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

怀孕期间对寨卡病毒的易感性增强：母体登革热抗体的作用

基本信息

批准号：
10265599
负责人：
Jean Kyou Lim
金额：
$ 42.19万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-17 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10265599
关键词：
Adult Affect Africa Americas Antibodies Antibody Specificity Antibody-Dependent Enhancement Anxiety Area Asia Binding Biological Models Birth Brain Brazil Cells Central American Cognition Congenital Abnormality Country Culicidae Data Dengue Dengue Virus Dependence Development Disease Disease Outbreaks Disease Outcome Fc Receptor Fetal Development Fetus Fever Flavivirus Geography Human IgG1 IgG2 IgG3 IgG4 Immunity Immunocompetent Immunocompromised Host Immunoglobulin G Individual Infection Knock-in Knock-in Mouse Knockout Mice Learning Link Long-Term Effects Low Birth Weight Infant Maternal Health Measures Membrane Membrane Proteins Memory Mental Depression Microcephaly Minor Modeling Molecular Mothers Motor Mus Neonatal Pacific Islands Pathogenesis Placenta Populations at Risk Predisposition Pregnancy Reflex action Role STAT2 gene Sensory Serotyping Social Behavior South America South American Spontaneous abortion Surface Symptoms Testing Variant Viral Pathogenesis Virion Virus Virus Replication Vision ZIKV disease ZIKV infection Zika Virus cohort conditional knockout cross reactivity env Gene Products fetal in utero in vivo mortality neonatal Fc receptor offspring placental infection pregnant pup seropositive trophoblast virology

项目摘要

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).

Zika病毒（ZIKV）是一种与登革热病毒密切相关的蚊子传播的黄病毒（DENV）。自1947年发现以来，ZIKV仍然相对没有引起人们的注意，主要在非洲和亚洲的部分地区引起小规模的局部暴发，并且与轻度症状（例如轻度发烧）有关。但是，在过去的十年中，Zikv开始在地理上蔓延到整个太平洋岛屿，最终到达南美，造成了2015年在巴西开始的爆炸性爆发，并迅速传播到其他南美国家和中美洲国家。这伴随着怀孕期间的ZIKV感染与胎儿和婴儿（包括小头畸形）的出生缺陷之间的惊人联系。目前尚不清楚哪些因素可能导致了美洲大规模的ZIKV爆发或严重的疾病表现，但是一个潜在的变量是，美洲的许多处于危险中的人口都具有对DENV的免疫力。有充分的文献证明，对一种DENV的一种血清型的免疫力可以改变随后感染的疾病发病机理，而DENV血清型，这是一种称为抗体依赖性增强的现象（ADE）。由于ZIKV爆发发生在世界各地的DENV是地方性的地区，并且由于Zikv和Denv的高度相关性，因此了解和表征先前对DENV加剧ZIKV疾病的程度至关重要。在此应用中，我们将通过使用三种模型系统（免疫功能低下的STAT2 - / - 小鼠，免疫能力的人源化STAT2敲击小鼠以及被ZIKV EX VIVO感染的人类胎盘ePuptants（人类胎盘层），将重点关注DENV抗体如何在怀孕的背景下影响ZIKV感染。