Human Monoclonals to Dengue Virus

登革病毒（DENV）引起一种重要的和重新出现的病毒性疾病， 估计全球每年有1亿人感染。实质证据显示 严重登革热的发病机制涉及以下因素之间的复杂相互作用： 病毒复制和宿主免疫应答。预先存在的DENV抗体是一种主要的 发展为严重DENV疾病的危险因素。更好地理解 血清中抗体滴度与记忆B细胞的能力之间的关系， 在二次异源DENV感染后重新激活对于 指导开发有效的登革热疫苗。这些努力 由于缺乏可靠的小动物模型， 病毒感染和宿主免疫之间的相互作用，导致严重的疾病， 人类该项目的总体目标是评估新的和现有的菌株， 人源化小鼠，包括骨髓/肝/胸腺NOD-scid IL2r γ缺失小鼠（BLT-100）。 NSG）作为研究登革病毒感染、免疫、 和发病机制。对于这个建议，我们将检查抗体和B细胞对 在BLT-NSG小鼠中控制原发性和继发性DENV感染。 我们将通过以下具体目标实现这些目标。 1.研究DENV特异性抗体应答的特异性和功能性 在BLT-NSG小鼠中的初次和二次病毒感染期间产生。 2.表征血液和组织驻留细胞中的B细胞亚群， 在BLT-NSG小鼠中的原发性和继发性DENV感染。

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 IL2rγnull 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.