方法我们将在鼻咽分泌物中确定特定的蛋白质或蛋白质模式，这些蛋白质或蛋白质模式可能与RSV诱导的疾病的发病或严重程度有关，并与更多的MIP-1α或其他上皮来源的趋化因子的产生有关。这些研究将有助于确定新的战略，迅速识别、预防或早期治疗婴儿时期最严重的呼吸道合胞病毒感染临床形式，从而减少反复发作的喘息和哮喘的长期负担。