Pathways of vertical Zika virus transmission in nonhuman primate pregnancy

非人灵长类动物怀孕期间寨卡病毒垂直传播的途径

基本信息

批准号：
9894729
负责人：
THADDEUS G GOLOS
金额：
$ 73.92万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-25 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894729
关键词：
Address African American Animal Model Brain Brazil Cells Congenital Abnormality Decidua Development Fetal Membranes Fetal Tissues Fetus First Pregnancy Trimester Flow Cytometry Future Goals Histopathology Human Immune Immune response Immune system Immunologist Impairment In Situ Hybridization Incidence Infant Infection Inflammation Interferons Interruption Intervention Lesion Leukocytes Macaca Macaca mulatta Maternal-Fetal Exchange Microcephaly Modeling Monkeys Nervous system structure Neuraxis Organ Outcome Pathogenesis Pathologist Pathology Pathway interactions Phenotype Placenta Polynesian Population Pregnancy Pregnancy loss Process Publishing Puerto Rican Rodent Model Site Stains Systemic infection Testing Third Pregnancy Trimester Time Tissues Uterus Vertical Disease Transmission Viral Antigens Viral Genome Viral Load result Viral Proteins Virus Virus Replication Visual system structure Work ZIKV infection Zika Virus adverse outcome cell type congenital zika syndrome fetal fetal infection high dimensionality immunocytochemistry in vivo insight malformation neonate nonhuman primate phenotypic biomarker placental infection pregnant reproductive response targeted treatment therapy development unpublished works viral RNA viral transmission

项目摘要

Infection with Zika virus (ZIKV) in pregnancy has been associated with an increased incidence of a spectrum of birth defects collectively referred to as Congenital Zika Syndrome (CZS). We have demonstrated that the rhesus macaque is susceptible to ZIKV strains of French Polynesian, African, and American (Puerto Rican) origin, and our published and unpublished work has shown that vertical transmission in rhesus macaques is highly efficient: 5 of 5 fetuses, whether maternal infection was administered in the first or the third trimester, resulted in detectable vRNA in fetal tissues, and histopathology (chiefly inflammation) in fetal organs. Nonetheless, there is minimal understanding of the pathway by which ZIKV traverses the maternal-fetal barrier in vivo. Understanding how virus is afforded access to the fetal compartment will allow consideration of possible interventions. We have revised this proposal to study vertical transmission in the rhesus monkey during the first month after maternal infection to directly address this need, with the following Specific Aims. Specific Aim 1. To determine the pathway by which ZIKV transits the maternal-fetal interface in vertical transmission in vivo by assessing viral RNA burden in maternal, placental and fetal tissues. Specific Aim 2. To define the cellular impact of ZIKV infection by assessing tissue histopathology in parallel with virus localization at the maternal-fetal interface and in fetal tissues. Specific Aim 3. To define decidual leukocyte and placental Hofbauer cell populations with high-dimensional flow cytometry, and directly assess ZIKV infection with intracellular ZIKV antigen staining. With these Aims we will use the NHP model to comprehensively advance our understanding of the pathway and trajectory of vertical transmission of ZIKV. We will define the viral burden at the maternal-fetal interface during the processes leading to fetal infection. We will identify the cellular compartments which contain ZIKV protein and replicating virus. Finally, we will define the immunological responses in the maternal decidua and the fetal placenta during vertical transmission. To accomplish these goals, we will work with a team of expert NHP virologists who have established the macaque model of ZIKV infection, and pathologists and reproductive immunologists who can provide expert and comprehensive assessment of both maternal and fetal outcomes of ZIKV infection. The development of therapies requires insight into pathogenesis. By defining the pathway(s) of vertical transmission, we will have established a relevant NHP experimental platform for testing approaches to interrupt vertical transmission and the development of CZS in human infants.

怀孕期间感染寨卡病毒 (ZIKV) 与一系列疾病的发病率增加有关出生缺陷统称为先天性寨卡综合症（CZS）。我们已经证明了恒河猴对法属波利尼西亚、非洲和美洲（波多黎各）的寨卡病毒株敏感起源，我们已发表和未发表的工作表明，恒河猴的垂直传播是高效：5个胎儿中的5个，无论母体感染是在妊娠早期还是妊娠晚期进行的，导致胎儿组织中可检测到 vRNA，以及胎儿器官中的组织病理学（主要是炎症）。尽管如此，人们对 ZIKV 穿越母胎屏障的途径知之甚少。体内。了解病毒如何进入胎儿室将有助于考虑可能的干预措施。我们修改了这项提案以研究恒河猴的垂直传播在产妇感染后的第一个月内，直接满足这一需求，具体目标如下。具体目标 1. 确定 ZIKV 垂直穿过母胎界面的途径通过评估母体、胎盘和胎儿组织中的病毒RNA负荷来评估体内传播。具体目标 2. 通过并行评估组织病理学来确定 ZIKV 感染的细胞影响病毒定位于母胎界面和胎儿组织中。具体目标 3. 以高维定义蜕膜白细胞和胎盘 Hofbauer 细胞群流式细胞术，并通过细胞内 ZIKV 抗原染色直接评估 ZIKV 感染。为了实现这些目标，我们将使用 NHP 模型来全面推进我们对该途径的理解 ZIKV 的垂直传播轨迹。我们将定义母胎界面的病毒负荷在导致胎儿感染的过程中。我们将识别含有 ZIKV 的细胞区室蛋白质和复制病毒。最后，我们将定义母体蜕膜中的免疫反应和胎儿胎盘垂直传播。为了实现这些目标，我们将与专家团队合作建立 ZIKV 感染猕猴模型的 NHP 病毒学家，以及病理学家和生殖学家免疫学家可以对孕产妇和胎儿的结局提供专家和全面的评估 ZIKV 感染。治疗方法的开发需要深入了解发病机制。通过定义路径垂直传播，我们将建立相关的NHP实验平台进行测试阻断人类婴儿垂直传播和 CZS 发展的方法。