Role of NLRX1 in dengue virus infection
NLRX1在登革热病毒感染中的作用
基本信息
- 批准号:8476934
- 负责人:
- 金额:$ 2.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-03-02 至 2012-09-30
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAntiviral AgentsArbovirusesArthralgiaArthropodsBindingBlood VesselsCASP8 geneCD34 geneCell LineCell TransplantationCellsClinicalCulicidaeDengueDengue VirusDetectionDevelopmentDiseaseDisease ProgressionDisease modelEnhancing AntibodiesExtravasationFamilyFamily memberFeverFlavivirus InfectionsGoalsHematopoietic stem cellsHepatic TissueHepatitis CHepatocyteHumanHuman Cell LineHuman bodyIRF3 geneImmuneImmune responseImmunityImmunocompromised HostIn VitroIndividualInfectionInflammatoryInterferon Type IInterferon-betaInterferonsJournalsKnockout MiceLaboratoriesLeucine-Rich RepeatLicensingLiverManuscriptsMediatingMitochondriaModelingMusMyalgiaNatureNucleotidesOrgan failurePathogenesisPlayPopulationPrimatesProductionProtein FamilyProteinsPublic HealthRNARegulationResearchRiskRoleSendai virusSerotypingSignal TransductionSimian virus 5Stem cellsStimulusStressSurfaceSystemTherapeuticTransplantationVaccinesViralVirusVirus Diseasescytokinehuman diseasein vivoinfluenzavirusmembermicrobialmouse modelnovelpathogenpreventprogenitorreceptorreconstitutionresponsesensorsmall hairpin RNAsmall moleculevirus infection mechanismvirus pathogenesis
项目摘要
DESCRIPTION (provided by applicant): Dengue virus is the most prevalent human arbovirus on earth, infecting an estimated 50-100 million individuals annually. Despite this public health burden, there are currently no licensed vaccines or therapeutics to treat dengue. The host type I interferon response is known to play a critical role in limiting replication and spread of dengue virus, and as such dengue has evolved countermeasures by which it blocks interferon signaling, but not production, in infected cells. The NLR (nucleotide binding domain and leucine-rich-repeat-containing or NOD-like receptor) family of proteins has been identified as initiators and regulators of innate immune responses to a wide range of pathogens including some viruses. NLRX1, a new member of the NLR family, has been shown to act as a negative regulator of MAVS-mediated antiviral signaling, and studies have indicated that knockdown of NLRX1 expression leads to increased interferon production in the presence of viral infection. To date, however, the role of NLRX1 in dengue virus infection has not been explored. Additionally, dengue virus research has been limited by the lack of suitable small animal models in which to study dengue pathogenesis and host immune responses to infection. Those that have been developed are limited in their ability to study human innate immune responses to infection. The goal of this proposal is to examine the role of NLRX1 in the human innate immune response to a variety of relevant dengue virus infections using both in vitro and in vivo systems. Aim 1 will examine the functional role of NLRX1 in dengue- infected human cells. In this aim we will knockdown NLRX1 in human monocytic cells to determine how NLRX1 modulates MAVS-mediated antiviral signaling during infection with dengue. This will also be examined in the context of receptor-mediated vs. antibody-enhanced infection. Aim 2 will establish a novel humanized mouse model of viscerotropic dengue virus infection in which to study human immune responses. We will generate Rag2-gC double knockout (DKO) mice humanized with human immune cells and human liver cells (AFC8-hu HSC/Hpe mice) in order to examine viscerotropic DENV disease and human immune responses to infection. Aim 3 will utilize this humanized mouse model of DENV disease to assess the role human NLRX1 plays in innate immune response to and disease progression of DENV infection. We will use shRNA knockdown of NLRX1 in human cells engrafted into AFC8-hu HSC/Hpe mice and compare DENV infection with that of mice with unaltered NLRX1 levels. Taken together the results of this proposal will provide critical information about innate immune responses to DENV infection and provide a novel small animal model in which to study DENV pathogenesis and human immune responses.
