Regulation of Rotavirus Replication, Virulence, and Host Range Restriction by the Innate Immune System
先天免疫系统对轮状病毒复制、毒力和宿主范围限制的调节
基本信息
- 批准号:10091389
- 负责人:
- 金额:$ 47.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-02-15 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:Adaptor Signaling ProteinAddressAnimalsAntiviral AgentsAreaBiological AssayBiological ModelsBiologyBystander EffectCellsChemicalsChildCommunicable DiseasesComplexCryoelectron MicroscopyCullin ProteinsDataDown-RegulationEnteralEnzymesEpithelial CellsGastroenteritisHematopoieticHumanIRF3 geneImmune EvasionImpairmentIn VitroInnate Immune ResponseInnate Immune SystemInterferon ReceptorInterferonsIntestinesMediatingMitochondriaMitochondrial ProteinsMolecularMucosal ImmunityMucous MembraneMusMutagenesisNatural ImmunityPathogenesisPatternPhasePhosphorylationPreventionProductionProtein InhibitionProteinsRNA CapsReceptor GeneReceptor InhibitionRegulationResearchRoleRotavirusRotavirus InfectionsRotavirus NSP1 proteinSH2D3A geneSTAT1 geneSignal TransductionSignaling ProteinSmall Interfering RNAStructureSystemTBK1 geneUbiquitinationVaccinesViralViral ProteinsVirulenceVirulentVirusbeta-Transducin Repeat-Containing Proteinscullin-3diarrheal diseaseenteric pathogengastrointestinalin vivoin vivo Modelintestinal epitheliumknock-downnon-Nativepathogenpathogenic virusprotein degradationreceptorresponsesensorsuccessubiquitin-protein ligase
项目摘要
PROJECT SUMMARY/ABSTRACT
Rotaviruses (RVs) are highly infectious viruses of great importance because they are the most common
cause of severe gastroenteritis in young children. We will address three fundamental topics in rotavirology
(RV) that will expand our understanding of the molecular mechanisms regulating RV innate immune evasion.
1. Determine the structural basis and in vivo activity of NSP1-mediated β-TrCP degradation.
Despite the RV NSP1 protein's well-documented ability to induce IRF3 and/or β-TrCP degradation, the
mechanisms regulating this degradation are unknown. Human RV NSP1s specifically target β-TrCP. We
have recently identified an unexpected role of the host Cullin-E3 ligase complex in NSP1's degradative
functions. In this aim we will dissect how NSP1 is able to hijack the host Cullin-E3 ligase complex, induce β-
TrCP degradation, block NF-κB activation and thereby promote homologous RV replication.
2. Identify the molecular mechanisms underlying MAVS degradation by VP3 in a strain- and host-
specific fashion both in vitro and in vivo.
We previously showed that ssRNA byproducts from RV infection are potent activators of cytosolic sensors
RIG-I and MDA5, both of which converge on mitochondrial antiviral signaling protein (MAVS) to relay innate
signaling and induce IFN expression. Unexpected preliminary findings suggest that MAVS is targeted for
proteasomal degradation by the RV VP3 protein in a host range restricted (HRR) manner. Here we will
explore the complex interplay between VP3 and MAVS from different RV species at a mechanistic level and
evaluate the importance of VP3-mediated MAVS degradation in promoting RV replication in vitro and in vivo.
3. Identify the mechanism of RV NSP1-mediated inhibition of STAT1 activation and the intestinal cell
origin of the IFN responses to RV infection.
Despite the ability to efficiently suppress the induction of type I IFN in intestinal epithelial cells (IECs),
homologous RV infection still induces substantial levels of type I and III IFNs in the gut. This IFN production
suggests that RVs must be able to subvert IFN-mediated antiviral amplification as well as blocking IFN
induction. RV NSP1 efficiently inhibits IFN-mediated STAT1 phosphorylation. New findings indicate RV
blocks STAT1 activation by depleting multiple IFN receptors, likely by NSP1-directed degradation. RVs can
also block IFN-directed STAT1 activation in uninfected cells in vitro. Whether this effect also occurs in vivo is
unknown. We propose to identify the hematopoietic cell and IEC origins of type I and III IFNs elicited by RV
infection. We will also examine the mechanistic determinants of RV-mediated IFN receptor degradation and
inhibition of STAT1 activation and determine if differences in these functions contribute to RV HRR.
