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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）是一种蚊媒黄病毒，与登革热病毒（DENV）密切相关。自1947年被发现以来，寨卡病毒一直相对不为人注意，主要在非洲和亚洲部分地区引起小规模的地方性疫情，并伴有轻微症状，如轻度发烧。然而，在过去十年中，寨卡病毒开始在太平洋岛屿上传播，最终到达南美洲，在那里引发了2015年在巴西开始的爆炸性疫情，并迅速蔓延到其他南美和中美洲国家。与此同时，怀孕期间感染寨卡病毒与胎儿和婴儿出生缺陷（包括小头畸形）之间存在惊人的联系。目前尚不清楚哪些因素可能导致了寨卡病毒在美洲的大规模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先前对DENV具有免疫力。有充分证据表明，先前存在的对一种DENV血清型的免疫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）。由于寨卡病毒疫情发生在世界各地DENV流行的地区，并且由于寨卡病毒与DENV高度相关，因此了解和描述先前感染DENV会加重寨卡病毒疾病的程度至关重要。在这项应用中，我们将通过使用三种模型系统（免疫功能低下的Stat2-/-小鼠，免疫功能正常的人源化Stat2敲入小鼠和体外感染ZIKV的人胎盘外植体），重点研究DENV抗体如何影响妊娠背景下的ZIKV感染。