Parainfluenza virus 3 interactions with dendritic cells

副流感病毒 3 型与树突状细胞的相互作用

• 批准号: 6917518
• 负责人: Gabriele Luca GUSELLA
• 金额: $ 25.29万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917518
• 关键词: Paramyxovirus; dendritic cells; exo alpha sialidase; glycoproteins; hemagglutinin; human tissue; immunoregulation; microorganism hemagglutinin; microorganism immunology; monocyte; mucosa; respiratory epithelium; respiratory infections; respiratory virus; tissue /cell culture; virus protein

DESCRIPTION (provided by applicant): Despite decades of study, the immunobiology of paramyxoviruses such as RSV and parainfluenza remains poorly understood and a subject of intense controversy. This gap in knowledge has hampered the development of safe and effective vaccines and antiviral strategies. DCs are the most efficient antigen presenting cells (APCs) in inducing CTL responses to viruses. Interference with DC function, is a mechanism evolved by viruses to disrupt host defenses and survive immunological responses. The overall aim of this application is to define the in vitro interactions of human parainfluenza virus with dendritic cells (DCs). HPF3 infection can promote DC maturation while paradoxically interfering with their proper antigen presenting functions. Recent data suggest that the viral surface glycoproteins, the Hemagglutinin-Neuraminidase (HN) and the fusion protein (F), may mediate these effects. Our overall hypothesis is that interactions with DCs encountered shortly after infection of the respiratory mucosa are key determinants of HPF3 immunity and pathogenesis. Disruption of DC functions and impairment of cellular responses mediated by HN and F may contribute to the failure to establish long lasting protective immunity. Our first goal is to define the effects of the viral glycoproteins on differentiation and maturation of human DCs in vitro. We will dissect the specific contributions of HN and F and will determine whether particular functions of HN differentially affect this process. We will analyze how HPF3 infection -and exposure to the viral glycoproteins- influences migration and differentiation of monocytes into DCs in a tissue culture model of cell transmigration through endothelium. This model allows us to study how viral pathogens regulate DCs in a tissue setting, resembling more closely the natural conditions found in the mucosa of the human respiratory tract. Our second goal is to analyze HN and F immunoregulatory roles on the interaction of DCs with T cells in vitro. We will establish whether in vitro, HN and/or F account for the impairment of the stimulatory properties observed in HPF3 infected DCs by a direct cell contact-dependent mechanism. In addition, we will determine whether infection induces DCs to polarize T lymphocytes towards the expression of Th2 or Th1 type cytokines and whether HN and F are key determinants of this polarization. The definition of the viral glycoprotein(s) and their functions associated to the modulation of DCs will contribute to the ongoing effort for vaccine development through the generation of safer and more effective recombinant forms of HPF3. The identification of the viral domains important for HPF3-mediated immunoregulation will provide the target for novel antiviral pharmacologic strategies.

描述（由申请人提供）： 尽管经过数十年的研究，RSV 和副流感等副粘病毒的免疫生物学仍然知之甚少，并且是一个存在激烈争议的话题。这种知识差距阻碍了安全有效的疫苗和抗病毒策略的开发。 DC 是诱导病毒 CTL 反应最有效的抗原呈递细胞 (APC)。干扰 DC 功能是病毒进化出来的一种机制，用于破坏宿主防御并在免疫反应中生存。本申请的总体目标是确定人副流感病毒与树突状细胞 (DC) 的体外相互作用。 HPF3感染可以促进DC成熟，同时矛盾地干扰其正确的抗原呈递功能。最近的数据表明，病毒表面糖蛋白、血凝素神经氨酸酶 (HN) 和融合蛋白 (F) 可能介导这些效应。我们的总体假设是，呼吸道粘膜感染后不久与 DC 的相互作用是 HPF3 免疫和发病机制的关键决定因素。 DC 功能的破坏以及 HN 和 F 介导的细胞反应受损可能导致无法建立持久的保护性免疫。我们的首要目标是确定病毒糖蛋白对体外人类 DC 分化和成熟的影响。我们将剖析 HN 和 F 的具体贡献，并确定 HN 的特定功能是否会对该过程产生不同的影响。我们将在细胞通过内皮迁移的组织培养模型中分析 HPF3 感染以及接触病毒糖蛋白如何影响单核细胞向 DC 的迁移和分化。该模型使我们能够研究病毒病原体如何在组织环境中调节 DC，更接近人类呼吸道粘膜中的自然条件。我们的第二个目标是分析 HN 和 F 对 DC 与 T 细胞体外相互作用的免疫调节作用。我们将在体外确定 HN 和/或 F 是否通过直接细胞接触依赖性机制来解释在 HPF3 感染的 DC 中观察到的刺激特性的损害。此外，我们将确定感染是否会诱导 DC 使 T 淋巴细胞极化为 Th2 或 Th1 型细胞因子的表达，以及 HN 和 F 是否是这种极化的关键决定因素。 病毒糖蛋白的定义及其与 DC 调节相关的功能将有助于通过生成更安全、更有效的 HPF3 重组形式来持续开发疫苗。对 HPF3 介导的免疫调节重要的病毒结构域的鉴定将为新型抗病毒药理学策略提供目标。