Maternal Antibody-Mediated Enhancement of Dengue Pathogenesis

摘要 登革病毒(DENV)是对全球健康的重大威胁。然而，免疫的确切作用是 抗原相似性的四种DENV血清型的免疫保护和致病机制 相互之间的地理范围以及其他密切相关的黄病毒知之甚少。特别是， 抗体可通过介导抗体(Ab)依赖的增强作用促进DENV的发病。 感染(ADE)。这个项目的重点是确定抗黄病毒抗体应答的特征 使用DENV感染小鼠幼鼠的流行病学相关小鼠模型进行ADE与保护的比较 由母体获得的黄病毒抗体增强。我们公布的和新的数据表明，黄病毒 接种-感染组合既可以促进发病，也可以促进保护。我们的初步数据也 显示缺乏T滤泡辅助者(TFH)细胞反应的小鼠不能诱导DENV IgG反应，以及 用一种激动型抗体刺激OX40的小鼠，OX40是一种属于 肿瘤坏死因子受体超家族，表现出增强的DENV免疫球蛋白反应，提示TFH的大小 应答水平与抗体对DENV的应答水平相关。因此，我们假设，推动TFH 应答将增加广谱中和抗体(BNab)应答的产生，从而介导保护和 在DENV感染期间将ADE降至最低。我们将使用一种基于RNA复制子的疫苗来检验这一假设 在以下特定目标中诱导强大的T细胞和抗体反应的平台：(1)确定如何 不同黄病毒抗原免疫母鼠对Tfh细胞和抗体应答及易感性的影响 在它们的后代中繁殖。(2)检测免疫变量和候选T细胞是否存在操纵 共刺激通路增强母体Tfh细胞和抗体反应并诱导对DENV2的保护性反应 在后代中感染。这些研究将提供对调控因素和机制的关键见解 对DENV2感染的保护性免疫。迫切需要这种知识来为发展提供信息 保护婴幼儿、高度脆弱人群和其他黄病毒的DENV疫苗 在全球范围内安全有效的疫苗，包括在两种或两种以上黄病毒共同传播的国家。 这项拟议的工作是基于我们在研究体液和细胞免疫机制方面的良好记录 在黄病毒感染期间使用最先进的小鼠模型。该项目还将受益于我们的 合作者在TFH细胞、T细胞共刺激分子、人类黄病毒抗体反应方面的专业知识， 新疫苗平台的开发，以及基因组学分析。

ABSTRACT Dengue virus (DENV) represents a major threat to global health. However, the precise role of the immune system in protecting against and pathogenesis of the four DENV serotypes, which share antigenic similarities and geographic ranges with each other and other closely related flaviviruses are poorly understood. In particular, antibodies can contribute to DENV pathogenesis by mediating antibody (Ab)-dependent enhancement of infection (ADE). This project focuses on defining the features of the anti-flavivirus Ab response that contributes to ADE vs protection using epidemiologically relevant mouse models in which DENV infection of mouse pups is enhanced by maternally acquired flavivirus Abs. Our published and new data demonstrate that flavivirus vaccination-infection combinations can promote either pathogenesis or protection. Our preliminary data also show that mice lacking T follicular helper (Tfh) cell responses are unable to induce DENV IgG response, and that mice treated with an agonistic Ab that stimulates OX40, a T cell costimulatory molecule belonging to the TNF receptor superfamily, exhibit a boosted DENV IgG response, suggesting that the magnitude of the Tfh response correlates with the level of Ab response to DENV. Therefore, we hypothesize that promoting Tfh responses will increase the production of broadly-neutralizing Ab (bnAb) responses that mediate protection and minimize ADE during DENV infection. We will test this hypothesis by using an RNA replicon-based vaccine platform that induces robust T cell and Ab responses in the following Specific Aims: (1) Determine how vaccination with different flavivirus antigens affects Tfh cell and Ab responses in maternal mice and susceptibility to DENV ADE in their offspring. (2) Test whether manipulation of immunization variables and candidate T cell costimulatory pathways boosts maternal Tfh cell and Ab responses and induces a protective response to DENV2 infection in offspring. These studies will provide critical insights into the factors and mechanisms that regulate ADE vs protective immunity to DENV2 infection. This knowledge is urgently needed to inform development of DENV vaccines that protect infants and young children, the highly vulnerable populations, and other flaviviral vaccines that are safe and effective worldwide, including in countries with co-circulation of 2 or more flaviviruses. The proposed work is based on our strong track record in investigating humoral and cellular immune mechanisms during flavivirus infections using state-of-the-art mouse models. The project will also benefit from our collaborators’ expertise in Tfh cells, T cell costimulatory molecules, flaviviral Ab response in humans, development of novel vaccine platforms, and genomics assays.