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：
10612070
负责人：
John Gerard Purdy
金额：
$ 36.89万
依托单位：
UNIVERSITY OF ARIZONA
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：
https://reporter.nih.gov/project-details/10612070
关键词：
Antiviral Agents Antiviral Response Area Aryl Hydrocarbon Receptor Attention Attenuated Binding Biological Assay Biological Process Biology CRISPR/Cas technology Cause of Death Cells Clinical Cytomegalovirus Cytomegalovirus Infections Data Disease Engineering Enzymes Goals HIF1A gene Health Human Hypoxia Inducible Factor Immune Evasion Immune response Immune system Infection Knowledge Kynurenine Mediating Mediator Metabolic Metabolism Modeling Molecular Organ Pathogenesis Pathway interactions Pregnancy Process Production Proteins Proviruses Research Role Signal Pathway Signal Transduction Solid Stem cell transplant Transplant Recipients Tryptophan Metabolism Pathway Vaccines Viral Viral Proteins Virus Virus Diseases Virus Integration Virus Replication Work attenuation chronic infection congenital infection disability extracellular human pathogen metabolomics novel novel strategies novel therapeutic intervention prevent receptor internalization response virus 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。