Innate Immune Response to Human Metapneumovirus Infection

描述(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。人类偏肺病毒(HMPV)是最近发现的一种人类病原体，可引起相当大一部分上呼吸道和下呼吸道感染，不仅发生在儿童身上，而且还存在于老年人和免疫功能低下的患者中。目前还没有针对hMPV的有效治疗方法或疫苗，许多关于hMPV引起的肺部疾病的发病机制和宿主免疫反应的基本问题还没有得到回答。我们最近发现，hMPV糖蛋白G的表达在体外和体内都能有效地抑制I型干扰素的产生，以及细胞因子和趋化因子的分泌。这种作用是通过抑制病毒诱导的核因子-β(NF-β)和干扰素调节因子(IRF)的激活来实现的，这表明G蛋白在调节hMPV感染所触发的早期细胞内信号事件中发挥了作用。事实上，我们发现G蛋白特异性地靶向hMPV诱导的细胞反应，该反应由呼吸道上皮细胞胞浆RNA解旋酶维甲酸诱导基因-I(RIG-I)和原代免疫细胞中的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依赖和非依赖的细胞信号的机制(S)，并开始确定G蛋白在体内调节先天和获得性免疫反应中的作用。在完成拟议的研究后，我们将获得关于hMPV诱导的细胞信号机制的新的关键信息，这可能使我们能够特异性地调节病毒诱导的基因表达，从而抗病毒和先天免疫/炎症反应。此外，这些研究的结果将有助于开发更安全和更有效的hMPV疫苗。 与公共卫生相关：人类偏肺病毒(HMPV)是最近发现的一种病毒，是毛细支气管炎、肺炎和流感样综合征以及哮喘恶化的主要原因，现在被认为是社区的一个重大公共卫生问题。我们最近发现hMPV糖蛋白G是一个重要的毒力因子，负责抑制对hMPV感染的先天免疫反应。这项拨款申请的目的是利用分子病毒学、细胞生物学和免疫学技术相结合的方法，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，以降低与hMPV感染相关的发病率和死亡率。

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.