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

• 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
• 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phenotypic biomarker; placental infection; pregnant; reproductive; response; targeted treatment; therapy development; unpublished works; viral RNA; viral transmission

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is susceptible to ZIKV strains of French Polynesian, African, and American (Puerto Rican) origin, and our published and unpublished work has shown that vertical transmission in rhesus macaques is highly efficient: 5 of 5 fetuses, whether maternal infection was administered in the first or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.

妊娠期间感染寨卡病毒(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征(CZS)。我们已经证明了 恒河猴对法属波利尼西亚人、非洲人和美国人(波多黎各人)的ZIKV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个胎儿中有5个，无论孕妇感染是在妊娠早期还是晚期， 导致在胎儿组织中检测到vRNA，并在胎儿器官中检测到组织病理学(主要是炎症)。 然而，人们对ZIKV穿越母胎屏障的途径知之甚少。 在活体内。了解病毒是如何进入胎儿隔室的，将有助于考虑 可能的干预措施。我们已经修改了这项研究恒河猴垂直传播的建议 在产妇感染后的第一个月内直接解决这一需求，具有以下具体目标。 具体目的1.确定ZIKV在垂直方向上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负荷来实现体内传播。 具体目的2.通过平行评估组织病理学来确定寨卡病毒感染对细胞的影响 病毒定位于母胎界面和胎儿组织。 特定目的3.用高维数据确定蜕膜白细胞和胎盘Hofbauer细胞群 流式细胞术，用细胞内ZIKV抗原染色直接评价ZIKV感染情况。 带着这些目标，我们将使用NHP模型来全面推进我们对这条路径的理解 和ZIKV的垂直传动轨迹。我们将定义母胎交界处的病毒负荷 在导致胎儿感染的过程中。我们将确定装有ZIKV的蜂窝隔间 蛋白质和复制病毒。最后，我们将定义母体蜕膜的免疫反应和 胎儿胎盘在垂直传播过程中。为了实现这些目标，我们将与一支专家团队合作 建立了ZIKV感染猕猴模型的NHP病毒学家，以及病理学家和生殖科医生 能够对母婴结局提供专家和全面评估的免疫学家 寨卡病毒感染。治疗方法的发展需要对发病机制有深入的了解。通过定义路径(S) 垂直传输方面，我们将建立相关的NHP实验平台进行测试 阻断垂直传播的方法与人类婴儿CZS的发展。