Maternal Antibody-Mediated Enhancement of Dengue Pathogenesis

摘要 登革病毒（DENV）是对全球健康的主要威胁。然而，免疫系统的确切作用 系统在保护免受和致病的四种DENV血清型，共享抗原相似性 和地理范围以及其他密切相关的黄病毒的了解很少。特别是， 抗体可以通过介导抗体（Ab）依赖性增强DENV的致病性， 感染（ADE）。该项目的重点是定义的特点，抗黄病毒抗体反应，有助于 使用流行病学相关的小鼠模型，其中小鼠幼仔的DENV感染是 通过母体获得的黄病毒抗体增强。我们发表的和新的数据表明，黄病毒 接种-感染组合可促进发病或保护。我们的初步数据还 显示缺乏T滤泡辅助（Tfh）细胞应答的小鼠不能诱导DENV IgG应答，和 用刺激OX 40的激动性Ab治疗的小鼠，OX 40是一种T细胞共刺激分子， TNF受体超家族表现出增强的DENV IgG应答，这表明Tfh的大小与DENV IgG的表达有关。 应答与对DENV的Ab应答水平相关。因此，我们假设促进Tfh 反应将增加介导保护作用的广泛中和抗体（bnAb）反应的产生， 在DENV感染期间尽量减少ADE。我们将通过使用基于RNA复制子的疫苗来验证这一假设 在以下特定目的中诱导稳健的T细胞和Ab应答的平台：（1）确定如何 不同黄病毒抗原疫苗接种对母鼠Tfh细胞和Ab应答及易感性的影响 在他们的后代中，(2)测试是否操纵免疫变量和候选T细胞 共刺激途径增强母体Tfh细胞和Ab应答并诱导对DENV 2的保护性应答 感染后代。这些研究将提供关键的洞察因素和机制，调节 ADE与对DENV 2感染的保护性免疫。迫切需要这些知识， 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。 拟议的工作是基于我们在调查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， 开发新的疫苗平台和基因组学分析。

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.