Determining Tropism and Mechanisms of Ebola Virus Entry in Placental Tissues

确定埃博拉病毒进入胎盘组织的趋向性和机制

• 批准号: 10605584
• 负责人: Hanora Anne Marie Van Ert
• 金额: $ 3.9万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-15 至 2025-07-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605584
• 关键词: 2019-nCoV; Academic Medical Centers; Africa; Antigens; Binding; C Type Lectin Receptors; C-Type Lectins; Cell membrane; Cell surface; Cells; Cessation of life; Chorionic villi; Clinical; Communicable Diseases; Containment; Data; Dendritic Cells; Development; Discipline of obstetrics; Disease Outbreaks; Ebola Hemorrhagic Fever; Ebola virus; Endosomes; Endothelial Cells; Environment; Epithelial Cells; Evaluation; Experimental Animal Model; Family member; Fellowship; Fetal Death; Fetal Development; Fetal Tissues; Fetus; Fibroblasts; Filoviridae Infections; Filovirus; Funding; Future; Glycoproteins; Goals; Health; Health Sciences; Human; Immune response; Immunology; In Vitro; Individual; Infection; Iowa; Knowledge; Macrophage; Maternal-Fetal Exchange; Maternal-fetal medicine; Mentors; Mentorship; Microbiology; Modeling; Mothers; Outcome; Pathogenesis; Pathology; Personal Satisfaction; Persons; Phosphatidylserines; Physicians; Placenta; Play; Polysaccharides; Population; Positioning Attribute; Predisposition; Pregnancy; Pregnant Women; Process; Production; Productivity; RNA Viruses; Reproductive Health; Research; Research Design; Research Personnel; Residencies; Role; Route; Scientist; Series; Source; Syncytiotrophoblast; Techniques; Testing; Therapeutic; Tissues; Training; Transportation; Treatment Protocols; Tropism; Universities; Viral; Viral Hemorrhagic Fevers; Viral Pathogenesis; Viremia; Virion; Virus; Virus Diseases; Virus Replication; Woman; Work; Zaire Ebola virus; Zika Virus; cell type; emerging pathogen; experience; fetal; fetal loss; fetus cell; glycosylation; human morbidity; human mortality; improved; in vivo; insight; late endosome; member; monocyte; neonatal death; neonate; pathogen; peripheral blood; phosphatidylserine receptor; placental infection; receptor; skills; symposium; tenure track; therapeutic development; training opportunity; transmission process; viral RNA; viral transmission; virology

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.

项目总结/摘要 在怀孕期间，母亲的病毒感染可能会对她的健康产生灾难性的影响，或者对她的孩子产生灾难性的影响。 发育中胎儿的生存能力。最近，新出现的病原体疫情，如涉及寨卡病毒的疫情， （ZIKV），SARS-CoV-2或埃博拉病毒（EBOV）强调了胎盘的作用如何未得到充分研究， 病毒感染的传播。该项目特别关注EBOV在妊娠期间的细胞嗜性。 埃博拉病毒病（EVD）是由埃博拉病毒或埃博拉病毒属内的其他成员感染引起的。 妊娠期间，EVD导致约100%的胎儿或新生儿死亡，伴或不伴额外的 母亲来自非洲EBOV暴发的轶事数据表明，EBOV直接感染胎盘， 组织，从而将病毒传播到胎儿室，但严格的实验评估胎盘 感染尚未进行; EBOV对胎盘细胞的向性，细胞进入的机制， 目前尚不清楚母亲感染胎儿的途径。目的1将检测EBOV在胎盘中的嗜性 组织中此外，由于EBOV已被证明通过与细胞的相互作用与许多细胞类型结合并内化到其中， 目的2研究将评估三种PS受体对EBOV的作用， 胎盘和胎儿感染。这些研究将使用两个低遏制EBOV模型进行 病毒，rVSV-EBOV-GP-GFP和EBOV Δ VP 30，已被广泛用于了解丝状病毒 向性和受体利用。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， 了解妊娠期EVD的灾难性发病机制。此外，这项工作将提供见解 用于开发治疗方案，以改善EVD的母体和胎儿结局。 本建议书中的经验、技术、指导和概念都是专门为Ms. Hanora货车Ert和她的训练目标。作为一个发展中的研究人员热衷于改善健康和 货车Ert女士目前正在哥伦比亚大学的MSTP完成她的学业。 爱荷华州在温迪·莫里博士和马克·莫伦博士的科学指导下， 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 具备必要的研究技能。此外，MSTP、产科/妇科部和 爱荷华州大学的微生物学和免疫学提供了充足的培训机会， 研讨会系列，参加学术会议的资金，会见知名人士的机会， 病毒学、免疫学和妇产科领域，以及支持和合作的研究环境。 女士货车厄特将完成她的MSTP培训，并继续在妇产科，临床产妇， 胎儿医学奖学金，并最终在学术医疗中心的终身职位，以继续 研究胎盘内母胎界面的宿主-病原体免疫应答。