IRF-3/5/7-Independent Antiviral Immunity

 描述（由申请人提供）：登革热病毒（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，登革出血热/登革休克综合征是全球最流行的蚊媒病毒性疾病。I型干扰素（IFN）的信号传导对于在DENV感染期间保护宿主至关重要。虽然没有 小鼠中转录因子IRF-3、IRF-5和IRF-7中的一种或多种足以增加对各种病毒感染的易感性，缺乏所有这三种转录因子的小鼠（TKO）仍然对DENV攻击具有抗性，而DENV攻击在I型IFN受体缺陷小鼠中是致命的。这表明存在宿主保护所需的针对DENV的IRF-3、IRF-5和IRF-7独立性（下文称为IRF-3/5/7独立性）机制。这种途径的鉴定是重要的，因为抗病毒免疫的IFN型和干扰素刺激基因（ISG）应答的转录调节尚未完全了解，新的研究表明，存在多种转录因子以细胞特异性宿主种特异性、时间特异性或病毒特异性方式调节I型IFN产生和ISG表达。在拟议的研究中，我们试图定义负责保护免受DENV的转录因子，尽管在小鼠和人巨噬细胞中缺乏主要转录因子IRF-3、IRF-5和IRF-7。我们的初步数据表明，IRF-3/5/7非依赖性途径是I型IFN依赖性的。我们将检验这样的假设，即在不存在IRF-3、IRF-5和IRF-7的情况下，I型IFN和ISG应答仍可能通过IRF-1、ELF 4或其他与抗病毒免疫力具有先前未知关系的转录因子的活性而发生以保护免受DENV。 具体目标是：1。研究I型IFN信号在IRF-3/5/7非依赖性保护机制中对DENV感染的作用。2.评价IRF-1和ELF 4在IRF-3/5/7非依赖性通路中的作用。3.鉴定调节IRF-3/5/7非依赖性通路的新型转录因子。

 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.