Mechanisms of Zika Virus Maternal-Fetal Transmission

寨卡病毒母婴传播机制

• 批准号: 9902480
• 负责人: Michael S Diamond
• 金额: $ 60.09万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902480
• 关键词: Adult; Africa; Animals; Antibodies; Autophagocytosis; Autophagosome; Binding; Biogenesis; Blood Circulation; Blood capillaries; Brain; Brain Injuries; Brazil; Cell Line; Cells; Central America; Child; Clinical; Clinical Research; Country; Culicidae; Data; Dengue Virus; Diamond; Disease; Endothelial Cells; Endothelium; Epidemic; Family; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetus; Fever; Flavivirus; Foundations; Goals; Guillain-Barré Syndrome; Head; Host Defense; Human; Humoral Immunities; IgG Receptors; Immune; Immunoglobulin G; Immunologics; In Vitro; Individual; Infection; Injury; Interferon Type I; Interferons; Knock-out; Knockout Mice; Laboratories; Lead; Link; Maternal-Fetal Transmission; Mexico; Microcephaly; Micronesia; Modeling; Monoclonal Antibodies; Mononuclear; Mothers; Mus; Myeloid Cells; Natural Immunity; Neonatal; Outcome; Pathogenesis; Pathology; Pathway interactions; Placenta; Pregnancy; Pregnant Women; Process; Public Health; Publishing; Receptor Activation; Receptor Protein-Tyrosine Kinases; Recycling; Risk; Role; Serotyping; Signal Transduction; Skin; South America; Spontaneous abortion; Testing; Tropism; Vaccination; Viral; Viral Pathogenesis; Viremia; Virus; Virus Activation; Virus Replication; West Nile virus; Woman; Work; ZIKV disease; ZIKV infection; Zika Virus; adverse outcome; base; cell type; conditional knockout; cross reactivity; defense response; experimental study; fetal; fetus cell; improved; in utero; in vivo; insight; loss of function; maternal risk; neuroblast; neurovirulence; neutralizing antibody; novel therapeutic intervention; particle; pathogen; placental infection; pregnant; public health relevance; receptor; receptor expression; secondary infection; trafficking; transmission process; trophoblast; viral transmission

Project Summary: Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that has become a global public health threat. ZIKV infection has now been causally linked to cases of Guillain-Barre syndrome in adults and microcephaly, intrauterine growth restriction (IUGR), and spontaneous abortion in the setting of maternal infection during pregnancy. Given the recognition of this causal relationship, it is imperative to determine the mechanism(s) of maternal-fetal transmission. Insights into such mechanisms could improve our ability to reduce the burden of the effects of Zika virus infection during pregnancy. The goal of this collaborative and interactive project is to define how host defense responses can control or possibly contribute to ZIKV pathogenesis during and after pregnancy. The premise is based on the extensive newly published data showing that ZIKV infection of pregnant mice results in infection of the placenta, in utero transmission, and injury to the developing fetus. O ur central hypotheses are that maternal-fetal transmission occurs because ZIKV overcomes placental trophoblast host defenses (autophagy) (Aim 1), usurps TAM receptors to enter placental trophoblasts and endothelial cells (Aim 2); and this entire process is enhanced in flavivirus-immune individuals or animals who have sufficient levels of cross-reactive, non-neutralizing anti-ZIKV antibodies that promote ADE (Aim 3). Collectively, our efforts will be highly significant for understanding ZIKV pathogenesis. This work will provide a foundation for clinical studies that define the risks of maternal to child transmission of ZIKV, generate possible new therapeutic approaches, and determine the interaction between ZIKV and natural immunity to other flaviviruses.

项目摘要： 寨卡病毒（ZIKV）是一种新兴的蚊子传播的黄病毒，已成为全球公共卫生威胁。 ZIKV感染现已与成人和小头畸形的Guillain-Barre综合征病例有关 宫内生长限制（IUGR）和在母亲感染期间的自发流产 怀孕。考虑到这种因果关系的认识，必须确定机制 母亲传播。对这种机制的见解可以提高我们减轻负担的能力 怀孕期间寨卡病毒感染的影响。这个协作和互动项目的目标是 定义宿主防御反应如何控制或可能导致ZIKV发病机理 怀孕。前提是基于广泛的新发布的数据，表明ZIKV感染 怀孕的小鼠会导致胎盘感染，子宫内传播和发育中的胎儿受伤。 o ur 中心假设是 出现母亲的传播是因为ZIKV克服了胎盘滋养细胞 宿主防御（自噬）（AIM 1），篡夺TAM受体进入胎盘滋养细胞和内皮细胞 （目标2）;在有足够的Flavivivirus-bmmune的个体或动物中，整个过程都得到了增强 促进ADE的交叉反应性，非中和抗ZIKV抗体的水平（AIM 3）。总体而言，我们的 努力对于理解ZIKV发病机理将非常重要。这项工作将为 定义孕产妇向儿童传播ZIKV的风险的临床研究，产生可能的新 治疗方法，并确定ZIKV与自然免疫之间的相互作用 黄病毒。