描述(由申请人提供):登革病毒是地球上最流行的人类虫媒病毒,估计每年感染5000万至1亿人。尽管有这种公共卫生负担,但目前还没有获得许可的疫苗或治疗方法来治疗登革热。已知宿主I型干扰素应答在限制登革病毒的复制和传播中起关键作用,并且因此登革已经进化出对抗措施,通过该对抗措施,其阻断感染细胞中的干扰素信号传导,但不阻断其产生。NLR(nucleotide binding domain and leucine-rich-repeat-containing or NOD-like receptor,核苷酸结合结构域和富含亮氨酸重复序列或NOD样受体)蛋白家族已被鉴定为对包括一些病毒在内的广泛病原体的先天免疫应答的启动子和调节子。NLRX 1是NLR家族的新成员,已被证明是MAVS介导的抗病毒信号传导的负调节因子,并且研究表明,在病毒感染的情况下,NLRX 1表达的敲低导致干扰素产生增加。然而,迄今为止,NLRX 1在登革病毒感染中的作用尚未被探索。此外,登革热病毒研究受到缺乏合适的小动物模型的限制,在这些模型中研究登革热发病机制和宿主对感染的免疫反应。已经开发的那些在研究人类对感染的先天免疫反应方面的能力有限。本提案的目的是使用体外和体内系统研究NLRX 1在人类先天免疫应答中对各种相关登革病毒感染的作用。目的1将研究NLRX 1在登革热感染的人类细胞中的功能作用。在这个目标中,我们将敲低人单核细胞中的NLRX 1,以确定NLRX 1如何在登革热感染期间调节MAVS介导的抗病毒信号传导。这也将在受体介导与抗体增强感染的背景下进行检查。目的2建立一种新的嗜内脏型登革病毒感染人源化小鼠模型,用于研究人体免疫反应。我们将产生用人免疫细胞和人肝细胞人源化的Rag 2-gC双敲除(DKO)小鼠(AFC 8-hu HSC/Hpe小鼠),以检查内脏嗜性DENV疾病和对感染的人免疫应答。目的3将利用这种DENV疾病的人源化小鼠模型来评估人NLRX 1在DENV感染的先天免疫应答和疾病进展中的作用。我们将在植入AFC 8-hu HSC/Hpe小鼠的人细胞中使用NLRX 1的shRNA敲低,并将DENV感染与NLRX 1水平未改变的小鼠进行比较。综上所述,该提案的结果将提供关于对DENV感染的先天免疫应答的关键信息,并提供一种新的小动物模型,在其中研究DENV发病机制和人类免疫应答。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
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 }}
Douglas G Widman其他文献
Douglas G Widman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('Douglas G Widman', 18)}}的其他基金
相似海外基金
Development of a new generation of antiviral agents that are effective against drug-resistant viruses and prevent serious illness and sequelae.
开发新一代抗病毒药物,可有效对抗耐药病毒并预防严重疾病和后遗症。
- 批准号:
23K18186 - 财政年份:2023
- 资助金额:
$ 2.61万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
A versatile structure-based therapeutic platform for development of VHH-based antitoxin and antiviral agents
一个多功能的基于结构的治疗平台,用于开发基于 VHH 的抗毒素和抗病毒药物
- 批准号:
10560883 - 财政年份:2023
- 资助金额:
$ 2.61万 - 项目类别:
Genetically encoded bicyclic peptide libraries for the discoveryof novel antiviral agents
用于发现新型抗病毒药物的基因编码双环肽库
- 批准号:
10730692 - 财政年份:2021
- 资助金额:
$ 2.61万 - 项目类别:
Design and synthesis of nucleosides to develop antiviral agents and oligonucleotide therapeutics
设计和合成核苷以开发抗病毒药物和寡核苷酸疗法
- 批准号:
21K06459 - 财政年份:2021
- 资助金额:
$ 2.61万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Genetically encoded bicyclic peptide libraries for the discoveryof novel antiviral agents
用于发现新型抗病毒药物的基因编码双环肽库
- 批准号:
10189880 - 财政年份:2021
- 资助金额:
$ 2.61万 - 项目类别:
Computer-aided identification and synthesis of novel broad-spectrum antiviral agents
新型广谱抗病毒药物的计算机辅助鉴定和合成
- 批准号:
2404261 - 财政年份:2020
- 资助金额:
$ 2.61万 - 项目类别:
Studentship
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
- 批准号:
10222540 - 财政年份:2020
- 资助金额:
$ 2.61万 - 项目类别:
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
- 批准号:
10669717 - 财政年份:2020
- 资助金额:
$ 2.61万 - 项目类别:
Association between sedentary lifestyle and liver cancer development in hepatitis C patients treated with direct-acting antiviral agents
接受直接抗病毒药物治疗的丙型肝炎患者久坐的生活方式与肝癌发展之间的关系
- 批准号:
20K10713 - 财政年份:2020
- 资助金额:
$ 2.61万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
- 批准号:
10174522 - 财政年份:2020
- 资助金额:
$ 2.61万 - 项目类别: