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：
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
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/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

项目摘要

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）是一种BNIAID优先剂，是一种神经型黄素，是美国人类蚊子 - 传播脑炎的主要原因。 WNV的持续扩散，加上缺乏特定的治疗剂或疫苗来对抗或防止感染，施加了迫切需要确定控制感染和免疫力的病毒和宿主过程。 WNV在人类中的发病机理的定义很低，但是WNV感染的小鼠模型忠实地概括了人类观察到的WNV发病机理的主要阶段，它为引起WNV疾病的机制提供了重大见解。先天免疫反应（由RIG-I像受体[RLR]信号传导介导）和体液和细胞介导的反应对于防止WNV感染至关重要。 RLR信号通路在WNV感染过程中触发抗病毒免疫防御和程序保护性免疫的功能。我们的研究最近揭示了病毒感染过程中RLR信号传导与CD8+ T细胞免疫的调节之间的新联系。为了支持我们的发现，其他小组现在已经牵涉了MAV，这是RLR介导的先天免疫信号传导所需的中心适配蛋白，并调节慢性病毒感染过程中CD8+ T细胞反应的调节，驱动CD4+ T细胞在细菌感染过程中的CD4+ T细胞极化，并调节TH1和TH17的响应在自身启发性持续性过程中的调节，以证明其对免疫的调节性，以使其具有较轻的质量，以实现该质量的构成。然而，尚不清楚T细胞免疫的MAVS调节的免疫机制。我们试图通过开发一种新的研究工具来以细胞和组织特异性方式研究MAVS免疫调节来填补这一空白。在AIM 1中，我们将生成可以与表达Cre的小鼠交叉的MAVSFL/FL小鼠以上下文依赖性的方式融入MAVS表达。在AIM 2中，我们将生成MAVS-DC KO和MAVS-CD8 KO小鼠，它们分别缺乏树突状细胞（DC）和CD8+ T细胞中的MAVS表达。我们将使用这些小鼠评估防止WNV感染的保护，控制病毒发病机理以及CD8+ T细胞免疫反应的发展。这项研究的结果将揭示WNV感染过程中T细胞免疫的免疫调节的背后的免疫机制。这些研究可能会发现病毒感染和疫苗接种期间RLR信号通路的治疗和免疫调节潜力。