Metabolite-mediated Signaling in Cell-to-Cell Spread of Human Cytomegalovirus
人巨细胞病毒细胞间传播中代谢介导的信号转导
基本信息
- 批准号:10403581
- 负责人:
- 金额:$ 37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-10 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAntiviral AgentsAntiviral ResponseAreaAryl Hydrocarbon ReceptorAttentionAttenuatedBindingBiological AssayBiological ProcessBiologyCRISPR/Cas technologyCause of DeathCellsClinicalCytomegalovirusCytomegalovirus InfectionsDataDiseaseEngineeringEnzymesEquilibriumGoalsHealthHumanHypoxia Inducible FactorImmune responseImmune systemInfectionKnowledgeKynurenineLeadLifeMediatingMediator of activation proteinMetabolicMetabolismModelingMolecularOrganPathogenesisPathway interactionsPregnancyProcessProductionProteinsProvirusesResearchRoleSignal PathwaySignal TransductionSolidStem cell transplantTransplant RecipientsTryptophan Metabolism PathwayVaccinesViralViral ProteinsVirusVirus DiseasesVirus ReplicationWorkattenuationbasechronic infectioncongenital infectiondisabilityextracellularhuman pathogenmetabolomicsnovelnovel strategiesnovel therapeutic interventionpreventreceptor internalizationresponsevirus host interaction
项目摘要
Human cytomegalovirus (HCMV) establishes a life-long persistent infection by evading the immune system, in part, by direct cell-to-cell viral spread. In solid organ or stem cell transplant recipients, HCMV spread leads to end-organ diseases that can cause death. During pregnancy, HCMV spread causes congenital infection and is a leading cause of congenital disabilities. No HCMV treatment offers a cure, and there is no vaccine. Thus, there is a need for new treatments to limit infection based on novel discoveries in HCMV biology. Viral proteins required for HCMV cell-to-cell spread are known, but the host processes involved in HCMV cell-to-cell spread have received less attention. Clinical strains of HCMV spread most efficiently through cell-to-cell means, but the molecular mechanisms—including host metabolic ones—essential to HCMV cell-to-cell spread are largely unknown. Understanding host mechanisms regulating cell-to-cell spread may lead to new understandings of how to reduce HCMV infection. Our research has uncovered a novel role of metabolite signaling in promoting HCMV spread. This project's overall goal is to mechanistically understand virus-host interactions regulating metabolite signaling essential to HCMV cell-to-cell spread. We found a metabolite in tryptophan metabolism—kynurenine (KYN)—enhances HCMV spread. In addition to its metabolic role, KYN is a signaling messenger. KYN signals through aryl hydrocarbon receptor (AhR). We show that activation of AhR supports HCMV replication. Moreover, we found that hypoxia-inducible factor 1α (HIF1α), through its metabolic regulatory function, limits the production of KYN and suppresses HCMV infection. We hypothesize that metabolite-mediated signaling from infected cells to uninfected cells promotes HCMV cell-to-cell spread, which is attenuated by a HIF1α-dependent cellular response. The proposed research will determine molecular mechanisms involved in the enhancement of HCMV infection by KYN-metabolite signaling (aim 1) and define virus-host interactions regulating HIF1α attenuation of HCMV cell-to-cell spread (aim 2). The experimental approach will integrate virus assays, CRISPR/Cas9 engineering, and untargeted metabolomics to understand HCMV biology. Our findings will provide a mechanistic understanding of metabolite signaling and AhR activity in promoting HCMV cell-to-cell spread and the HIF1α-dependent host-response that targets metabolite signaling to reduce infection. Our studies will advance our knowledge in an understudied area of HCMV research that will provide significant steps-forward in developing novel strategies to treat HCMV infection and limit HCMV-related disease.
人巨细胞病毒 (HCMV) 通过逃避免疫系统(部分是通过直接细胞间病毒传播)建立终生持续感染。在实体器官或干细胞移植受者中,HCMV 传播会导致终末器官疾病。怀孕期间,HCMV 传播会导致先天性感染,并且是导致先天性残疾的主要原因,目前还没有疫苗可以治愈 HCMV,因此需要新的治疗方法来限制感染。 HCMV 细胞间传播所需的病毒蛋白是已知的,但 HCMV 细胞间传播所涉及的宿主过程却很少受到关注。意思是,但 HCMV 细胞间传播所必需的分子机制(包括宿主代谢机制)在很大程度上尚不清楚。了解调节细胞间传播的宿主机制可能会导致人们对如何减少 HCMV 感染有新的认识。发现了一个代谢物信号传导在促进 HCMV 传播中的新作用 该项目的总体目标是从机制上了解调节 HCMV 细胞间传播所必需的代谢物信号传导的相互作用。除了其代谢作用外,KYN 还通过芳基烃受体 (AhR) 发出信号。此外,我们发现缺氧诱导因子 1α (HIF1α) 通过其代谢调节功能,限制 KYN 的产生并抑制 HCMV 感染,我们捕获了从受感染细胞到未感染细胞的代谢介导的信号传导。细胞间传播,这种传播会因 HIF1α 依赖性细胞反应而减弱。这项研究将确定通过 HIF1α 增强 HCMV 感染的分子机制。 KYN 代谢信号传导(目标 1)并定义调节 HIF1α HCMV 细胞间传播减弱的病毒-宿主相互作用(目标 2)。该实验方法将整合病毒测定、CRISPR/Cas9 工程和非靶向代谢组学,以了解 HCMV 生物学。我们的研究结果将为促进 HCMV 细胞间传播和 HIF1α 依赖的代谢物信号传导和 AhR 活性提供机制理解。我们的研究将提高我们在 HCMV 研究领域的知识,这将为开发治疗 HCMV 感染和限制 HCMV 相关疾病的新策略提供重大进展。
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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John Gerard Purdy其他文献
John Gerard Purdy的其他文献
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{{ truncateString('John Gerard Purdy', 18)}}的其他基金
Mechanisms of Human Cytomegalovirus Reprogramming of Lipid Metabolism
人类巨细胞病毒重编程脂质代谢的机制
- 批准号:
10656249 - 财政年份:2021
- 资助金额:
$ 37万 - 项目类别:
Metabolite-mediated Signaling in Cell-to-Cell Spread of Human Cytomegalovirus
人巨细胞病毒细胞间传播中代谢介导的信号转导
- 批准号:
10304351 - 财政年份:2021
- 资助金额:
$ 37万 - 项目类别:
Mechanisms of Human Cytomegalovirus Reprogramming of Lipid Metabolism
人类巨细胞病毒重编程脂质代谢的机制
- 批准号:
10273931 - 财政年份:2021
- 资助金额:
$ 37万 - 项目类别:
Metabolite-mediated Signaling in Cell-to-Cell Spread of Human Cytomegalovirus
人巨细胞病毒细胞间传播中代谢介导的信号转导
- 批准号:
10612070 - 财政年份:2021
- 资助金额:
$ 37万 - 项目类别:
Mechanisms of Human Cytomegalovirus Reprogramming of Lipid Metabolism
人类巨细胞病毒重编程脂质代谢的机制
- 批准号:
10438866 - 财政年份:2021
- 资助金额:
$ 37万 - 项目类别:
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