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着独特的联系。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，MIP-1α（一种病毒诱导的气道上皮趋化因子的原型）的鼻咽浓度与 RSV 感染儿童的疾病严重程度相关，并且遗传性缺乏 MIP-1 α (-/-) 的小鼠具有肺部炎症显着减少。我们假设 MIP-α 凭借其对 NK 细胞和 CTL 的活性，充当 RSV 先天性免疫和适应性免疫之间的桥梁，从而在限制病毒复制方面发挥着至关重要的作用，但也会诱发粘膜炎症、喘息和气道高反应性（AHR）。在该项目中，我们提出以下目标： 1. 确定 MIP-1 α 在控制病毒复制和 RSV 诱导的肺部炎症、AHR 和疾病发展中的作用。使用 MIP-1alpha -/- 小鼠，我们将检验以下假设：MIP-let 表达对于病毒清除是必需的，而且还与 AHR 的发病机制和 RSV 感染的临床疾病有关。 2. 研究 RSV 感染中 MIP-1 et 对 NK 细胞迁移和激活以及 NK 细胞驱动的 CTL 反应的需求。我们将测试 MIP-1alpha 是否促进 NK 细胞迁移至肺部、激活和抗病毒功能，以及是否调节 NK 依赖性 RSV 特异性 CTL 反应。 3. 分析 RSV 诱导蛋白的谱 使用采用 2D SDS-PAGE 和 MALDI-TOF 质谱的高通量蛋白质组学方法，对对照小鼠或 MIP-1 α 缺陷型小鼠的肺进行分析。我们将生成 RSV 感染小鼠的肺蛋白数据库，以识别受 MIP-let 依赖性途径影响的下游蛋白/介质。 4. 分析气道粘膜部位的不同蛋白质模式是否可以区分自然获得性 RSV 感染后疾病严重程度或趋化因子反应程度不同的婴儿。通过高通量 通过蛋白质组学方法，我们将鉴定鼻咽分泌物中的特定蛋白质或蛋白质模式，这些蛋白质或蛋白质模式可能有助于 RSV 诱导疾病的发病机制或严重程度，并且与 MIP-1α 或其他上皮衍生趋化因子的大量产生相关。这些研究将有助于确定新的策略，以迅速识别、预防或早期治疗婴儿期 RSV 感染最严重的临床形式，从而减轻反复喘息和哮喘的长期负担。