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，与登革热病毒（DENV）密切相关。自1947年发现以来，ZIKV一直相对不被注意，主要在非洲和亚洲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，在过去的十年中，ZIKV开始在太平洋岛屿上传播，最终到达南美洲，在那里它引起了2015年在巴西开始的爆炸性爆发，并迅速蔓延到其他南美和中美洲国家。这伴随着怀孕期间ZIKV感染与胎儿和婴儿出生缺陷（包括小头畸形）之间的惊人联系。目前还不清楚是什么因素导致了美洲大规模的ZIKV爆发或严重的疾病表现，但一个潜在的变量是美洲大部分高危人群对DENV具有预先存在的免疫力。有充分的证据表明，对一种血清型DENV的预先存在的免疫力可以改变随后感染不同DENV血清型的疾病发病机制，这种现象称为抗体依赖性增强（ADE）。因为ZIKV爆发已经发生在DENV流行的世界各地的地区，并且由于ZIKV和DENV的高度相关性，所以理解和表征先前感染DENV使ZIKV疾病恶化的程度是至关重要的。在本申请中，我们将集中于DENV抗体如何通过利用三种模型系统（免疫受损的Stat 2-/-小鼠、免疫活性的人源化STAT 2敲入小鼠和离体感染ZIKV的人胎盘外植体）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).