A General Molecular Strategy for Attenuation of Human Pathogenic Arenaviruses

人类致病性沙粒病毒减毒的通用分子策略

基本信息

  • 批准号:
    9217579
  • 负责人:
  • 金额:
    $ 24.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-02-05 至 2019-01-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Several arenaviruses cause hemorrhagic fever (HF) disease in humans and pose a serious public health problem in their endemic regions. Thus, the Old World arenavirus (OWA) Lassa (LASV) infects several hundred thousand individuals yearly in West Africa resulting in a high number of Lassa fever (LF) cases associated with high morbidity and mortality. Moreover, evidence indicates that the worldwide-distributed OWA LCMV is a neglected clinically important human pathogen. In addition, several arenaviruses including LASV and LCMV pose a credible biodefense threat. Existing anti-arenaviral therapy is limited to an off-label use of ribavirin that is only partially effective, and there are no FDA-licensed, or currently in clinical trials, arenavirus vaccines. However, the MOPV/LASV reassortant (ML29) is a candidate live-attenuated vaccine (L-AttV) for LASV that has shown promising results in animal models. Nevertheless, as with many other traditional L-AttV, the mechanism of ML29 attenuation remains unknown, which raises concerns about the phenotypic stability of ML29 in response to additional mutations. The central goal of this application is to test the hypothesis that we can convert a pathogenic OWA into an attenuated form with features of L-AttV via replacement of its L IGR by a genetically defined synthetic S-like IGR (Ssyn). Our hypothesis is supported by our recent following findings: 1) We could rescued rLCMV(IGR/S-S) with the same S-IGR in both S and L genome segments, and found that it was highly attenuated in vivo. 2) Mice immunized with rLCMV(IGR/S-S) were protected against a lethal challenge with wild type (WT) LCMV. 3) We have obtained evidence that a high degree of sequence plasticity within the S IGR is compatible with virus viability, which supports the feasibility of engineering recombinant arenaviruses with a synthetic S IGR (Ssyn) in the L segment as a general molecular strategy for arenavirus attenuation. To test our hypothesis we propose to complete the following specific aims: Aim 1. Characterize rLCMV (IGR/S-Ssyn): We have rescued rLCMV(IGR/S-Ssyn) where a synthetic S IGR (Ssyn) substituted for the L-IGR. We will characterize rLCMV(IGR/S-Ssyn) in cultured cells and using the mouse model of LCMV infection test the hypothesis that rLCMV(IGR/S-Syn) displays key features for L-AttV. Aim 2: Generate and characterize rLASV(IGR/S-Ssyn): We will generate rLASV(IGR/S-Ssyn) and test the hypothesis that it is attenuated in vivo but able to induce protective immunity against a letha challenge with WT LASV in a well-established guinea pig model of LASV infection. Aim 3. Examine the stability of rLCMV(IGR/S-Ssyn): We will test the hypothesis that rLCMV(IGR/S-Ssyn) is genetically stable during multiplication under different growth conditions. The successful completion of this application will uncover a general molecular strategy for arenavirus attenuation that can facilitate a novel strategy to develop L-AttV to combat human pathogenic arenaviruses.
 描述(申请人提供):几种禽流感病毒在人类中引起出血热(HF)疾病,并在其流行地区造成严重的公共卫生问题。因此,东半球阿拉伯病毒(OWA)拉萨(LASV)每年感染西非数十万人,导致与高发病率和高死亡率相关的大量拉沙热(LF)病例。此外,有证据表明,世界各地分布的OWA LCMV是一种被忽视的临床重要人类病原体。此外,包括LASV和LCMV在内的几种禽类病毒构成了可信的生物防御威胁。现有的抗阿拉伯病毒疗法仅限于非标签使用利巴韦林,仅有部分有效,而且没有FDA许可的或目前处于临床试验中的阿拉伯病毒疫苗。然而,MOPV/LASV重组疫苗(ML29)是一种候选的LASV减毒活疫苗(L-阿特V),在动物模型中显示出良好的效果。然而,与许多其他传统的L病毒一样,ML29的衰减机制仍不清楚,这引发了人们对ML29对额外突变的表型稳定性的担忧。这项应用的中心目标是检验这样一个假设,即我们可以通过将其L IGR替换为基因定义的合成S样IGR(SYN)来将致病的OWA转化为具有L-AttV特征的减毒形式。我们的假设得到了以下发现的支持:1)我们可以在S和S基因组片段中回收具有相同的S-IGR的重组LCMV(IGR/L-IGR),并发现它在体内高度减毒。2)免疫小鼠可抵抗野生型(WT)LCMV的致死性攻击。3)我们获得的证据表明,S IGR内高度的序列可塑性与病毒活性是相容的,这支持了在L片段中设计合成S IGR(Ssyn)的重组ArenaVirus作为ArenaVirus减毒的一般分子策略的可行性。为了验证我们的假设,我们建议完成以下具体目标:目的1.鉴定重组人巨细胞病毒(IgR/S-Ssyn):我们拯救了rLCMV(IgR/S-Ssyn),其中合成的S Ig R(Ssyn)取代了L-Ig R。我们将在培养细胞中鉴定rLCMV(IGR/S-Syn),并利用LCMV感染的小鼠模型检验rLCMV(IGR/S-Syn)显示出L-AttV的关键特征的假设。目的:制备并鉴定重组LASV(IGR/S-Ssyn):我们将制备rLASV(IGR/S-Ssyn),并在已建立的LASV感染的豚鼠模型上验证其在体内减毒但能够诱导保护性免疫的假说。目的3.检测重组LCMV(IGR/S-Ssyn)的稳定性:检验rLCMV(IGR/S-Ssyn)在不同生长条件下繁殖过程中遗传稳定的假说。这项应用的成功完成将揭示一种一般的禽流感病毒减毒的分子策略,可以促进一种新的策略来开发L-AttV来对抗人类致病性禽流感病毒。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic Region
  • DOI:
    10.1128/mbio.00186-20
  • 发表时间:
    2020-03-01
  • 期刊:
  • 影响因子:
    6.4
  • 作者:
    Cai, Yingyun;Iwasaki, Masaharu;de la Torre, Juan Carlos
  • 通讯作者:
    de la Torre, Juan Carlos
Molecular Engineering of a Mammarenavirus with Unbreachable Attenuation.
具有不可破坏的减毒能力的乳腺病毒的分子工程。
  • DOI:
    10.1128/jvi.01385-22
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Sakabe,Saori;Cubitt,Beatrice;Martinez-Sobrido,Luis;delaTorre,JuanC
  • 通讯作者:
    delaTorre,JuanC
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Juan C. de la Torre其他文献

