Human Monoclonals to Dengue Virus

人类单克隆登革热病毒

基本信息

批准号：
8583521
负责人：
ANUJA MATHEW
金额：
$ 23.46万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2013-05-23 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8583521
关键词：
Address Adult Animal Model Antibodies Antibody Formation Antibody-Dependent Enhancement Area B-Lymphocyte Subsets B-Lymphocytes Blood Bone Marrow Cells Child Clinical Clinical Trials Complex Country Dengue Dengue Hemorrhagic Fever Dengue Virus Development Disease Dose Epidemiologic Studies Epitopes Goals Hematopoietic stem cells Hospitalization Hospitals Human Immune Immune response Immune system Immunity Immunization Individual Infant Infection Kinetics Knockout Mice Licensing Life Liver Memory B-Lymphocyte Modeling Mothers Mus Outcome Pathogenesis Patients Risk Factors Role Serotyping Serum Source Specificity Spleen T cell response T-Lymphocyte Thymus Gland Tissues Vaccine Design Vaccines Viral Virus Diseases cross reactivity experience global health human monoclonal antibodies improved mouse model neutralizing antibody novel peripheral blood public health relevance response secondary infection vaccine development

项目摘要

DESCRIPTION (provided by applicant): Dengue viruses (DENV) cause an important and re-emerging viral disease, resulting in an estimated 100 million infections globally each year. Substantial evidence indicates that the pathogenesis of severe dengue disease involves a complex interaction between viral replication and host immune responses. Pre-existing DENV antibodies are a major risk factor to develop severe DENV disease. An improved understanding of the relationship between antibody titers in the sera and the ability of memory B cells to reactivate following a secondary heterologous DENV infection would be invaluable to guide the development of an effective dengue vaccine. These efforts have been significantly inhibited by the lack of a reliable small animal model that recapitulates the interactions between virus infection and host immunity that cause severe disease in humans. The overall objective of this project is to evaluate novel and existing strains of humanized mice including Bone marrow/Liver/Thymus NOD-scid IL2r?null mice (BLT- NSG) as a reliable small animal model for the study of dengue virus infection, immunity, and pathogenesis. For this proposal we will examine antibody and B cell responses to controlled primary and secondary DENV infections in BLT-NSG mice. We will address the objectives through the following specific aims. 1. Investigate the specificity and functionality of DENV-specific antibody responses generated during primary and secondary viral infections in BLT-NSG mice. 2. Characterize B cell subsets in blood and tissue resident cells that respond to primary and secondary DENV infections in BLT-NSG mice.

描述（由申请人提供）：登革热病毒（DENV）引起重要且重新出现的病毒疾病，每年在全球估计有1亿个感染。大量证据表明，严重的登革热疾病的发病机理涉及病毒复制与宿主免疫反应之间的复杂相互作用。现有的DENV抗体是发展严重DENV疾病的主要危险因素。对血清中抗体滴度与记忆B细胞在继发性异源DENV感染后重新激活的能力之间的关系的了解是无价的，可以指导有效的登革热疫苗的发展。由于缺乏可靠的小动物模型，这些努力被严重抑制，该模型概括了病毒感染与引起人类严重疾病的宿主免疫之间的相互作用。该项目的总体目的是评估包括骨髓/肝脏/胸腺nod-scid IL2R iL2R null小鼠（BLT-NSG）的新颖和现有菌株，作为一种可靠的小动物模型，用于研究登革热病毒感染，免疫力和发病机理。对于此提案，我们将检查BLT-NSG小鼠中对受控原发性和继发性DENV感染的抗体和B细胞反应。我们将通过以下特定目标解决目标。 1。研究BLT-NSG小鼠原发和继发病毒感染期间DENV特异性抗体反应的特异性和功能。 2。表征血液和组织驻留细胞中对BLT-NSG小鼠原发性和继发性DENV感染反应的B细胞亚群。