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: 10403581
• 负责人: John Gerard Purdy
• 金额: $ 37万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 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/10403581
• 关键词: Address; 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; Equilibrium; Goals; Health; Human; Hypoxia Inducible Factor; Immune response; Immune system; Infection; Knowledge; Kynurenine; Lead; Life; Mediating; Mediator of activation protein; 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 Replication; Work; attenuation; base; chronic infection; congenital infection; disability; extracellular; human pathogen; metabolomics; novel; novel strategies; novel therapeutic intervention; prevent; receptor internalization; response; virus host interaction

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.

人类巨细胞病毒（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，从而导致死亡。怀孕期间，HCMV 传播会导致先天性感染，是导致先天性残疾的主要原因。 HCMV 治疗方法无法治愈，也没有疫苗。因此，需要基于 HCMV 生物学的新发现来限制感染的新疗法。 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受到的关注较少。 HCMV 临床毒株通过细胞间传播最有效，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带来对如何减少 HCMV 感染的新认识。我们的研究发现了代谢物信号在促进 HCMV 传播中的新作用。该项目的总体目标是从机制上了解病毒-宿主相互作用调节代谢物信号传导，这对 HCMV 细胞间传播至关重要。我们发现色氨酸代谢中的一种代谢物——犬尿氨酸 (KYN)——可以增强 HCMV 的传播。除了其代谢作用外，KYN 也是一种信号信使。 KYN 通过芳烃受体 (AhR) 发出信号。我们表明 AhR 的激活支持 HCMV 复制。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。我们假设代谢物介导的从受感染细胞到未受感染细胞的信号传导促进了 HCMV 细胞间传播，而 HIF1α 依赖性细胞反应会减弱这种传播。拟议的研究将确定通过 KYN 代谢物信号传导增强 HCMV 感染的分子机制（目标 1），并定义调节 HIF1α 减弱 HCMV 细胞间传播的病毒-宿主相互作用（目标 2）。该实验方法将整合病毒检测、CRISPR/Cas9 工程和非靶向代谢组学，以了解 HCMV 生物学。我们的研究结果将提供对促进 HCMV 细胞间传播的代谢信号传导和 AhR 活性的机制理解，以及针对代谢信号传导以减少感染的 HIF1α 依赖性宿主反应。我们的研究将增进我们在 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。