Reverse-genetic approaches to the study of Borna disease virus
伯尔尼病病毒研究的反向遗传学方法
  • DOI:
    10.1038/nrmicro1489
  • 发表时间:
    2006-09-11
  • 期刊:
  • 影响因子:
    103.300
  • 作者:
    Juan C. de la Torre
  • 通讯作者:
    Juan C. de la Torre
Establishment of recombinant ML29 platform for the generation of polyvalent live-attenuated vaccines against Lassa virus and other infectious agents
建立重组 ML29 平台,用于生产针对拉沙病毒和其他传染原的多价减毒活疫苗
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Masaharu Iwasaki;Beatrice Cubitt;Daisuke Motooka;Dylan M. Johnson;Igor S. Lukashevich;Juan C. de la Torre
  • 通讯作者:
    Juan C. de la Torre

Juan C. de la Torre的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Juan C. de la Torre', 18)}}的其他基金

Improving The Scripps Research Institute BSL3 Capabilities to Combat Viruses of Pandemic Concern
提高斯克里普斯研究所 BSL3 对抗流行病病毒的能力
  • 批准号:
    10611798
  • 财政年份:
    2022
  • 资助金额:
    $ 24.06万
  • 项目类别:
Designing mammarenavirus live vaccines with unbreachable attenuation
设计具有不可破坏的减毒效果的乳腺病毒活疫苗
  • 批准号:
    10664016
  • 财政年份:
    2022
  • 资助金额:
    $ 24.06万
  • 项目类别:
Designing mammarenavirus live vaccines with unbreachable attenuation
设计具有不可破坏的减毒效果的乳腺病毒活疫苗
  • 批准号:
    10535058
  • 财政年份:
    2022
  • 资助金额:
    $ 24.06万
  • 项目类别:
Development and validation of antivirals against hemorrhagic fever viruses of pandemic concern
针对大流行病的出血热病毒的抗病毒药物的开发和验证
  • 批准号:
    10514329
  • 财政年份:
    2022
  • 资助金额:
    $ 24.06万
  • 项目类别:
Modulation of Lassa Virus vRNP Activity By Host Cell Factors
宿主细胞因子对拉沙病毒 vRNP 活性的调节
  • 批准号:
    9321544
  • 财政年份:
    2017
  • 资助金额:
    $ 24.06万
  • 项目类别:
A General Molecular Strategy for Attenuation of Human Pathogenic Arenaviruses
人类致病性沙粒病毒减毒的通用分子策略
  • 批准号:
    9112491
  • 财政年份:
    2016
  • 资助金额:
    $ 24.06万
  • 项目类别:
Activity-Based Protein Profiling of Arenavirus-Host Interactions
基于活性的沙粒病毒-宿主相互作用的蛋白质分析
  • 批准号:
    8970028
  • 财政年份:
    2015
  • 资助金额:
    $ 24.06万
  • 项目类别:
Profiling Serine Hydrolase Activity At The Virus-Host Interface
病毒-宿​​主界面丝氨酸水解酶活性分析
  • 批准号:
    8869489
  • 财政年份:
    2015
  • 资助金额:
    $ 24.06万
  • 项目类别:
Profiling Serine Hydrolase Activity At The Virus-Host Interface
病毒-宿​​主界面丝氨酸水解酶活性分析
  • 批准号:
    9085225
  • 财政年份:
    2015
  • 资助金额:
    $ 24.06万
  • 项目类别:
Immune cell dynamics during central nervous system viral infection
中枢神经系统病毒感染期间的免疫细胞动力学
  • 批准号:
    7581118
  • 财政年份:
    2009
  • 资助金额:
    $ 24.06万
  • 项目类别:

