Determining Tropism and Mechanisms of Ebola Virus Entry in Placental Tissues

项目摘要/摘要 在怀孕期间，母亲的病毒感染可能会对她的健康造成灾难性的影响，或者对 发育中的胎儿的存活率。最近，新出现的病原体暴发，如涉及寨卡病毒的疫情 (ZIKV)、SARS-CoV-2或埃博拉病毒(EBOV)突显了胎盘在 病毒感染的传播。这个项目特别关注EBOV在怀孕期间的细胞嗜性。 埃博拉病毒病(EVD)是由感染埃博拉病毒或埃博拉病毒属其他成员引起的。 在怀孕期间，EVD会导致~100%的胎儿或新生儿丢失，无论是否有额外的 母亲。来自非洲EBOV疫情的坊间数据表明，EBOV直接感染胎盘 组织，从而将病毒传播到胎儿隔室，但严格的胎盘实验评估 尚未进行感染；EBOV对胎盘细胞的趋向性，细胞进入的机制，以及 从母亲到胎儿的感染途径目前尚不清楚。目标1将检测胎盘中EBOV的趋向性 纸巾。此外，由于EBOV已被证明通过与多种细胞类型的相互作用与多种细胞类型结合并内化 磷脂酰丝氨酸受体(PS)，AIM 2研究将评估三种PS受体在EBOV中的作用 胎盘和胎儿的感染。这些研究将使用两个低遏制EBOV模型进行 已被广泛用于了解丝状病毒的病毒，rVSV-eBOV-gp-gfp和ebovΔVP30 趋向性和受体的使用。从这些严格设计的研究中获得的知识将阐明细胞 胎盘内感染的人群对胎儿传播很重要，这是迈向 了解妊娠期EVD的灾难性发病机制。此外，这项工作将提供洞察力 用于开发治疗方案，以改善埃博拉病毒病的母婴结局。 该提案中的经验、技术、指导和概念都是专门为MS量身定做的。 Hanora Van ERT和她的训练目标。作为一名发展中的研究人员，热衷于改善健康和 孕妇的福祉，Van ERT女士目前正在完成她在加州大学MSTP的学业 爱荷华州在温迪·莫里博士和马克·桑蒂兰博士的科学指导下接受个性化 在病毒学、免疫学和生殖健康科学的交叉点接受培训，以满足她的热情 拥有必要的研究技能。此外，MSTP、妇产科和卫生部 爱荷华大学的微生物学和免疫学提供了大量的培训机会 研讨会系列，资助出席学术会议，有机会与当地知名人士见面 病毒学、免疫学和妇产科领域，以及支持性和协作性研究环境。 Van ERT女士将完成她的MSTP培训，并在妇产科获得研究住院医师资格。 胎儿医学奖学金，并最终在学术医学中心继续担任终身教职 研究胎盘内母胎界面的宿主-病原体免疫反应。

Project Summary/Abstract During pregnancy, viral infections in the mother may have catastrophic effects on her health, or on the viability of the developing fetus. Recently, emerging pathogen outbreaks such as those involving Zika Virus (ZIKV), SARS-CoV-2 or Ebola Virus (EBOV) have highlighted how understudied the role of the placenta is in transmission of viral infections. This project specifically focuses on the cell tropism of EBOV during pregnancy. Ebola Virus Disease (EVD) is caused by infection with EBOV or other members within the Ebolavirus genus. During pregnancy, EVD results in loss of ~100% of fetuses or neonates with or without the additional loss of the mother. Anecdotal data from EBOV outbreaks in Africa suggest that EBOV directly infects placental tissues, thus transmitting virus to the fetal compartment, but rigorous experimental evaluation of placental infection has not been performed; the tropism of EBOV for placental cells, mechanisms of cellular entry, and route of infection from mother to fetus are currently unknown. Aim 1 will examine tropism of EBOV in placental tissues. Further, as EBOV has been shown to bind to and internalize into many cell types via interactions with phosphatidylserine (PS) receptors, Aim 2 studies will evaluate the role of three PS receptors on EBOV infection of the placenta and fetus. These studies will be performed using two low containment EBOV model viruses, rVSV-EBOV-GP-GFP and EBOV ΔVP30, that have been used extensively to understand filovirus tropism and receptor usage. The knowledge gained from these rigorously designed studies will elucidate cell populations within the placenta infected and important for fetal transmission as a first step toward understanding the catastrophic pathogenesis of EVD in pregnancy. Additionally, this work will provide insights for the development of therapeutic treatment options to improve the maternal and fetal outcomes of EVD. The experiences, techniques, mentoring, and concepts in this proposal were specifically tailored to Ms. Hanora Van Ert and her training goals. As a developing researcher passionate about improving the health and wellbeing of pregnant women, Ms. Van Ert is currently completing her studies in the MSTP at University of Iowa under the scientific mentorship of Dr. Wendy Maury and Dr. Mark Santillan receiving individualized training at the intersection of virology, immunology, and reproductive health sciences to supply her passion with the necessary research skills. Additionally, the MSTP, Department of OB/Gyn, and Department of Microbiology and Immunology at the University of Iowa provide ample training opportunities in the forms of seminar series, funding for attending academic conferences, opportunities to meet prominent people in the fields of virology, immunology, and OB/Gyn, as well as a supportive and collaborative research environment. Ms. Van Ert will complete her MSTP training and pursue a research residency in OB/Gyn, clinical Maternal- fetal medicine fellowship, and ultimately tenure track position at an academic medical center to continue investigating the host-pathogen immune response at the maternal-fetal interface within the placenta.