项目总结/文摘
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Rotavirus VP3 targets MAVS for degradation to inhibit type III interferon expression in intestinal epithelial cells.
- DOI:10.7554/elife.39494
- 发表时间:2018-11-21
- 期刊:
- 影响因子:7.7
- 作者:Ding S;Zhu S;Ren L;Feng N;Song Y;Ge X;Li B;Flavell RA;Greenberg HB
- 通讯作者:Greenberg HB
STAG2 deficiency induces interferon responses via cGAS-STING pathway and restricts virus infection.
- DOI:10.1038/s41467-018-03782-z
- 发表时间:2018-04-16
- 期刊:
- 影响因子:16.6
- 作者:Ding S;Diep J;Feng N;Ren L;Li B;Ooi YS;Wang X;Brulois KF;Yasukawa LL;Li X;Kuo CJ;Solomon DA;Carette JE;Greenberg HB
- 通讯作者:Greenberg HB
VP4- and VP7-specific antibodies mediate heterotypic immunity to rotavirus in humans.
- DOI:10.1126/scitranslmed.aam5434
- 发表时间:2017-06-21
- 期刊:
- 影响因子:17.1
- 作者:Nair N;Feng N;Blum LK;Sanyal M;Ding S;Jiang B;Sen A;Morton JM;He XS;Robinson WH;Greenberg HB
- 通讯作者:Greenberg HB
{{
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 }}
Harry Bernard Greenberg其他文献
Harry Bernard Greenberg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('Harry Bernard Greenberg', 18)}}的其他基金
Regulation of Rotavirus Replication, Virulence, and Host Range Restriction by the Innate Immune System
先天免疫系统对轮状病毒复制、毒力和宿主范围限制的调节
- 批准号:
9308428 - 财政年份:2017
- 资助金额:
$ 47.16万 - 项目类别:
Mucosal and Systemic Immune Responses to Influenza Virus
对流感病毒的粘膜和全身免疫反应
- 批准号:
8990809 - 财政年份:2015
- 资助金额:
$ 47.16万 - 项目类别:
Project 2: Regulation of Rotavirus Host Range, Neutralization, and M cell Interactions in Enteric Biomimetics
项目2:肠道仿生学中轮状病毒宿主范围、中和和M细胞相互作用的调节
- 批准号:
10392441 - 财政年份:2015
- 资助金额:
$ 47.16万 - 项目类别:
Project 2: Regulation of Rotavirus Host Range, Neutralization, and M cell Interactions in Enteric Biomimetics
项目2:肠道仿生学中轮状病毒宿主范围、中和和M细胞相互作用的调节
- 批准号:
10191938 - 财政年份:2015
- 资助金额:
$ 47.16万 - 项目类别:
Mucosal and Systemic Immune Responses to Influenza Virus
对流感病毒的粘膜和全身免疫反应
- 批准号:
8825882 - 财政年份:2015
- 资助金额:
$ 47.16万 - 项目类别:
Project 2: Regulation of Rotavirus Host Range, Neutralization, and M cell Interactions in Enteric Biomimetics
项目2:肠道仿生学中轮状病毒宿主范围、中和和M细胞相互作用的调节
- 批准号:
10614394 - 财政年份:2015
- 资助金额:
$ 47.16万 - 项目类别:
Mucosal and Systemic Immune Responses to Influenza Virus
对流感病毒的粘膜和全身免疫反应
- 批准号:
9188802 - 财政年份:2015
- 资助金额:
$ 47.16万 - 项目类别:
Spectrum Stanford Center for Clinical and Translational Research and Education
Spectrum 斯坦福临床和转化研究与教育中心
- 批准号:
8743339 - 财政年份:2013
- 资助金额:
$ 47.16万 - 项目类别:
Spectrum Stanford Center for clinical and Translational Research and Education
Spectrum 斯坦福临床和转化研究与教育中心
- 批准号:
8743338 - 财政年份:2013
- 资助金额:
$ 47.16万 - 项目类别:
Spectrum Stanford Center for clinical and Translational Research and Education
Spectrum 斯坦福临床和转化研究与教育中心
- 批准号:
8914747 - 财政年份:2013
- 资助金额:
$ 47.16万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 47.16万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 47.16万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 47.16万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 47.16万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 47.16万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 47.16万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 47.16万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 47.16万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 47.16万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 47.16万 - 项目类别:
Research Grant














{{item.name}}会员




