Novel Function(s) of Arenavirus NP Exoribonuclease
Arenavirus NP 核糖核酸外切酶的新功能
基本信息
- 批准号:10624457
- 负责人:
- 金额:$ 20万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-18 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:5&apos-exoribonucleaseAddressAffectAfricaArenavirusArenavirus InfectionsBiochemicalBiologicalBiological AssayBiologyBolivian Hemorrhagic Fever VirusCategory A pathogenCellsClassificationContainmentCultured CellsDataDefective VirusesDiseaseDouble-Stranded RNAEnsureExoribonucleasesFamilyFutureGenesGenetic TranscriptionGenomeHumanImmune EvasionImpairmentIn VitroInfectionIntercistronic RegionInterferonsJunin virusKnowledgeLassa FeverLassa virusLife Cycle StagesLymphocytic choriomeningitis virusMediatingMessenger RNAModelingMolecularMutationNatural ImmunityNorthern BlottingNucleoproteinsPathogenicityProductionPublic HealthRNARNA VirusesRNA chemical synthesisRNA replicationRNA-Directed RNA PolymeraseRepliconRoleSignal TransductionStructureTechniquesTechnologyTimeVaccinesVariantViralViral PackagingVirionVirusVirus DiseasesVirus ReplicationWestern AfricaZoonosesantiviral drug developmentbiosafety level 4 facilitydeep sequencingexperimental studygenomic RNAhigh riskin vivoinnovationinsightmutantnovelnucleoside analogparticlepreventprototypesingle moleculetranscription terminationviral RNAviral genomicsvirology
项目摘要
PROJECT SUMMARY/ABSTRACT
Several mammalian arenaviruses cause severe and fatal zoonotic diseases in humans, for which vaccines and
treatments are very limited. Lassa virus (LASV) is the causative agent for Lassa fever (LF) that is currently
endemic in Western Africa. Despite its importance to public health, important knowledge gaps still exist in the
basic biology for LASV and other highly pathogenic arenaviruses, partly due to the limitation of high containment
BSL4 facilities required for infection experiments. The RNA synthesis of RNA virus is generally error prone as
viral RNA-dependent RNA polymerase lacks proofreading activity. As negative-sense RNA virus, how arenavirus
ensures proper RNA synthesis is largely unclear. The LASV nucleoprotein has a DEDDH 3' to 5' exoribonuclease
motif (ExoN), of which its function in virus life cycle is still a puzzle. The current paradigm in the field is that the
NP ExoN activity efficaciously degrades virus-derived double-stranded RNA and is the key to LASV evasion of
innate immunity. Intriguingly, the ExoN motif is highly conserved in NPs of all arenaviruses, regardless of
pathogenicity. Therefore, it is very likely that the NP ExoN has important but yet-to-be-identified function(s) in
arenavirus replication in addition to immune evasion. In this project, we aim to define the important role(s) of
arenavirus NP ExoN in virus replication.
Our preliminary data indicated that: 1). Loss of NP ExoN activity resulted in aberrant genomic RNA production
and a drastic reduction in LASV RNA level in IFN-deficient cells; and 2). Loss of NP ExoN activity increased
LASV sensitivity to mutagenic nucleoside analogue treatment. We propose that LASV NP ExoN promotes proper
viral RNA synthesis, controls aberrant viral genomic RNA formation and/or ensures the fidelity of viral RNA
replication. To define the impact of NP ExoN on the integrity and functionality of viral genomic RNA, we will
explore to utilize an innovative long-read sequencing technology to systematically investigate the sequence and
abundancy of genomic RNAs at single molecule level. Arenavirus has been known to form defective interfering
particles, which regulates virus infection in vivo and in vitro. The molecular basis for DI genome remains elusive
due to technical obstacle. The long-read sequencing technology may enable us to identify DI candidates and the
potential role of NP ExoN in regulating DI formation. We will also investigate whether arenavirus NP ExoN has
proofreading activity that ensures the fidelity of viral RNA replication.
