IRF-3/5/7-Independent Antiviral Immunity

 描述(申请人提供)：登革病毒(DENV)是登革热(DF)和危及生命的登革出血热/登革休克综合征(DHF/DSS)的病原体，DHF/DSS是全球最流行的蚊媒病毒性疾病。在DENV感染期间，I型干扰素(IFN)的信号转导对于保护宿主至关重要。虽然没有 小鼠体内的一个或多个转录因子IRF-3、IRF-5和IRF-7足以增加对各种病毒感染的易感性，缺乏这三种转录因子(TKO)的小鼠仍然对在I型干扰素受体缺陷小鼠中致命的DENV攻击具有抵抗力。这表明存在不依赖于IRF-3、IRF-5和IRF-7(以下称为独立于IRF-3/5/7)的机制来对抗DENV，这是主机保护所需的。由于新的研究表明存在多种转录因子以细胞特异性、宿主特异性、时间特异性或病毒特异性的方式调节I型干扰素的产生和ISG的表达，因此鉴定这一途径非常重要，因为人们还不完全了解干扰素和干扰素刺激基因(ISG)对抗病毒免疫的转录调控。在拟议的研究中，我们试图定义在小鼠和人巨噬细胞中都缺乏主要转录因子IRF-3、IRF-5和IRF-7的情况下，负责保护DENV的转录因子。我们的初步数据表明，IRF-3/5/7不依赖的途径是I型干扰素依赖的。我们将检验这一假设，即在缺乏IRF-3、IRF-5和IRF-7的情况下，I型干扰素和ISG反应仍然发生，以保护免受DENV感染，可能是通过IRF-1、ELF4或其他先前未知与抗病毒免疫相关的转录因子的活性。 研究的具体目的是：1.研究I型干扰素信号在非IRF-3/5/7非依赖机制中对DENV感染的保护作用。2.探讨IRF-1和ELF4在IRF-3/5/7非依赖性通路中的作用。3.寻找调控IRF-3/5/7非依赖途径的新转录因子。

 DESCRIPTION (provided by applicant): Dengue virus (DENV) is the causative agent of dengue fever (DF) and the life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), the most prevalent mosquito-borne viral diseases worldwide. Signaling by type I interferon (IFN) is critical for protecting the host during DENV infection. Although the absence of one or multiple of transcription factors IRF-3, IRF-5, and IRF-7 in mice is sufficient to increase susceptibility to infection with various viruses, mice lacking all three (TKO) remain resistant to DENV challenge that is lethal in type I IFN receptor-deficient mice. This indicates the presence of an IRF-3, IRF-5, and IRF-7-independent (hereafter termed IRF-3/5/7-independent) mechanism against DENV that is required for host protection. Identification of this pathway is important because the transcriptional regulation of type IFN and interferon-stimulated gene (ISG) response for antiviral immunity is not fully understood, as new studies reveal that multiple transcription factors exist to regulate type I IFN production and ISG expression in a cell-specific host species-specific, time-specific, or virus-specific manner. In the proposed studies, we seek to define the transcription factors that are responsible for protection against DENV despite the absence of major transcription factors IRF-3, IRF-5, and IRF-7 in both mouse and human macrophages. Our preliminary data suggest that the IRF-3/5/7-independent pathway is type I IFN- dependent. We will test the hypothesis that in the absence of IRF-3, IRF-5, and IRF-7, type I IFN and ISG responses still occur to protect against DENV, potentially through activities of IRF-1, ELF4, or other transcription factors with previously unknown relation to antiviral immunity. The Specific Aims are: 1. To investigate the role of type I IFN signaling in the IRF-3/5/7-independent mechanism of protection against DENV infection. 2. To evaluate the role of IRF-1 and ELF4 in the IRF-3/5/7-independent pathway. 3. To identify novel transcription factors that regulate the IRF-3/5/7-independent pathway.