Generation of MAVS conditional KO mice to study cell-type specific immunity

生成 MAVS 条件 KO 小鼠以研究细胞类型特异性免疫

• 批准号: 8787074
• 负责人: Mehul Shamal Suthar
• 金额: $ 8.93万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-18 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787074
• 关键词: Adaptor Signaling Protein; Address; Antiviral Agents; Autoimmune encephalitis; Automobile Driving; Bacterial Infections; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; California; Categories; Cells; Chronic; Communities; Core Facility; Cost Savings; Dendritic Cells; Dendritic cell activation; Development; Flavivirus; Focal Infection; Future; Generations; Goals; Health; Human; Immune; Immune response; Immunity; Immunologic Receptors; Infection; Infection Control; Infection prevention; Knockout Mice; Knowledge; Manuscripts; Mediating; Microinjections; Mosquito-Borne Encephalitis; Mus; National Institute of Allergy and Infectious Disease; Natural Killer Cells; Pathogenesis; Pathway interactions; Phase; Play; Process; Public Health; Publications; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Research; Research Design; Research Personnel; Risk; Role; Services; Signal Pathway; Signal Transduction; Site; Systemic infection; T cell regulation; T cell response; T-Cell Activation; T-Lymphocyte; Technology; Therapeutic; Tissues; Transgenic Mice; United States; Universities; Vaccination; Vaccines; Viral; Viral Pathogenesis; Virus Diseases; Virus Replication; West Nile virus; cell type; combat; embryonic stem cell; experience; gene function; in vivo; innovation; insight; interest; member; mouse model; neurotropic; neutrophil; novel; novel vaccines; programs; receptor; recombinase; response; tool; virus pathogenesis

DESCRIPTION (provided by applicant): West Nile virus (WNV), a category B NIAID priority agent, is a neurotropic flavivirus that is the leading cause of mosquito-borne encephalitis of humans in the United States. The continuing spread of WNV, combined with the lack of specific therapeutics or vaccines to combat or prevent infection, imparts a pressing need to identify the viral and host processes that control infection and immunity. The pathogenesis of WNV in humans is poorly defined, but a mouse model of WNV infection, which faithfully recapitulates the major phases of WNV pathogenesis observed in humans, has provided significant insights into the mechanisms that cause WNV disease. The innate immune response (mediated by RIG-I like receptor [RLR] signaling) and the humoral and cell-mediated responses are critical for protection against WNV infection. The RLR signaling pathway functions to trigger antiviral immune defenses and program protective immunity during WNV infection. Our studies have recently revealed a novel connection between RLR signaling and regulation of CD8+ T cell immunity during virus infection. In support of our findings, other groups have now implicated MAVS, the central adaptor protein required for RLR-mediated innate immune signaling, with regulation of CD8+ T cell responses during chronic viral infection, driving CD4+ T cell polarization during bacterial infection, and regulating TH1 and TH17 responses during autoimmune encephalitis, thus demonstrating the importance of RLR signaling in programming T cell immunity. However, the immunological mechanism underlying MAVS regulation of T cell immunity are not well understood. We seek to fill this gap in our knowledge by developing a new research tool to study MAVS immune regulation in a cell and tissue-specific manner. In Aim 1, we will generate Mavsfl/fl mice that can be crossed with cre-expressing mice to ablate MAVS expression in a context-dependent manner. In Aim 2, we will generate MAVS-DC KO and MAVS-CD8 KO mice, which lack MAVS expression in dendritic cells (DCs) and CD8+ T cells, respectively. We will use these mice to evaluate protection against WNV infection, control of viral pathogenesis, and development of CD8+ T cell immune responses. The results from this study will reveal the immunological mechanisms underlying MAVS-mediated immune regulation of T cell immunity during WNV infection. These studies will potentially uncover the therapeutic and immune-modulating potential of the RLR signaling pathway during virus infection and vaccination.

描述（由申请人提供）：西尼罗河病毒（WNV）是 NIAID B 类优先病原体，是一种嗜神经性黄病毒，是美国人类蚊媒脑炎的主要原因。西尼罗河病毒的持续传播，加上缺乏对抗或预防感染的特异性疗法或疫苗，迫切需要确定控制感染和免疫的病毒和宿主过程。西尼罗河病毒在人类中的发病机制尚不清楚，但西尼罗病毒感染的小鼠模型忠实地再现了在人类中观察到的西尼罗河病毒发病机制的主要阶段，为导致西尼罗河病毒疾病的机制提供了重要的见解。先天免疫反应（由 RIG-I 样受体 [RLR] 信号传导介导）以及体液和细胞介导的反应对于预防西尼罗河病毒感染至关重要。 RLR 信号通路在西尼罗河病毒感染期间触发抗病毒免疫防御并编程保护性免疫。我们最近的研究揭示了病毒感染期间 RLR 信号传导与 CD8+ T 细胞免疫调节之间的新联系。为了支持我们的研究结果，其他研究小组现在将 MAVS（RLR 介导的先天免疫信号传导所需的中心接头蛋白）与 MAVS 联系起来，在慢性病毒感染期间调节 CD8+ T 细胞反应，在细菌感染期间驱动 CD4+ T 细胞极化，并在自身免疫性脑炎期间调节 TH1 和 TH17 反应，从而证明了 RLR 信号传导在编程 T 细胞免疫中的重要性。然而，MAVS 调节 T 细胞免疫的免疫学机制尚不清楚。我们寻求通过开发一种新的研究工具以细胞和组织特异性方式研究 MAVS 免疫调节来填补我们的知识空白。在目标 1 中，我们将生成 Mavsfl/fl 小鼠，它们可以与表达 cre 的小鼠杂交，以上下文依赖的方式消除 MAVS 表达。在目标 2 中，我们将生成 MAVS-DC KO 和 MAVS-CD8 KO 小鼠，它们分别在树突状细胞 (DC) 和 CD8+ T 细胞中缺乏 MAVS 表达。我们将使用这些小鼠来评估对西尼罗河病毒感染的保护、病毒发病机制的控制以及 CD8+ T 细胞免疫反应的发展。这项研究的结果将揭示 WNV 感染期间 MAVS 介导的 T 细胞免疫免疫调节的免疫学机制。这些研究将有可能揭示 RLR 信号通路在病毒感染和疫苗接种过程中的治疗和免疫调节潜力。