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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：
10462665
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/10462665
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

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).

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）。由于ZIKV疫情发生在世界各地DENV流行的地区，并且由于ZIKV和DENV的高度相关性，了解和描述既往感染DENV加剧ZIKV疾病的程度至关重要。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。