Understanding the Molecular Determinants of Reassortment in Orthobunyaviruses and Phleboviruses.

项目总结/摘要 基因组重组驱动了我们在分段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，导致它们的快速进化。 流感病毒之间的重配是宿主范围和毒力的公认驱动因素。虽然 在布尼亚病毒中经常发生重配，并可产生高毒力的重组体， 阿里病毒，潜在的机制是未知的。了解这些病毒如何重新排序和修改 毒力将使我们能够预测潜在的病毒出现或调节宿主范围， 跳.本项目的目标是研究重配和毒力的分子决定因素 在正布尼亚病毒和白蛉病毒中。这些是具有小RNA的三节段负义RNA病毒， (S)、中等（M）和大（L）区段，其编码核衣壳蛋白、糖蛋白GnGc和病毒蛋白GnGc。 聚合酶（L蛋白）。一些病毒也编码非结构蛋白的S和/或M 片段目的1，将调查优先病原体之间的区段相容性 血小板减少综合征病毒和Heartland病毒，使用正向和反向遗传学方法。目标二， 将研究感染细胞内的同源和异源片段动力学。目标3，将调查 Oropouche病毒的天然复制物和SFTSV和HRTV的潜在复制物的毒力。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， 我们将能够理解病毒重组的分子决定因素。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。我的导师团队由 副粘病毒和跨物种病毒传播专家保罗·杜普雷教授，安妮塔·麦克罗伊博士， 裂谷热病毒（RVFV）传播和免疫学专家艾米哈特曼博士，RVFV专家 以及流感病毒生物学专家Seema Lakdawala博士， 重组在强大的导师和合作者的支持下，我将接受所需技能的培训， 完成提出的目标。在K99第一阶段完成后， 独立和成功的研究立场，有助于布尼亚病毒领域。

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.