The Anatomy of Viral Persistence: Lymphocyte Migration and Lymphoid Structure

病毒持久性的解剖：淋巴细胞迁移和淋巴结构

• 批准号: 8766153
• 负责人: Cherie Tracy Ng
• 金额: $ 9.45万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2014-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766153
• 关键词: Acute; Affect; Anatomy; Architecture; B-Lymphocytes; Cell Communication; Cell Survival; Cells; Chronic; Coupled; Dendritic Cells; Development; Evaluation; Fostering; Goals; HIV; Hepatitis B Virus; Hepatitis C virus; Homing; Immune; Immune response; Immunity; Immunosuppression; Infection; Interferon Type I; Interferons; Kinetics; Knowledge; Laboratories; Lead; Lymphocyte; Lymphocyte Activation; Lymphocytic choriomeningitis virus; Lymphoid; Lymphoid Tissue; Maintenance; Modeling; Molecular; Morphology; Mus; Organ; Outcome; Play; Population; Regulation; Research; Role; Signal Transduction; Structure; System; T cell response; T-Lymphocyte; Testing; Time; Viral; Virus; Virus Diseases; adaptive immunity; cell type; improved; in vivo imaging; migration; novel therapeutics; public health relevance; response; therapeutic development; tool

DESCRIPTION (provided by applicant): The structure and microarchitecture of secondary lymphoid organs (SLO) plays a fundamental role in the initiation and maintenance of immune responses. Cells that are important to structure and microarchitecture are often targets of viral infection and disruption of SLO structure occurs in many viruses (including HIV), yet little is known about how lymphoid disruption occurs during viral infection and how this affects immune responses and viral clearance. The goal of this application is to unravel the mechanisms involved in SLO disorganization during viral infection and to directly assess the impact on the coordination and kinetics of lymphocyte activation and viral clearance with the hypothesis that deregulation of immune cell interactions impedes immunity to chronic infections and contributes to immune suppression during chronic infections. Using a well-established system of persistent non-lytic viral infection to model changes in SLO architecture during chronic infection coupled with a key discovery in this model that type I interferon signaling is important in disruption of splenic architecture, I will use molecular and cellular approaches to (1) dissect the mechanism by which SLO disruption occurs, (2) examine how abnormal SLO morphology interrupts cell-cell interactions, and (3) whether manipulation of architecture can influence immune responses and viral outcome. In addition to expanding our knowledge of control and regulation of adaptive immunity, this research will inform the development of therapeutic strategies during viral infection.

描述（由申请人提供）：次级淋巴器官（SLO）的结构和微结构在免疫应答的启动和维持中起着重要作用。对结构和微结构至关重要的细胞通常是病毒感染的靶标，许多病毒（包括HIV）都会发生SLO结构的破坏，但人们对病毒感染期间淋巴细胞的破坏是如何发生的，以及这如何影响免疫反应和病毒清除知之甚少。本应用的目的是揭示病毒感染期间SLO紊乱的机制，并直接评估对淋巴细胞活化和病毒清除的协调和动力学的影响，假设免疫细胞相互作用的放松阻碍了对慢性感染的免疫，并有助于慢性感染期间的免疫抑制。利用一个成熟的持续非溶性病毒感染系统来模拟慢性感染期间SLO结构的变化，并在该模型中发现I型干扰素信号在脾结构破坏中很重要，我将使用分子和细胞方法来(1)剖析SLO破坏发生的机制，(2)检查异常的SLO形态如何中断细胞-细胞相互作用，(3)结构的操纵是否会影响免疫反应和病毒结局。除了扩大我们对适应性免疫控制和调节的认识外，这项研究还将为病毒感染期间治疗策略的发展提供信息。