Enhanced susceptibility to Zika virus during pregnancy: a role for maternal dengue antibodies

寨卡病毒(ZIKV)是一种由蚊子传播的黄病毒，与登革病毒(DENV)关系密切。自1947年发现以来，ZIKV一直相对不被注意，主要在非洲和亚洲的部分地区引起小规模的局部疫情，并与轻微症状有关，如轻度发烧。然而，在过去十年中，ZIKV开始在地理上横跨太平洋岛屿传播，最终到达南美洲，在那里引发了爆炸性疫情，于2015年在巴西开始，并迅速蔓延到其他中南美洲国家。伴随而来的是妊娠期间ZIKV感染与胎儿和婴儿出生缺陷(包括小头畸形症)的发展之间的惊人联系。目前尚不清楚哪些因素可能导致美洲大规模寨卡病毒暴发或严重的疾病表现，但一个潜在的变量是，美洲的许多高危人群对DENV具有预先存在的免疫力。已有文献表明，对一种DENV血清型的预先免疫可以改变随后感染另一种DENV血清型的疾病的发病机制，这种现象被称为抗体依赖增强(ADE)。由于ZIKV暴发发生在世界各地DENV流行的地区，并且由于ZIKV与DENV高度相关，因此了解和描述先前感染DENV加重ZIKV疾病的程度至关重要。在这一应用中，我们将利用三个模型系统(免疫低下的Stat2-/-小鼠、免疫活性的人源化STAT2敲入小鼠和体外感染ZIKV的人胎盘外植体)，重点研究DENV抗体如何在妊娠背景下影响ZIKV感染。

Zika virus (ZIKV) is a mosquito-transmitted flavivirus that is closely related to dengue virus (DENV). Since its discovery in 1947, ZIKV remained relatively unnoticed, causing small, local outbreaks primarily in parts of Africa and Asia, and was associated with minor symptoms, such as mild fever. However, in the last decade, ZIKV started to spread geographically across the Pacific islands, eventually reaching South America, where it caused an explosive outbreak that started in Brazil in 2015 and rapidly spread to other South and Central American countries. This has been accompanied by a startling link between ZIKV infection during pregnancy and the development of birth defects among fetuses and babies, including microcephaly. It is unclear what factors may have led to the massive ZIKV outbreak or the severe disease manifestations in the Americas, but one potential variable is that much of the at-risk population in the Americas has preexisting immunity to DENV. It is well documented that preexisting immunity to one serotype of DENV can alter the disease pathogenesis of a subsequent infection with a different DENV serotype, a phenomenon called antibody-dependent enhancement (ADE). Because ZIKV outbreaks have occurred in regions around the world where DENV is endemic and due to the high degree of relatedness of ZIKV and DENV, it is critical to understand and characterize the extent to which prior infection with DENV exacerbates ZIKV disease. In this application, we will focus on how DENV antibodies impact ZIKV infection in the context of pregnancy by utilizing three model systems (immunocompromised Stat2-/- mice, immunocompetent humanized STAT2 knock-in mice, and human placental explants infected with ZIKV ex vivo).