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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

基本信息

批准号：
8623700
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
项目类别：
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/8623700
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 Future Generations Goals 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 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 public health relevance receptor recombinase response tool virus pathogenesis

项目摘要

Abstract 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. !!

抽象的西尼罗河病毒 (WNV) 是 B 类 NIAID 优先病原体，是一种嗜神经性黄病毒，是导致以下疾病的主要原因：美国爆发人类蚊媒脑炎。西尼罗河病毒的持续传播，加上由于缺乏对抗或预防感染的具体疗法或疫苗，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定义，而是西尼罗河病毒感染的小鼠模型，忠实地再现了西尼罗河病毒的主要阶段在人类中观察到的发病机制，为了解导致西尼罗河病毒的机制提供了重要的见解疾病。先天免疫反应（由 RIG-I 样受体 [RLR] 信号传导介导）以及体液和免疫反应细胞介导的反应对于预防西尼罗河病毒感染至关重要。 RLR信号通路的功能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。我们的研究有最近揭示了 RLR 信号传导与 CD8+ T 细胞免疫调节之间的新联系病毒感染。为了支持我们的发现，其他小组现在也将 MAVS（中央接头蛋白）牵涉其中 RLR 介导的先天免疫信号传导所需，在慢性过程中调节 CD8+ T 细胞反应病毒感染，在细菌感染期间驱动 CD4+ T 细胞极化，并调节 TH1 和 TH17 自身免疫性脑炎期间的反应，从而证明了 RLR 信号传导在编程 T 细胞免疫。然而，MAVS 调节 T 细胞的免疫学机制免疫还没有被很好地理解。我们寻求通过开发新的研究工具来填补我们的知识空白以细胞和组织特异性方式研究 MAVS 免疫调节。在目标 1 中，我们将生成 Mavsfl/fl 小鼠可以与表达 cre 的小鼠杂交，以上下文依赖的方式消除 MAVS 表达。在目标 2，我们将生成 MAVS-DC KO 和 MAVS-CD8 KO 小鼠，它们在树突中缺乏 MAVS 表达分别是 DC 细胞和 CD8+ T 细胞。我们将使用这些小鼠来评估对西尼罗河病毒的保护作用感染、控制病毒发病机制以及 CD8+ T 细胞免疫反应的发展。结果来自这项研究将揭示 MAVS 介导的 T 细胞免疫调节的免疫学机制西尼罗河病毒感染期间的免疫力。这些研究将有可能揭示治疗和免疫调节的方法 RLR信号通路在病毒感染和疫苗接种过程中的潜力。 !!