At the end of this project, we may discover novel and important function(s) of arenavirus NP ExoN in virus life
cycle and move the field forward. Using LASV as a model, we may better understand how arenavirus virus
ensures proper viral RNA synthesis. With the novel long-read sequencing technology, this study may overcome
technical barrier and increase our knowledge on basic virology of pathogenic arenaviruses. The data may open
up new directions. For instance, future studies on the mechanisms underlying the important roles of NP ExoN
are warranted. This project may also facilitate antiviral development by targeting NP ExoN activity.
项目总结/摘要
几种哺乳动物沙粒病毒在人类中引起严重和致命的人畜共患病,
治疗非常有限。拉沙病毒(LASV)是拉沙热(LF)的病原体,目前
西非的地方病。尽管它对公共卫生很重要,但在公共卫生领域仍然存在着重要的知识差距。
LASV和其他高致病性沙粒病毒的基础生物学,部分原因是高遏制的限制
感染实验所需的BSL 4设施。RNA病毒的RNA合成通常容易出错,
病毒RNA依赖性RNA聚合酶缺乏校对活性。沙粒病毒作为一种负义RNA病毒,
如何确保正确的RNA合成在很大程度上是不清楚的。LASV核蛋白具有DEDDH 3'至5'核糖核酸外切酶,
序列(ExoN),其在病毒生活史中的作用至今仍是一个谜。该领域目前的范例是,
NP ExoN活性有效地降解病毒衍生的双链RNA,并且是LASV逃避病毒的关键。
先天免疫有趣的是,ExoN基序在所有沙粒病毒的NP中是高度保守的,无论是否存在。
致病性因此,NP ExoN很可能在细胞内具有重要但尚待鉴定的功能。
沙粒病毒复制以及免疫逃避。在这个项目中,我们的目标是定义的重要作用(S)
沙粒病毒NP ExoN在病毒复制中的作用。
我们的初步数据表明:1)。NP ExoN活性的丧失导致异常的基因组RNA产生
和IFN缺陷细胞中LASV RNA水平的急剧降低;和2). NP ExoN活性损失增加
LASV对诱变核苷类似物治疗的敏感性。我们提出LASV NP ExoN促进适当的
病毒RNA合成,控制异常病毒基因组RNA形成和/或确保病毒RNA的保真度
复制的为了确定NP ExoN对病毒基因组RNA的完整性和功能性的影响,我们将
探索利用创新的长读序测序技术系统地研究序列,
在单分子水平上的基因组RNA的表达。已知沙粒病毒可形成缺陷性干扰
颗粒,其在体内和体外调节病毒感染。DI基因组的分子基础仍然难以捉摸
由于技术障碍。长读段测序技术可以使我们能够鉴定DI候选物,并且使我们能够鉴定DI候选物。
NP ExoN在调节DI形成中的潜在作用。我们还将研究沙粒病毒NP ExoN是否具有
确保病毒RNA复制保真度的校对活动。
在本项目的最后,我们可能会发现沙粒病毒NP ExoN在病毒生活中的新的和重要的功能
循环并向前移动场地。利用LASV作为模型,我们可以更好地了解沙粒病毒如何
确保病毒RNA的正常合成通过新的长读序测序技术,这项研究可以克服
提高对致病性沙粒病毒基础病毒学的认识。数据可能会打开
新的方向。例如,未来对NP ExoN重要作用机制的研究
都是正当的该项目还可以通过靶向NP ExoN活性促进抗病毒开发。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Cheng Huang', 18)}}的其他基金
Novel Function(s) of Arenavirus NP Exoribonuclease
Arenavirus NP 核糖核酸外切酶的新功能
- 批准号:
10525101 - 财政年份:2022
- 资助金额:
$ 20万 - 项目类别:
Famine Exposure During the First 1000 Days and Intellectual Disability
前 1000 天内的饥荒和智力障碍
- 批准号:
8283342 - 财政年份:2012
- 资助金额:
$ 20万 - 项目类别:
Famine Exposure During the First 1000 Days and Intellectual Disability
前 1000 天内的饥荒和智力障碍
- 批准号:
8509754 - 财政年份:2012
- 资助金额:
$ 20万 - 项目类别:
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