Innate Immune Response to Human Metapneumovirus Infection

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，不仅在儿童、而且在老年人和免疫功能低下的患者中引起很大一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 诱导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。

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.