Molecular Immunopathogenesis of DHF/DSS

DHF/DSS 的分子免疫发病机制

• 批准号: 7460184
• 负责人: Alan L Rothman
• 金额: $ 42.32万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460184
• 关键词: Acute; Acute Disease; Adverse event; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Avidity; B-Cell Activation; B-Lymphocytes; Cells; Clinical; Complex; Culicidae; Data; Data Analyses; Dendritic Cells; Dengue; Dengue Virus; Disease; Disease Marker; Exposure to; Frequencies; Funding; Genetic Polymorphism; Genotype; Goals; Host Factor 1 Protein; Immune; Immune response; Immune system; Immunity; Immunization; Immunologics; In Vitro; Individual; Infection; Inflammatory; Kinetics; Laboratories; Lead; Memory; Memory B-Lymphocyte; Modeling; Molecular; Morbidity - disease rate; Outcome; Peripheral Blood Mononuclear Cell; Phenotype; Placebos; Plasma; Plasmablast; Play; Prevention strategy; Production; Range; Research; Serotyping; Severities; Severity of illness; Shock; Specificity; T memory cell; T-Lymphocyte; Testing; Tumor Necrosis Factor-Beta; Vaccination; Vaccines; Viral; Virus; Virus Diseases; cytokine; human TNF protein; immunopathology; improved; in vivo; mortality; novel vaccines; programs; promoter; response; vaccine development

The long-term objective of this project is to define the immunological mechanisms that determine the outcome of dengue virus (DV) infection. A large body of information supports the model of immunopathogenesis of severe dengue disease; however, open questions remain about the principal determinants of disease. DV interaction with host innate and adaptive immunity responses is highly complex, and can result in the production of pro-inflammatory, antiinflammatory, and/or vasoactive cytokines. This Project seeks to understand the contribution of individual components of the immune response to different clinical disease manifestations. These findings will be important for vaccine development, by identifying the key immunologic correlates of vaccine-induced protection as opposed to immunopathology on subsequent exposure to DV. The Specific Aims of this Project are: 1. to define the viral and innate host determinants of the cellular response to DV infection, by determining the dendritic cell (DC) cytokine response to DV strains associated with different disease severity and the association of DC responses with host genotypes; 2. to define the immunological mechanisms contributing to clinical disease in acute DV infection, by determining the kinetics of activation and expansion of DV-specific B cells and T cells; 3. to define immunological correlates of the response to tetravalent DV immunization, by determining the associations between pre-existing DV-specific immunity and the response to vaccination and between the vaccine-induced DV-specific immunity and clinical outcome (adverse events, protection, and breakthrough DV infections). Dengue is an important tropical mosquito-borne viral disease that causes shock as a result of the body's immune response. We will study how different parts of the host immune system react to infection with dengue virus to understand how virus infection causes disease. This research will help guide the development of vaccines and new treatments for dengue.

该项目的长期目标是确定免疫机制， 确定登革热病毒（DV）感染的结果。大量的信息支持了 严重登革热病的免疫发病机制模型;然而，关于 疾病的主要决定因素。DV与宿主天然免疫和获得性免疫的相互作用 反应是高度复杂的，并可导致产生促炎性，炎性， 和/或血管活性细胞因子。本项目旨在了解 不同的临床疾病表现的免疫反应的各个组成部分。这些 这些发现对于疫苗的开发将是重要的，通过确定关键的免疫相关性， 疫苗诱导的保护，而不是免疫病理学对随后暴露于DV。 该项目的具体目标是： 1.为了定义对DV感染的细胞应答的病毒和先天宿主决定因素，通过 确定树突状细胞（DC）细胞因子对与不同病毒相关的DV毒株的应答， 疾病严重程度以及DC反应与宿主基因型的关联; 2.为了确定在急性DV感染中导致临床疾病的免疫学机制， 通过测定DV特异性B细胞和T细胞的活化和扩增的动力学; 3.为了定义对四价DV免疫的应答的免疫学相关性，通过 确定预先存在的DV特异性免疫性与对以下的应答之间的关联： 疫苗接种和疫苗诱导的DV特异性免疫与临床结果之间的关系 （不良事件、保护和突破性DV感染）。 登革热是一种重要的热带蚊媒病毒性疾病， 身体免疫反应的一部分我们将研究宿主免疫系统的不同部分如何反应 了解病毒感染如何导致疾病。这项研究将 帮助指导登革热疫苗和新疗法的开发。