相似海外基金

Multi-component interventions to reducing unhealthy diets and physical inactivity among adolescents and youth in sub-Saharan Africa (Generation H)
采取多方干预措施减少撒哈拉以南非洲青少年的不健康饮食和缺乏身体活动(H 代)
  • 批准号:
    10106976
  • 财政年份:
    2024
  • 资助金额:
    $ 24.06万
  • 项目类别:
    EU-Funded
Exploring the mental health and wellbeing of adolescent parent families affected by HIV in South Africa
探讨南非受艾滋病毒影响的青少年父母家庭的心理健康和福祉
  • 批准号:
    ES/Y00860X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 24.06万
  • 项目类别:
    Fellowship
Decolonization, Appropriation and the Materials of Literature in Africa and its Diaspora
非洲及其侨民的非殖民化、挪用和文学材料
  • 批准号:
    EP/Y024516/1
  • 财政年份:
    2024
  • 资助金额:
    $ 24.06万
  • 项目类别:
    Research Grant
Exploring "Actionable Information" for Learning Improvement in Rural East Africa: A Positive Deviance Approach
探索东非农村地区学习改进的“可行信息”:积极偏差方法
  • 批准号:
    24K00390
  • 财政年份:
    2024
  • 资助金额:
    $ 24.06万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Water stressed cities: individual choice, access to water and pathways to resilience in sub-Saharan Africa
缺水城市:撒哈拉以南非洲地区的个人选择、水资源获取和恢复力途径
  • 批准号:
    MR/X022943/1
  • 财政年份:
    2024
  • 资助金额:
    $ 24.06万
  • 项目类别:
    Fellowship
Protecting Women from Economic shocks to fight HIV in Africa (POWER)
保护非洲妇女免受经济冲击,抗击艾滋病毒 (POWER)
  • 批准号:
    MR/Y003837/1
  • 财政年份:
    2024
  • 资助金额:
    $ 24.06万
  • 项目类别:
    Fellowship
Tackling antimicrobial resistance across dentistry in Sub-Saharan Africa.
解决撒哈拉以南非洲牙科领域的抗菌素耐药性问题。
  • 批准号:
    MR/Y019695/1
  • 财政年份:
    2024
  • 资助金额:
    $ 24.06万
  • 项目类别:
    Research Grant
ePowerCart - Affordable Mobile Clean Energy for Remote Communities in Rural Sub-Saharan Africa and India
ePowerCart - 为撒哈拉以南非洲和印度农村偏远社区提供经济实惠的移动清洁能源
  • 批准号:
    10076185
  • 财政年份:
    2024
  • 资助金额:
    $ 24.06万
  • 项目类别:
    Collaborative R&D
Co-designing effective Nature-based Solutions in coastal West Africa
在西非沿海共同设计有效的基于自然的解决方案
  • 批准号:
    NE/Z503460/1
  • 财政年份:
    2024
  • 资助金额:
    $ 24.06万
  • 项目类别:
    Research Grant
NIGHTCOOL: Deployment of FREECOOL+ for night cooling strategies in Africa
NIGHTCOOL:部署 FREECOOL 以实施非洲夜间制冷策略
  • 批准号:
    10105520
  • 财政年份:
    2024
  • 资助金额:
    $ 24.06万
  • 项目类别:
    Demonstrator
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了