Comprehensive genetic dissection of poxvirus membrane assembly and function
痘病毒膜组装和功能的全面基因解剖
基本信息
- 批准号:10575027
- 负责人:
- 金额:$ 25.2万
- 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:2022-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAmino AcidsBehavior assessmentBindingBiochemicalBiological AssayBiologyC-Type LectinsC-terminalCell surfaceCellsCollaborationsComplementComplexCowpox virusCytoplasmCytoplasmic TailDataDefectDevelopmentDissectionGPA33 geneGene CombinationsGenerationsGeneticGenetic ScreeningGenetic studyGrowthHumanImmunityIndividualInfectionInternetIntracellular MembranesLibrariesMammalsMass Spectrum AnalysisMediatingMembrane ProteinsMolecularMonkeypox virusMorphogenesisMutagenesisMutateMutationNatureOncolyticOrthopoxvirusPersonsPhenotypePoint MutationPopulationPoxviridaeProteinsProteomicsPublic HealthReportingRiskRoleSensitivity and SpecificitySerial PassageSeriesSiteSmallpoxSurfaceTherapeuticTherapeutic antibodiesVaccinatedVaccinationVaccinesVaccinia virusViralViral ProteinsVirionVirulenceVirusWorkZoonosescancer therapycell motilityextracellularfitnessgenomic locusimprovedin vivoloss of functionmembermembrane assemblymembrane biogenesismutantmutation screeningnew epidemicnext generation sequencingnoveloncolytic vectorparticlepoxvirus vectorspreventprotein protein interactionprototypereverse geneticstissue tropismtransmission processvirus geneticsvirus host interactionvirus virus interaction
项目摘要
The zoonotic potential of members of the genus Orthopoxvirus (orthopoxviruses) of mammal- infecting poxviruses represent a continued threat to global public health. A hallmark of the complex biology of orthopoxvirus multiplication in the host cell cytoplasm is the generation of two distinct infectious forms—intracellular mature virions (IMV), which remain largely cell- associated, and enveloped virions (EV), which are critical for extracellular viral spread. EVs bear a unique complement of eight virus-encoded membrane proteins at their surface that influence tissue tropism, long-range in vivo dissemination, and ultimately, virulence; provide key targets for vaccine-induced and therapeutic antibodies; and are important determinants of the therapeutic potential of oncolytic poxvirus vectors. Despite their importance, a comprehensive understanding of EVs is challenged by the complex networks of virus-host and virus-virus interactions that underlie their morphogenesis and function. Our overall objective is to unravel these functional protein interaction networks through a combination of genetic and proteomic approaches. Using a new platform for unbiased and deep mutagenesis of any genomic locus in the prototypic orthopoxvirus, vaccinia virus (VACV), we conducted deep-mutational scans (DMS) of two EV proteins, A33 and A34, in the context of infectious viral particles and identified novel regiospecific mutations that enhance EV fitness. We will elucidate the mechanisms of action of these mutants. In parallel, we will perform genetic modifier and proteomic screens to uncover new functional interactions of A33/A34 with viral and host proteins. Collectively, these studies will provide new information on how EVs—critical for both the virulence of orthopoxviruses and their utility as oncolytic vectors—assemble, egress, and spread to new cells during infection.
感染哺乳动物的痘病毒属(正痘病毒)成员的人畜共患病潜力对全球公共卫生构成持续威胁。正痘病毒在宿主细胞质中增殖的复杂生物学特征是产生两种不同的感染形式-细胞内成熟病毒粒子(IMV)和包膜病毒粒子(EV),前者主要与细胞相关,后者对细胞外病毒传播至关重要。EV在其表面携带8种编码病毒的膜蛋白的独特互补,这些蛋白影响组织趋向性、在体内的远程传播,并最终影响毒力;为疫苗诱导的抗体和治疗性抗体提供关键靶点;是溶瘤痘病毒载体治疗潜力的重要决定因素。尽管EVS很重要,但对EVS的全面理解受到了病毒-宿主和病毒-病毒相互作用的复杂网络的挑战,这些网络是EVS形态发生和功能的基础。我们的总体目标是通过遗传学和蛋白质组学相结合的方法来解开这些功能蛋白质相互作用网络。使用一个新的平台对原型正痘病毒(VACV)中的任何基因组位点进行无偏见和深度突变,我们在感染性病毒颗粒的背景下对两种EV蛋白A33和A34进行了深度突变扫描(DMS),并发现了增强EV适合性的新的区域特异性突变。我们将阐明这些突变体的作用机制。同时,我们将进行遗传修饰和蛋白质组筛选,以揭示A33/A34与病毒和宿主蛋白的新的功能相互作用。总而言之,这些研究将提供有关EV如何在感染期间组装、出口和传播到新细胞的新信息。EV对正痘病毒的毒力和作为溶瘤载体的效用都是至关重要的。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Kartik Chandran其他文献
Kartik Chandran的其他文献
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{{ truncateString('Kartik Chandran', 18)}}的其他基金
Einstein BSL3 Laboratory Renovation to Advance Biomedical Research on RNA Viruses of Pandemic Potential
爱因斯坦 BSL3 实验室改造将推进对可能引发大流行的 RNA 病毒的生物医学研究
- 批准号:
10611691 - 财政年份:2022
- 资助金额:
$ 25.2万 - 项目类别:
Optimizing SARS-CoV-2 wastewater based surveillance in urban and university campus settings.
优化城市和大学校园环境中基于 SARS-CoV-2 废水的监测。
- 批准号:
10320993 - 财政年份:2021
- 资助金额:
$ 25.2万 - 项目类别:
Optimizing SARS-CoV-2 wastewater based surveillance in urban and university campus settings.
优化城市和大学校园环境中基于 SARS-CoV-2 废水的监测。
- 批准号:
10264634 - 财政年份:2021
- 资助金额:
$ 25.2万 - 项目类别:
Project II: Biologics Engineering and Antibody Mechanism of Action
项目二:生物制剂工程与抗体作用机制
- 批准号:
10555312 - 财政年份:2019
- 资助金额:
$ 25.2万 - 项目类别:
Prometheus: A Platform for Rapid Development of Human Antibody-based Therapeutics and Prophylactics against Emerging Viral Threats
Prometheus:快速开发针对新兴病毒威胁的基于人类抗体的治疗和预防方法的平台
- 批准号:
10088385 - 财政年份:2019
- 资助金额:
$ 25.2万 - 项目类别:
Project II: Biologics Engineering and Antibody Mechanism of Action
项目二:生物制剂工程与抗体作用机制
- 批准号:
10088393 - 财政年份:2019
- 资助金额:
$ 25.2万 - 项目类别:
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