Innate Immune Response to Human Metapneumovirus Infection

对人类偏肺病毒感染的先天免疫反应

• 批准号: 8077420
• 负责人: Antonella Casola
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8077420
• 关键词: Acute; Affect; Amino Acids; Antigen-Presenting Cells; Antiviral Agents; Antiviral Response; Applications Grants; Asthma; Bronchiolitis; Cell membrane; Cells; Cellular Immunology; Cellular biology; Child; Childhood; Clinical; Communities; Dendritic Cells; Development; Dimerization; Disease; Elderly; Epidemiology; Epithelial Cells; Event; Family; GTP-Binding Proteins; Gene Expression; Genes; Grant; Host Defense; Human; Human Metapneumovirus; Immune; Immune response; Immune system; Immunocompromised Host; In Vitro; Infection; Inflammatory; Inflammatory Response; Interferon Type I; Interferons; Investigation; Lower Respiratory Tract Infection; Lung; Lung Inflammation; Lung diseases; Mediating; Molecular; Molecular Virology; Morbidity - disease rate; Mutation; Nuclear; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pneumonia; Population; Positioning Attribute; Production; Proteins; Public Health; RNA Helicase; RNA Viruses; Reagent; Recombinants; Relative (related person); Respiratory Tract Infections; Respiratory physiology; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Syndrome; System; T cell response; TLR4 gene; Techniques; Toll-like receptors; Tretinoin; Vaccines; Viral; Viral Proteins; Virulence; Virulence Factors; Virus; Virus Diseases; base; chemokine; cytokine; domain mapping; effective therapy; fighting; flu; glycoprotein G; human metapneumovirus G glycoprotein; in vivo; monocyte; mortality; mouse model; novel therapeutics; pathogen; positional cloning; protein expression; public health relevance; recombinant virus; response; toll-like receptor 4; transcription factor; vaccine candidate; viral RNA

DESCRIPTION (provided by applicant): Acute respiratory tract infections are a leading cause of morbidity and mortality in children worldwide. Human metapneumovirus (hMPV) is a recently identified human pathogen responsible for a significant portion of upper and lower respiratory tract infections not only in children but also in the elderly and in immunocompromised patients. No effective treatment or vaccine for hMPV is currently available and many fundamental questions regarding the pathogenesis of hMPV-induced lung disease and the host immune response have yet to be answered. We have recently found that hMPV glycoprotein G expression potently inhibits type I interferon (IFN) production, as well as secretion of cytokines and chemokine both in vitro and in vivo. This effect occurs via inhibition of viral-induced Nuclear Factor-?B (NF-?B) and Interferon Regulatory Factors (IRF) activation, suggesting a role of G protein in regulating early intracellular signaling events triggered by hMPV infection. Indeed, we found that G protein specifically targets hMPV-induced cellular responses mediated by the cytoplasmic RNA helicase retinoic acid-inducible gene-I (RIG-I) in airway epithelial cells and by Toll-like receptor (TLR)4 in primary immune cells. In this grant, we propose to identify the mechanism(s) by which hMPV G protein inhibits TLR-dependent and -independent cellular signaling and to start defining the role of G protein in modulating innate and adaptive immune responses in vivo. Upon completion of the proposed investigations, we will obtain new critical information regarding the mechanisms of hMPV-induced cellular signaling, which may allow us to specifically modulate viral-induced gene expression and therefore antiviral and innate immune/inflammatory responses. Furthermore, the results obtained from these studies will be instrumental for the development of safer and more effective hMPV vaccines. PUBLIC HEALTH RELEVANCE: Human metapneumovirus (hMPV), a recently identified virus, is a major cause of bronchiolitis, pneumonia and flu-like syndromes, as well as asthma exacerbations, and it is now considered a substantial public health problem for the community. We have recently identified hMPV glycoprotein G as an important virulence factor, responsible for inhibiting innate immune responses to hMPV infection. The aim of this grant application is to investigate the role of hMPV glycoprotein G in modulating host cellular responses using a combination of molecular virology, cellular biology and immunology techniques in order to develop novel therapeutic strategies and safer and more effective vaccine candidates to reduce the morbidity and mortality associated with hMPV infections.

描述（由申请人提供）：急性呼吸道感染是全世界儿童发病和死亡的主要原因。人类偏肺病毒（hMPV）是最近发现的一种人类病原体，不仅导致儿童、老年人和免疫功能低下患者的大部分上呼吸道和下呼吸道感染。目前还没有针对 hMPV 的有效治疗方法或疫苗，并且有关 hMPV 引起的肺部疾病的发病机制和宿主免疫反应的许多基本问题尚未得到解答。我们最近发现 hMPV 糖蛋白 G 表达可有效抑制 I 型干扰素 (IFN) 的产生，以及体外和体内细胞因子和趋化因子的分泌。这种效应是通过抑制病毒诱导的核因子-κB (NF-κB) 和干扰素调节因子 (IRF) 激活而发生的，表明 G 蛋白在调节 hMPV 感染触发的早期细胞内信号传导事件中发挥作用。事实上，我们发现 G 蛋白特异性靶向 hMPV 诱导的细胞反应，该细胞反应由气道上皮细胞中的细胞质 RNA 解旋酶视黄酸诱导基因-I (RIG-I) 和初级免疫细胞中的 Toll 样受体 (TLR)4 介导。在这项资助中，我们建议确定 hMPV G 蛋白抑制 TLR 依赖性和非依赖性细胞信号传导的机制，并开始定义 G 蛋白在调节体内先天性和适应性免疫反应中的作用。完成拟议的研究后，我们将获得有关 hMPV 诱导的细胞信号传导机制的新的关键信息，这可能使我们能够特异性调节病毒诱导的基因表达，从而调节抗病毒和先天免疫/炎症反应。此外，这些研究获得的结果将有助于开发更安全、更有效的 hMPV 疫苗。 公共卫生相关性：人类偏肺病毒 (hMPV) 是最近发现的一种病毒，是细支气管炎、肺炎和流感样综合征以及哮喘恶化的主要原因，目前被认为是社区的重大公共卫生问题。我们最近发现 hMPV 糖蛋白 G 是一种重要的毒力因子，负责抑制 hMPV 感染的先天免疫反应。本拨款申请的目的是结合分子病毒学、细胞生物学和免疫学技术，研究 hMPV 糖蛋白 G 在调节宿主细胞反应中的作用，以开发新的治疗策略和更安全、更有效的候选疫苗，以降低发病率和 hMPV 感染相关的死亡率。