Human Monoclonals to Dengue Virus

描述(申请人提供)：登革热病毒(DENV)导致一种重要的和重新出现的病毒性疾病，导致全球每年估计有1亿人感染。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抗体是发展成严重DENV疾病的主要危险因素。更好地了解血清中抗体效价与二次异种DENV感染后记忆B细胞重新激活的能力之间的关系，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和导致人类严重疾病的宿主免疫之间的相互作用，这些努力受到了极大的抑制。本项目的总体目标是评估新的和现有的人源化小鼠品系，包括骨髓/肝脏/胸腺NOD-SCID IL2R缺失小鼠(BLT-NSG)，作为研究登革热病毒感染、免疫和发病机制的可靠的小动物模型。在这项建议中，我们将检测BLT-NSG小鼠对受控的初次和继发性DENV感染的抗体和B细胞反应。我们将通过以下具体目标来解决这些目标。1.研究BLT-NSG小鼠在初次和继发性病毒感染过程中产生的DENV特异性抗体应答的特异性和功能性。2.鉴定BLT-NSG小鼠血液和组织中对原发和继发DENV感染做出反应的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.