Human Monoclonals to Dengue Virus

描述（由申请人提供）：登革热病毒（DENV）是一种重要且再次出现的病毒性疾病，每年在全球造成约1亿例感染。大量证据表明，严重登革热的发病机制涉及病毒复制和宿主免疫反应之间的复杂相互作用。预先存在的DENV抗体是发生严重DENV疾病的主要危险因素。进一步了解血清中抗体滴度与继发性异源登革热病毒感染后记忆B细胞再激活能力之间的关系，将对指导有效登革热疫苗的开发具有重要意义。由于缺乏一种可靠的小动物模型来概括病毒感染与宿主免疫之间的相互作用，从而导致人类严重疾病，这些努力受到了极大的抑制。该项目的总体目标是评估新的和现有的人源化小鼠菌株，包括骨髓/肝脏/胸腺NOD-scid IL2r？作为研究登革病毒感染、免疫和发病机制的可靠小动物模型。为了这个提议，我们将检测BLT-NSG小鼠对原发性和继发性DENV感染的抗体和B细胞反应。我们将通过以下具体目标来实现这些目标。1. 研究BLT-NSG小鼠原发性和继发性病毒感染时产生的denv特异性抗体反应的特异性和功能。2. 描述BLT-NSG小鼠对原发性和继发性DENV感染反应的血液和组织驻留细胞中的B细胞亚群。

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.