Understanding the Molecular Determinants of Reassortment in Orthobunyaviruses and Phleboviruses.

了解正布尼亚病毒和白蛉病毒重配的分子决定因素。

• 批准号: 10674269
• 负责人: Natasha Louise Tilston-Lunel
• 金额: $ 24.9万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-02 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10674269
• 关键词: Africa; Animals; Biological Assay; Biology; Cells; Code; Color; Congenital Abnormality; Coupled; Data; Disease; Engineering; Europe; Evolution; Far East; Fever; Fluorescent in Situ Hybridization; Frequencies; GTP-Binding Proteins; Gene Expression; Generations; Genes; Genetic Recombination; Genetic Transcription; Genome; Genomic Segment; Genomics; Genus Phlebovirus; Glycoproteins; Goals; Heartland virus; Human; Immunology; Individual; Infection; Knowledge; Ligation; Maps; Mentors; Mentorship; Methods; Modeling; Molecular; Monkeys; Mus; Nature; Nonstructural Protein; Nucleic Acid Regulatory Sequences; Nucleocapsid; Nucleocapsid Proteins; Organ; Oropouche virus; Orthobunyavirus; Outcome; Paramyxovirus; Parents; Pathogenesis; Persons; Phase; Phenotype; Polymerase; Positioning Attribute; Process; Proteins; RNA; RNA Viruses; Rattus; Reassortant Viruses; Reporter; Reporter Genes; Research; Rift Valley fever virus; Ruminants; Severe Fever with Thrombocytopenia Syndrome Virus; Signal Transduction; South America; Syndrome; System; Techniques; Testing; Thrombocytopenia; Ticks; Training; Untranslated Regions; Viral; Viral Hemorrhagic Fevers; Viral Pathogenesis; Virulence; Virulent; Virus; Virus Replication; Work; arthropod-borne; career; chemokine; co-infection; cytokine; design; forward genetics; genetic approach; genetic information; human pathogen; influenzavirus; novel; novel virus; pathogen; pathogenic virus; priority pathogen; professor; promoter; response; reverse genetics; skills; transcriptome sequencing; viral transmission

Project Summary/Abstract Genome reassortment drives the diversity we see in segmented RNA viruses. Unlike recombination, intact genes are readily exchanged between two co-infecting viruses, resulting in their rapid evolution. Reassortment amongst influenza viruses is a well-established driver of host range and virulence. Though reassortment occurs frequently amongst bunyaviruses and can result in highly virulent reassortants such as Ngari virus, the underlying mechanisms are unknown. Understanding how these viruses reassort and modify virulence will allow us to predict potential virus emergence or modulations in host range allowing potential species jumps. The goal of this project is to investigate the molecular determinants of reassortment and virulence amongst orthobunyaviruses and phleboviruses. These are tri-segmented negative sense RNA viruses with Small (S), Medium (M) and Large (L) segments encoding the nucleocapsid protein, glycoproteins GnGc and a viral polymerase (L protein), respectively. Some viruses also encode nonstructural proteins on the S and/or M segments. Aim 1, will investigate segment compatibility amongst the priority pathogens Severe fever with thrombocytopenia syndrome virus and Heartland virus, using a forward and reverse genetics approach. Aim 2, will investigate homologous and heterologous segment dynamics within infected cells. Aim 3, will investigate the virulence of natural reassortants of Oropouche virus and potential reassortants of SFTSV and HRTV. These studies are of significant importance, as only by understanding the fundamental aspects of the biology of these viruses will we be able to understand the molecular determinants of their reassortment. This proposal will support my long-term career goal of understanding novel virus emergence and evolution. My mentorship team consists of Professor Paul Duprex, an expert in paramyxoviruses and cross-species viral transmission, Dr. Anita McElroy, an expert in Rift Valley fever virus (RVFV) transmission and immunology, Dr. Amy Hartman, an expert in RVFV pathogenesis in rats and monkeys and Dr. Seema Lakdawala, an expert in influenza virus biology and reassortment. With the support of strong mentors and collaborators I will receive training in the skills required to complete the proposed aims. Upon completion of the K99 phase I will be in a strong position to pursue an independent and successful research position contributing to the bunyavirus field.

项目概要/摘要 基因组重排驱动了我们在分段 RNA 病毒中看到的多样性。与重组不同， 完整的基因很容易在两种共同感染的病毒之间交换，从而导致它们的快速进化。 流感病毒之间的重排是宿主范围和毒力的一个公认的驱动因素。尽管 重配在布尼亚病毒中经常发生，并可能导致高毒力的重配，例如 阿里病毒的潜在机制尚不清楚。了解这些病毒如何重组和修改 毒力将使我们能够预测潜在病毒的出现或宿主范围内的调节，从而允许潜在的物种 跳跃。该项目的目标是研究重配和毒力的分子决定因素 属于正布尼亚病毒和白蛉病毒。这些是三段负义 RNA 病毒，带有小 (S)、中 (M) 和大 (L) 片段编码核衣壳蛋白、糖蛋白 GnGc 和病毒 分别是聚合酶（L蛋白）。一些病毒还在 S 和/或 M 上编码非结构蛋白 段。目标 1，将调查优先病原体之间的片段兼容性 血小板减少综合征病毒和哈特兰病毒，使用正向和反向遗传学方法。目标2， 将研究受感染细胞内的同源和异源片段动态。目标 3，将调查 奥罗普切病毒天然重配体以及SFTSV和HRTV潜在重配体的毒力。这些 研究具有重要意义，因为只有了解这些生物学的基本方面 病毒将使我们能够了解其重排的分子决定因素。该提案将支持 我的长期职业目标是了解新型病毒的出现和进化。我的导师团队包括 副粘病毒和跨物种病毒传播专家 Paul Duprex 教授、Anita McElroy 博士、 裂谷热病毒 (RVFV) 传播和免疫学专家 Amy Hartman 博士，RVFV 专家 大鼠和猴子的发病机制以及流感病毒生物学和免疫学专家 Seema Lakdawala 博士 重组。在强有力的导师和合作者的支持下，我将接受所需技能的培训 完成拟议的目标。 K99 阶段完成后，我将处于有利地位，可以追求 独立且成功的研究职位为布尼亚病毒领域做出了贡献。