IRF-3/5/7-Independent Antiviral Immunity

IRF-3/5/7-独立的抗病毒免疫

• 批准号: 9029196
• 负责人: Sujan Shresta
• 金额: $ 44.25万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9029196
• 关键词: Antisense Oligonucleotides; Antiviral Agents; Antiviral Response; Biological Assay; Blood Circulation; Bone Marrow; CRISPR screen; CRISPR/Cas technology; Cell Culture Techniques; Cells; Chikungunya virus; Collaborations; Culicidae; Cytoprotection; Data; Dendritic Cells; Dengue; Dengue Hemorrhagic Fever; Dengue Infection; Dengue Shock Syndrome; Dengue Virus; Dependence; EMSA; Experimental Models; Family member; Flavivirus; Flow Cytometry; Gene Expression; Gene Silencing; Genes; Goals; Human; IFNAR1 gene; IRF1 gene; Immune; Infection; Institutes; Interferon Type I; Interferons; Kinetics; Knock-out; Knockout Mice; Knowledge; Life; Measures; Mediating; Modeling; Monoclonal Antibodies; Mus; Norovirus; Pathway interactions; Predisposition; Production; Publishing; RNA; Receptor Signaling; Reporter; Resistance; Role; Serotyping; Signal Transduction; Signaling Molecule; Small Interfering RNA; Spleen; System; Testing; Therapeutic; Time; Transcriptional Regulation; U937 Cells; Up-Regulation; Virus; Virus Diseases; Virus Replication; West Nile virus; antiviral immunity; bZIP Domain; base; cell type; follow-up; gene induction; human disease; macrophage; member; monocyte; novel; pathogen; programs; public health relevance; research study; response; transcription factor; transcriptome sequencing; type I interferon receptor

 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.

 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，这是全球最流行的蚊媒病毒性疾病。尽管缺乏 DENV 感染，但 I 型干扰素 (IFN) 发出的信号对于保护宿主至关重要。 小鼠体内的一种或多种转录因子 IRF-3、IRF-5 和 IRF-7 足以增加对各种病毒感染的易感性，缺乏这三种因子的小鼠 (TKO) 仍能抵抗对 I 型 IFN 致命的 DENV 攻击这表明存在宿主所需的 IRF-3、IRF-5 和 IRF-7 独立（以下称为 IRF-3/5/7 独立）机制。识别该途径很重要，因为抗病毒免疫的 IFN 型和干扰素刺激基因 (ISG) 反应的转录调节尚未完全了解，因为新的研究表明存在多种转录因子来调节 I 型 IFN 的产生和 ISG 的表达。在拟议的研究中，我们试图以细胞特异性、宿主物种特异性、时间特异性或病毒特异性的方式来定义负责防御 DENV 的转录因子，尽管缺乏主要转录因子 IRF-3，小鼠和人类巨噬细胞中的IRF-5和IRF-7表明，IRF-3/5/7独立途径是I型IFN依赖性的。我们将检验在不存在IRF-的情况下的假设。 3、IRF-5 和 IRF-7、I 型 IFN 和 ISG 反应仍然会发生，以预防 DENV，可能是通过 IRF-1、ELF4 或其他先前未知的与抗病毒免疫关系的转录因子的活性。 具体目标是： 1. I 型 IFN 信号传导在 IRF-3/5/7 独立的 DENV 感染保护机制中的作用 2. 评估 IRF-1 和 ELF4 在 IRF-3 中的作用。 /5/7独立途径。 3.鉴定调节IRF-3/5/7独立途径的新转录因子。