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: 8282740
• 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/8282740
• 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球儿童发病率和死亡率的主要原因。人类元瘤病毒（HMPV）是最近确定的人类病原体，不仅在儿童，而且在老年人和免疫功能低下的患者中，都导致了上下呼吸道感染的很大一部分。目前尚无有效的HMPV治疗方法或疫苗，有关HMPV诱导的肺部疾病的发病机理的许多基本问题尚未得到解决。我们最近发现，HMPV糖蛋白G表达有效抑制I型干扰素（IFN）产生，以及在体外和体内的细胞因子和趋化因子的分泌。这种效果是通过抑制病毒诱导的核因子 - ？b（NF-？b）和干扰素调节因子（IRF）激活而发生的，这表明G蛋白在调节HMPV感染触发的早期细胞内信号事件中的作用。确实，我们发现G蛋白特异性地靶向由胞质RNA解放酶黄酸诱导的细胞反应介导的气道上皮细胞中的细胞质RNA诱导基因-I（RIG-I），而原代免疫细胞中的TOLL样受体（TLR）4。在这笔赠款中，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的机制，并开始定义G蛋白在调节体内定期和适应性免疫反应中的作用。提出的研究完成后，我们将获得有关HMPV诱导的细胞信号传导机制的新关键信息，这可能使我们能够专门调节病毒诱导的基因表达，因此可以抗病毒和先天免疫/炎症反应。此外，从这些研究中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：最近确定的病毒人类元瘤病毒（HMPV）是造成细支气管炎，肺炎和流感状综合症以及哮喘病毒的主要原因，现在被认为是社区的实质性公共卫生问题。我们最近将HMPV糖蛋白G视为重要的毒力因子，负责抑制对HMPV感染的先天免疫反应。该赠款应用的目的是研究HMPV糖蛋白G在使用分子病毒学，细胞生物学和免疫学技术的组合来调节宿主细胞反应中的作用，以开发新的治疗策略，更安全，更有效的疫苗候选者，以减少与HMPV Infections相关的发病率和死亡率。