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.

项目概要/摘要 在怀孕期间，母亲体内的病毒感染可能会对她的健康或胎儿造成灾难性影响。 最近，新出现的病原体爆发，例如涉及寨卡病毒的病原体。 (ZIKV)、SARS-CoV-2 或埃博拉病毒 (EBOV) 强调了胎盘在疾病中的作用尚未得到充分研究。 该项目特别关注妊娠期间埃博拉病毒的细胞趋向性。 埃博拉病毒病 (EVD) 是由埃博拉病毒或埃博拉病毒属其他成员感染引起的。 在怀孕期间，埃博拉病毒病导致约 100% 的胎儿或新生儿死亡，无论是否伴有额外的胎儿或新生儿死亡 非洲埃博拉病毒爆发的轶事数据表明埃博拉病毒直接感染胎盘。 组织，从而将病毒传播到胎儿室，但对胎盘进行严格的实验评估 尚未进行感染；EBOV 对胎盘细胞的趋向性、细胞进入机制以及 目前尚不清楚从母亲到胎儿的感染途径。目标 1 将检查胎盘中 EBOV 的趋向性。 此外，埃博拉病毒已被证明可以通过与多种细胞类型的相互作用结合并内化到多种细胞类型中。 磷脂酰丝氨酸 (PS) 受体，Aim 2 研究将评估三种 PS 受体对 EBOV 的作用 这些研究将使用两种低遏制 EBOV 模型进行。 病毒，rVSV-EBOV-GP-GFP 和 EBOV ΔVP30，通常用于了解丝状病毒 从这些严格设计的研究中获得的知识将阐明细胞的向性和受体的用途。 胎盘内受感染且对胎儿传播很重要的人群，这是迈向这一目标的第一步 此外，这项工作还将提供了解妊娠期埃博拉病毒病的灾难性发病机制。 开发治疗方案以改善埃博拉病毒病的孕产妇和胎儿结局。 该提案中的经验、技术、指导和概念是专门为女士量身定制的。 Hanora Van Ert 和她的培训目标作为一名热衷于改善健康和健康的发展中的研究人员。 为了孕妇的福祉，Van Ert 女士目前正在完成她在曼彻斯特大学 MSTP 的学业 爱荷华州在 Wendy Maury 博士和 Mark Santillan 博士的科学指导下接受个性化治疗 在病毒学、免疫学和生殖健康科学的交叉领域接受培训，以激发她的热情 此外，MSTP、妇产科和妇产科也具备必要的研究技能。 爱荷华大学微生物学和免疫学提供充足的培训机会，其形式包括： 研讨会系列、参加学术会议的资助、结识业界知名人士的机会 病毒学、免疫学和妇产科领域，以及支持性和协作性的研究环境。 Van Ert 女士将完成她的 MSTP 培训，并在妇产科、临床孕产妇领域进行住院医师实习。 胎儿医学研究金，并最终在学术医疗中心继续获得终身教职 研究胎盘内母胎界面的宿主-病原体免疫反应。