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primate phenotypic biomarker placental infection pregnant reproductive response targeted treatment therapy development unpublished works viral RNA viral transmission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is susceptible to ZIKV strains of French Polynesian, African, and American (Puerto Rican) origin, and our published and unpublished work has shown that vertical transmission in rhesus macaques is highly efficient: 5 of 5 fetuses, whether maternal infection was administered in the first or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.

怀孕中寨卡病毒（ZIKV）感染与频谱的发生率增加有关统称为先天性寨卡综合症（CZS）的出生缺陷。我们已经证明了恒河猕猴容易受到法国波利尼西亚，非洲和美国（波多黎各）的ZIKV菌株的影响来源，我们发表的未发表的工作表明，恒河猕猴中的垂直传播是高效：5个胎儿中的5个，无论是在第一或三个月施用母体感染，导致胎儿组织中可检测到的VRNA，以及胎儿器官的组织病理学（主要是炎症）。尽管如此，对ZIKV穿越母体屏障的途径的理解很少体内。了解如何获得病毒进入胎儿室将允许考虑可能的干预措施。我们已经修订了此提案，以研究恒河猴中的垂直传播在产妇感染后的第一个月中，直接满足了这一需求，并具有以下特定目的。特定目的1。确定ZIKV在垂直方面转移母亲界面的途径通过评估母体，胎盘和胎儿组织中的病毒RNA负担来传播体内。特定的目的2。通过评估组织病理学并行评估ZIKV感染的细胞影响病毒定位在母亲界面和胎儿组织中。特定目的3。定义具有高维度的decidual白细胞和胎盘霍夫鲍尔细胞种群流式细胞仪，并直接评估细胞内ZIKV抗原染色的ZIKV感染。以这些目标，我们将使用NHP模型全面地提高我们对路径的理解和ZIKV垂直传播的轨迹。我们将在母亲界面定义病毒负担在导致胎儿感染的过程中。我们将确定包含ZIKV的蜂窝室蛋白质和复制病毒。最后，我们将定义母体Decidua的免疫反应，并垂直传输过程中的胎儿胎盘。为了实现这些目标，我们将与一个专家团队合作建立了ZIKV感染的猕猴模型以及病理学家和生殖的NHP病毒学家可以对孕产妇和胎儿结果进行专家和全面评估的免疫学家 ZIKV感染。疗法的发展需要深入了解发病机理。通过定义路径垂直传输，我们将建立一个相关的NHP实验平台人类婴儿中断垂直传播和CZ的发展的方法。