Human metapneumovirus glycoprotein G inhibits innate immune responses.
Human metapneumovirus glycoprotein G inhibits innate immune responses.
复制标题
人元病毒糖蛋白G抑制先天免疫反应。
DOI：
10.1371/journal.ppat.1000077
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发表时间：
2008-05-30
期刊：
影响因子：
6.7
通讯作者：
Casola, Antonella
中科院分区：
文献类型：
--
作者：
Bao, Xiaoyong;Liu, Tianshuang;Shan, Yichu;Li, Kui;Garofalo, Roberto P.;Casola, Antonella
人类偏肺病毒(HMPV)是婴儿以及老年人和免疫功能低下患者急性呼吸道感染的主要原因。目前还没有针对hMPV的有效治疗方法或疫苗。一种缺乏G蛋白的重组人乳头瘤病毒(rh MPV-ΔG)最近被开发为一种潜在的候选疫苗，并在啮齿动物感染模型的呼吸道中被证明是减毒的。其衰减的机制以及G蛋白在体内和体外对hMPV诱导的细胞反应的调节作用目前尚不清楚。在这项研究中，我们发现，与感染rh MPV-Δ的细胞相比，感染rh MPV-WT的呼吸道上皮细胞产生更高水平的趋化因子和I型干扰素。呼吸道上皮细胞感染rh MPV-ΔG后，核因子-κB和干扰素调节因子家族的转录因子激活增强，表现为核转位和/或磷酸化增加。与重组人MPV-WT相比，重组人MPV-ΔG还能促进依赖iRF和NF-κB的基因转录，而G蛋白的表达则相反地抑制这种转录。由于RNA解旋酶已被证明在启动病毒诱导的细胞信号转导中起着重要作用，我们研究了维甲酸诱导基因(RIG)-I是否是G蛋白抑制活性的靶标。我们发现G蛋白确实与RIG-I相关，并抑制依赖RIG-I的基因转录，从而确定了hMPV影响先天性免疫反应的一个重要机制。这是第一次研究hMPV G蛋白在细胞信号转导中的作用，并确认G蛋白是一个重要的毒力因子，因为它通过靶向主要的细胞内病毒RNA传感器RIG-I来抑制重要免疫和抗病毒介质的产生。人偏肺病毒(HMPV)是副粘病毒科的成员之一，是导致呼吸道疾病的重要原因。病毒特异性蛋白在hMPV感染和免疫逃避的发病机制中的作用在很大程度上尚不清楚。以往的工作表明，hMPV的糖蛋白G不是病毒融合和附着宿主细胞所必需的，而缺乏G蛋白的重组hMPV(rh MPV-ΔG)在感染动物模型的呼吸道中表现出减弱的表型。呼吸道上皮细胞是先天免疫系统的主要组成部分，也是hMPV感染的主要靶点。在这项研究中，我们证明了hMPVG蛋白通过阻断诱导性趋化因子和干扰素-α/β的产生而作为宿主抗病毒反应的主要抑制因子发挥作用。这项工作的一个主要发现是证明了hMPV G蛋白与细胞质病毒传感器RIG-I相互作用。因此，hMPVG蛋白抑制依赖RIG-I的信号通路，包括激活NF-κB和IRF-3，这两个转录因子是合成炎症和抗病毒细胞因子所必需的。了解hMPV蛋白的功能对于未来有效的抗病毒疗法的设计和候选疫苗的理论设计至关重要。
Human metapneumovirus (hMPV) is a leading cause of acute respiratory tract infection in infants, as well as in the elderly and immunocompromised patients. No effective treatment or vaccine for hMPV is currently available. A recombinant hMPV lacking the G protein (rhMPV-ΔG) was recently developed as a potential vaccine candidate and shown to be attenuated in the respiratory tract of a rodent model of infection. The mechanism of its attenuation, as well as the role of G protein in modulation of hMPV-induced cellular responses in vitro, as well as in vivo, is currently unknown. In this study, we found that rhMPV-ΔG-infected airway epithelial cells produced higher levels of chemokines and type I interferon (IFN) compared to cells infected with rhMPV-WT. Infection of airway epithelial cells with rhMPV-ΔG enhanced activation of transcription factors belonging to the nuclear factor (NF)-κB and interferon regulatory factor (IRF) families, as revealed by increased nuclear translocation and/or phosphorylation of these transcription factors. Compared to rhMPV-WT, rhMPV-ΔG also increased IRF- and NF-κB-dependent gene transcription, which was reversely inhibited by G protein expression. Since RNA helicases have been shown to play a fundamental role in initiating viral-induced cellular signaling, we investigated whether retinoic induced gene (RIG)-I was the target of G protein inhibitory activity. We found that indeed G protein associated with RIG-I and inhibited RIG-I-dependent gene transcription, identifying an important mechanism by which hMPV affects innate immune responses. This is the first study investigating the role of hMPV G protein in cellular signaling and identifies G as an important virulence factor, as it inhibits the production of important immune and antiviral mediators by targeting RIG-I, a major intracellular viral RNA sensor. Human metapneumovirus (hMPV), a member of the Paramyxoviridae family, is an important cause of respiratory morbidity throughout life. The contribution of viral-specific proteins to the pathogenesis of hMPV infection and immune evasion is largely unknown. Previous work has suggested that the glycoprotein G of hMPV is not necessary for the process of viral fusion and attachment to host cells, and a recombinant hMPV lacking the G protein (rhMPV-ΔG) shows an attenuated phenotype in the respiratory tract of animal models of infection. Airway epithelial cells, a major component of the innate immune system, are a primary target of hMPV infection. In this study, we show that hMPV G protein functions as a major inhibitory factor of the host antiviral response by blocking production of inducible chemokines and IFN-α/β. A major finding of this work is the demonstration that hMPV G protein interacts with RIG-I, a cytoplasmic viral sensor. As result, hMPV G protein inhibits RIG-I-dependent signaling pathways, including activation of NF-κB and IRF-3, two transcription factors necessary for the synthesis of inflammatory and antiviral cytokines. Understanding the function of hMPV proteins is critical for the future design of effective antiviral therapies and rationale design of vaccine candidates.
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