Immunity to dengue viruses

项目总结 好了！ 登革热病毒是由蚊子传播的黄病毒，对公众健康有巨大影响，可引起一系列 人类的疾病从轻微到致命不等。进展为严重的登革热疾病是由 调节Fc受体病毒和细胞因子产生的非中和抗登革热免疫球蛋白的存在 承载细胞。我们已经证明，抗登革热抗体的存在促进了向严重登革热疾病的进展 富含果糖基化Fc糖形式的登革热抗体，这种修饰可以增强Fc对 特异性激活Fc受体，FcγRIIIa。因此，我们的数据表明FcγRIIIa在糖尿病的发病机制中发挥了作用。 登革热。在这项建议中，我们将研究活的、减毒的四价化合物的第三阶段试验的样本 登革热病毒疫苗，CyD-TDV(登革热，赛诺菲巴斯德)，以确定参与人类免疫的机制 登革热病毒。最近对CyD-TDV第三阶段试验数据的分析表明，疾病的风险 在一些研究队列中，通过接种疫苗而增加。这一发现突显了理解 登革热疫苗的抗体反应是如何调节的，以及抗体的分子机制是什么 会增加登革热感染。本提案的目的是：a)确定抗体上Fc岩藻糖化的调节剂 由CyD-TDV疫苗接种或由人类自然登革热感染引发；b)确定后两者之间的联系 5年内接种疫苗/感染前抗登革热抗体谱与登革热易感性 疫苗接种后的随访期；c)确定FcγRIIIa影响登革热感染和 疾病发病机制。总的来说，这些目标将促进我们对机制的基本理解。 调节人类对登革热病毒的免疫力，并指导设计安全、有效的登革热病毒疫苗。

PROJECT SUMMARY ! Dengue viruses are mosquito-borne flaviviruses of immense public health impact that cause a spectrum of disease in humans ranging from mild to fatal. Progression to severe dengue disease is promoted by the presence of non-neutralizing anti-dengue IgGs that modulate virus and cytokine production in Fc receptor- bearing cells. We have shown that progression to severe dengue disease is promoted by the presence of anti- dengue antibodies with abundant afucosylated Fc glycoforms, a modification that enhances affinity of the Fc for a specific activating Fc receptor, FcγRIIIa. Thus, our data point to a role for FcγRIIIa in the pathogenesis of dengue disease. In this proposal we will study samples from Phase III trials of a live, attenuated tetravalent dengue virus vaccine, CYD-TDV (Dengvaxia, Sanofi Pasteur), to define mechanism involved in human immunity to dengue viruses. Recent analyses of data from the Phase III trials of CYD-TDV showed that risk for disease was increased in some study cohorts by vaccination. This finding highlights the importance of understanding how antibody responses to dengue vaccination are regulated and molecular mechanisms by which antibodies can enhance dengue infections. Aims in this proposal will: a) define regulators of Fc fucosylation on antibodies elicited by CYD-TDV vaccination or by natural dengue infection in humans; b) define associations between post- vaccination/pre-infection anti-dengue antibody repertoires and susceptibility to dengue disease during a 5-year follow-up period after vaccination; c) define mechanisms by which FcγRIIIa impacts dengue infections and disease pathogenesis. Collectively, these aims will advance our fundamental understanding of mechanisms regulating human immunity to dengue viruses and guide the design of safe, effective dengue virus vaccines.